curcumin and Liver-Neoplasms

Among all forms of cancers, hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. There are several treatment options for HCC ranging from loco-regional therapy to surgical treatment. Yet, there is high morbidity and mortality. Recent research focus has shifted towards more effective and less toxic cancer treatment options. Curcumin, the active ingredient in the Curcuma longa plant, has gained widespread attention in recent years because of its multifunctional properties as an antioxidant, anti-inflammatory, antimicrobial, and anticancer agent.. A systematic search of PubMed, Embase and Google Scholar was performed for studies reporting incidence of HCC, risk factors associated with cirrhosis and experimental use of curcumin as an anti-cancer agent.. This review exclusively encompasses the anti-cancer properties of curcumin in HCC globally and it's postulated molecular targets of curcumin when used against liver cancers.. This review is concluded by presenting the current challenges and future perspectives of novel plant extracts derived from C. longa and the treatment options against cancers.

Topics: Carcinoma, Hepatocellular; Curcuma; Curcumin; Humans; Liver Neoplasms; Plant Extracts

Liver cancer is the sixth most prevalent cancer and ranks third in cancer-related death, after lung and colorectal cancer. Various natural products have been discovered as alternatives to conventional cancer therapy strategies, including radiotherapy, chemotherapy, and surgery. Curcumin (CUR) with antiinflammatory, antioxidant, and antitumor activities has been associated with therapeutic benefits against various cancers. It can regulate multiple signaling pathways, such as PI3K/Akt, Wnt/β-catenin, JAK/STAT, p53, MAPKs, and NF-ĸB, which are involved in cancer cell proliferation, metastasis, apoptosis, angiogenesis, and autophagy. Due to its rapid metabolism, poor oral bioavailability, and low solubility in water, CUR application in clinical practices is restricted. To overcome these limitations, nanotechnology-based delivery systems have been applied to use CUR nanoformulations with added benefits, such as reducing toxicity, improving cellular uptake, and targeting tumor sites. Besides the anticancer activities of CUR in combating various cancers, especially liver cancer, here we focused on the CUR nanoformulations, such as micelles, liposomes, polymeric, metal, and solid lipid nanoparticles, and others, in the treatment of liver cancer.

Topics: Curcumin; Humans; Liver Neoplasms; Micelles; Phosphatidylinositol 3-Kinases; Signal Transduction

Hepatitis B virus (HBV) infection is a worldwide health problem, and chronic infection can cause many diseases ranging from liver fibrosis to hepatocellular carcinoma (HCC) by complicated mechanisms. Currently, the treatment of HBV infection mainly depends on interferons (IFNs) and nucleotide analogues (NAs); however, both have some limitations. In 2012, sodium taurocholate cotransporting polypeptide (NTCP) was identified as the entry receptor of HBV. Based upon this groundbreaking discovery, a series of molecules have been gradually developed and evaluated to discover novel entry inhibitors targeting NTCP. However, only two macromolecules have been used for potential clinical applications so far. In this Perspective, we focus on summarizing the structural features that convey the biological functions of NTCP, as well as further discuss the anti-HBV activity and selectivity of inhibitors in HBV-related diseases, which should provide clues in the future for the discovery of drug candidates targeting NTCP.

Topics: Carcinoma, Hepatocellular; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Hepatocytes; Humans; Interferons; Liver Neoplasms; Nucleotides; Organic Anion Transporters, Sodium-Dependent; Symporters; Virus Internalization

Polyphenols represent a structural class of mainly natural organic chemicals that contain multiple phenol structural units. The beneficial properties of polyphenols have been extensively studied for their antitumor, anti-inflammatory, and antibacterial effects, but nowadays, their medical applications are starting to be extended to many other applications due to their prebiotic role and their impact on the microbiota. This review focused on the use of polyphenols in cancer treatment. Their antineoplastic effects have been demonstrated in various studies when they were tested on numerous cancer lines and some in in vivo models. A431 and SCC13 human skin cancer cell lines treated with EGCG presented a reduced cell viability and enhanced cell death due to the inactivation of β-catenin signaling. Additionally, resveratrol showed a great potential against breast cancer mainly due to its ability to exert both anti-estrogenic and estrogenic effects (based on the concentration) and because it has a high affinity for estrogen receptors ERα and Erβ. Polyphenols can be combined with different classical cytostatic agents to enhance their therapeutic effects on cancer cells and to also protect healthy cells from the aggressiveness of antitumor drugs due to their anti-inflammatory properties. For instance, curcumin has been reported to reduce the gastrointestinal toxicity associated with chemotherapy. In the case of 5-FU-induced, it reduced the gastrointestinal toxicity by increasing the intestinal permeability and inhibiting mucosal damage. Co-administration of EGCG and doxorubicin induced the death of liver cancer cells. EGCG has the ability to inhibit autophagic activity and stop hepatoma Hep3B cell proliferation This symbiotic approach is well-known in medical practice including in multiple chemotherapy.

Topics: Anti-Bacterial Agents; Antineoplastic Agents; beta Catenin; Breast Neoplasms; Catechin; Curcumin; Cytostatic Agents; Doxorubicin; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Fluorouracil; Humans; Liver Neoplasms; Polyphenols; Receptors, Estrogen; Resveratrol

Liver cancer is the fifth (6.3% of all cancers i.e., 548,000 cases/year) and ninth (2.8% of all cancers i.e., 244,000 cases/year) most prevalent cancer worldwide in men and women, respectively. Although multiple choices of therapies are offered for Hepatocellular Carcinoma (HCC) like liver resection or transplant, radiofrequency ablation, transarterial chemoembolization, radioembolization, and systemic targeted agent, by the time of diagnosis, most of the cases of HCC are in an advanced stage, which renders therapies like liver transplant or resection and local ablation impractical; and targeted therapy has its shortcomings like general toxicity, imprecise selectivity, several adversative reactions, and resistance development. Therefore, novel drugs with specificity and selectivity are needed to provide the potential therapeutic response. Various researches have shown the potential of phytomedicines in liver cancer by modulating cell growth, invasion, metastasis, and apoptosis. However, their therapeutic potential is held up by their unfavorable properties like stability, poor water solubility, low absorption, and quick metabolism. Nonetheless, the advancement of nanotechnology-based innovative nanocarrier formulations has improved the phytomedicines' profile to be used in the treatment of liver cancer. Nanocarriers not only improve the solubility and stability of phytomedicines but also extend their residence in plasma and accomplish specificity. In this review, we summarize the advancements introduced by nanotechnology in the treatment of liver cancer. In particular, we discuss quite a few applications of nanophytomedicines like curcumin, quercetin, epigallocatechin-3-gallate, berberine, apigenin, triptolide, and resveratrol in liver cancer treatment.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Catechin; Curcumin; Drug Compounding; Drug Stability; Humans; Liver Neoplasms; Nanocapsules; Plant Extracts; Quercetin; Resveratrol; Solubility; Theranostic Nanomedicine

Immune modulation is a very modern medical field for targeting viral infections. In the race to develop the best immune modulator against viruses, curcumin, as a natural product, is inexpensive, without side effects, and can stimulate very well certain areas of the human immune system. As a bright yellow component of turmeric spice, curcumin has been the subject of thousands of scientific and clinical studies in recent decades to prove its powerful antioxidant properties and anticancer effects. Curcumin has been shown to influence inter- and intracellular signaling pathways, with direct effects on gene expression of the antioxidant proteins and those that regulate the immunity. Experimental studies have shown that curcumin modulates several enzyme systems, reduces nitrosative stress, increases the antioxidant capacity, and decreases the lipid peroxidation, protecting against fatty liver pathogenesis and fibrotic changes. Hepatitis B virus (HBV) affects millions of people worldwide, having sometimes a dramatic evolution to chronic aggressive infection, cirrhosis, and hepatocellular carcinoma. All up-to-date treatments are limited, there is still a gap in the scientific knowledge, and a sterilization cure may not yet be possible with the removal of both covalently closed circular DNA (cccDNA) and the embedded HBV DNA. With a maximum light absorption at 420 nm, the cytotoxicity of curcumin as photosensitizer could be expanded by the intravenous blue laser blood irradiation (IVBLBI) or photobiomodulation in patients with chronic hepatitis B infection, Hepatitis B e-antigen (HBeAg)-positive, noncirrhotic, but nonresponsive to classical therapy. Photobiomodulation increases DNA repair by the biosynthesis of complex molecules with antioxidant properties, the outset of repairing enzyme systems and new phospholipids for regenerating the cell membranes. UltraBioavailable Curcumin and blue laser photobiomodulation could suppress the virus and control better the disease by reducing inflammation/fibrosis and stopping the progression of chronic hepatitis, reversing fibrosis, and diminishing the progression of cirrhosis, and decreasing the incidence of hepatocellular carcinoma. Photodynamic therapy with blue light and curcumin opens new avenues for the effective prevention and cure of chronic liver infections and hepatocellular carcinoma. Blue laser light and UltraBioavailable Curcumin could be a new valuable alternative for medical applications in chronic B viral hepat

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Carcinoma, Hepatocellular; Curcumin; DNA Repair; DNA, Circular; DNA, Viral; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunologic Factors; Liver; Liver Cirrhosis; Liver Neoplasms; Low-Level Light Therapy; Photosensitizing Agents

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Hence there is a need to identify new therapeutic agents that improve the current repertoire of chemotherapeutic drugs. The antitumor activity of curcumin has been reported for several tumors, including CRC. A recent phase I trial showed that curcumin is safe and tolerable adjunct to FOLFOX (5-fluorouracil, folinic acid and oxaliplatin) chemotherapy in patient-derived colorectal liver metastases at doses up to 2 g daily. Another trial revealed the effect of combining curcumin with FOLFOX in patients with inoperable colorectal cancer. The aim of current review was to summarize the current knowledge about possible molecular mechanisms of curcumin in CRC with particular emphasis on preclinical and early clinical studies of colorectal cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Curcumin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds

Silibinin, a natural flavanone, derived from the milk thistle plant (Silybum marianum), was illustrated for several medicinal uses such as liver-protective, anti-oxidant, anti-cancer, anti-inflammation and many other. However, silibinin has poor absorbance and bioavailability due to low water solubility, thereby limiting its clinical applications and therapeutic efficiency. To overcome this problem, the combination of silibinin with phosphatidylcholine (PC) as a formulation was used to enhance the solubility and bioavailability. The results indicated that silibinin-PC taken orally markedly enhanced bioavailability and therapeutic efficiency. In addition, a deeper understanding of the signaling pathways modulated by silibinin is important to realize its potential in developing targeted therapies against liver disorders and cancer. Silibinin has been shown to inhibit many cell signaling pathways in preclinical models, demonstrating promising effects against liver disorders and cancer through in vitro and in vivo studies. This review summarizes the pharmacokinetic properties, bioavailability, safety data, clinical activities and modulatory effects of silibinin in different cell signaling pathways against liver disorders and cancer.

Topics: Animals; Biological Availability; Clinical Trials as Topic; Humans; Liver Neoplasms; Signal Transduction; Silybin; Silymarin

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. The clinical management of HCC remains a substantial challenge. Although surgical resection of tumor tissues seems promising, a high recurrence and/or metastasis rate accounting for disease-related death has led to an urgent need for improved postsurgical preventive/therapeutic clinical intervention. Developing advanced target-therapy agents such as sorafenib appears to be the only effective clinical intervention for patients with HCC to date, but only limited trials have been conducted in this regard. Because of their enhanced preventive/therapeutic effects, traditional Chinese herbal medicine (CHM)-derived compounds are considered suitable agents for HCC treatment. The CHM-derived compounds also possess multilevel, multitarget, and coordinated intervention effects, making them ideal candidates for inhibition of tumor progression and HCC metastasis. This article reviews the anticancer activity of various CHMs with the hope of providing a better understanding of how to best use CHM for HCC treatment.

Topics: Abietanes; Benzylisoquinolines; Berberine; Carcinoma, Hepatocellular; Curcumin; Drugs, Chinese Herbal; Humans; Liver Neoplasms; Medicine, Chinese Traditional; Resveratrol; Scutellaria baicalensis; Stilbenes

Primary liver cancer, also known as hepatocellular carcinoma (HCC), is one of the most lethal cancers having worldwide prevalence. Although most HCC cases are reported in the developing countries of Asia and Africa, there has been an alarming increase in HCC cases in Western Europe as well as United States. Chronic liver diseases, viral hepatitis, alcoholism as well as dietary carcinogens, such as aflatoxins and nitrosoamines, contribute to HCC. Liver transplantation as well as surgical resection at best offer limited treatment options. Thus, there exists a critical need to investigate and evaluate possible alternative chemopreventive and therapeutic strategies which may be effective in the control of liver cancer. HCC, most often, develops and progresses in a milieu of oxidative stress and inflammation. Phytochemicals, such as dietary polyphenols endowed with potent antioxidant as well as anti-inflammatory properties, provide a suitable alternative in affording alleviation of HCC. Curcumin, the principal polyphenolic curcuminoid, obtained from the turmeric rhizome Curcuma longa has long been used to cure several chronic ailments, such as neoplastic and neurodegenerative diseases. Studies suggest that curcumin may have antitumor, antioxidant, and anti-inflammatory properties. This article reviews the effects of curcumin in preclinical in vitro and in vivo models of HCC with particular emphasis to its antioxidant, apoptotic and anti-inflammatory effects as well as involvement in various molecular signaling mechanisms. This review also discusses potential challenges involved in the use of curcumin in HCC, such as bioavailability, pharmacokinetics, drug delivery as well as paucity of clinical studies.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Carcinoma, Hepatocellular; Curcumin; Humans; Liver Neoplasms

Hepatocellular carcinoma (HCC) is the fifth commonest malignancy worldwide and the incidence is rising. Surgery, including transplantation resection, is currently the most effective treatment for HCC; however, recurrence rates are high and long-term survival is poor. Identifying novel chemopreventive and chemotherapeutic agents and targeting them to patients at high risk of developing HCC or following curative treatment may go some way towards improving prognosis. This review examines current knowledge regarding the chemopreventive and chemotherapeutic potential of phytochemicals in heptocarcinogenesis. Both in-vitro and animal studies demonstrate that several phytochemicals, including curcumin, resveratrol, green tea catechins, oltipraz and silibinin, possess promising chemopreventive and chemotherapeutic properties. Despite this, very few clinical trials have been performed. Problems regarding validation of biomarkers, agent delivery, side effects and patient selection are barriers that need to be overcome to determine the potential of such agents in clinical practice.

Topics: Animals; Antineoplastic Agents, Phytogenic; Brassicaceae; Caffeine; Capsaicin; Carcinoma, Hepatocellular; Catechin; Chemoprevention; Curcumin; Flavonoids; Humans; Liver Neoplasms; Phenols; Plant Extracts; Polyphenols; Resveratrol; Stilbenes

The need for low toxicity adjuncts to standard care chemotherapy in inoperable colorectal cancer, with potential to improve outcomes and decrease the side-effect burden, is well recognised. Addition of the low toxicity diet-derived agent, curcumin (the active ingredient of turmeric), to standard oxaliplatin-based therapy has shown promise in numerous pre-clinical studies.. This study is the first to combine daily oral curcumin with standard care FOLFOX-based (5-fluorouracil, folinic acid and oxaliplatin) chemotherapy in colorectal cancer patients with inoperable liver metastases: the CUFOX trial. CUFOX comprises a Phase 1 dose-escalation study (3 + 3 + 3 design) to determine an acceptable target dose of curcumin with which to safely proceed to a Phase IIa open-labelled randomised controlled trial. Thirty three participants with histological or cytological confirmation of inoperable colorectal cancer will then be randomised to oxaliplatin-based chemotherapy with the addition of daily oral curcumin at the target dose determined in Phase I, or to standard care oxaliplatin-based chemotherapy alone (recruiting at a ratio of 2:1).. Primary outcome measures will be the determination of a target dose which is both safe and tolerable for long-term administration to individuals in receipt of first-line oxaliplatin-based chemotherapy for inoperable colorectal cancer. Secondary outcome measures will include observation of any changes in neuropathic side-effects of chemotherapy, improvement to progression-free or overall survival and identification of putative efficacy biomarkers in plasma. The results will be disseminated via presentation at national and international conferences, via publication in appropriate peer-reviewed journals and via the Cancer Research UK/Department of Health Experimental Cancer Medicine Centre Network. This trial has full ethical and institutional approval, and commenced recruitment in February 2012.. ClinicalTrials.gov ( NCT01490996 , registered 7(th) December 2011), European Drug Regulating Authorities (EudraCT 2011-002289-19, registered 13(th) May 2011), UKCRN ID#10672.

Topics: Administration, Oral; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Clinical Protocols; Colorectal Neoplasms; Curcumin; Disease Progression; Disease-Free Survival; Drug Administration Schedule; England; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Research Design; Time Factors; Treatment Outcome

In vitro and pre-clinical studies have suggested that addition of the diet-derived agent curcumin may provide a suitable adjunct to enhance efficacy of chemotherapy in models of colorectal cancer. However, the majority of evidence for this currently derives from established cell lines. Here, we utilised patient-derived colorectal liver metastases (CRLM) to assess whether curcumin may provide added benefit over 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in cancer stem cell (CSC) models. Combination of curcumin with FOLFOX chemotherapy was then assessed clinically in a phase I dose escalation study. Curcumin alone and in combination significantly reduced spheroid number in CRLM CSC models, and decreased the number of cells with high aldehyde dehydrogenase activity (ALDH(high)/CD133(-)). Addition of curcumin to oxaliplatin/5-FU enhanced anti-proliferative and pro-apoptotic effects in a proportion of patient-derived explants, whilst reducing expression of stem cell-associated markers ALDH and CD133. The phase I dose escalation study revealed curcumin to be a safe and tolerable adjunct to FOLFOX chemotherapy in patients with CRLM (n = 12) at doses up to 2 grams daily. Curcumin may provide added benefit in subsets of patients when administered with FOLFOX, and is a well-tolerated chemotherapy adjunct.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Fluorouracil; Heterografts; Humans; Leucovorin; Liver Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Organoplatinum Compounds; Oxaliplatin; Spheroids, Cellular

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high recurrence and mortality rate. In this study, a series of β-cyclocitral-derived mono-carbonyl curcumin analogs were synthesized and their anticancer properties were evaluated. Among the series, A19 exhibited the strongest cytotoxic activity by inhibiting cell viability and colony formation, inducing cell cycle G2/M phase arrest and cell apoptosis of HCC HepG2 and Huh-7 cells, while having almost no cytotoxicity on normal liver MIHA cells. Mechanistically, our results demonstrated that A19 triggered intense DNA damage via suppression of the ERK/JNK/p38 MAPK signaling pathway. Additionally, a combination of A19 with sorafenib significantly induced synergistic cytotoxicity in HCC cells. Overall, our results indicate the potential of A19 as a novel chemotherapeutic drug administered either separately or in combined therapy for HCC treatment.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Curcumin; Hep G2 Cells; Humans; Liver Neoplasms; Signal Transduction

Lenvatinib is a multi-kinase inhibitor approved as a first-line treatment for patients with unresectable advanced hepatocellular carcinoma (HCC). However, its response rate is unsatisfactory, primarily due to the acquisition of resistance, which limits its clinical significance for treating patients with HCC. Recent evidence suggests that epidermal growth factor receptor (EGFR) activation can trigger Lenvatinib-resistance; and is considered an important therapeutic target in HCC. Curcumin, one of the most studied naturally occurring botanicals with robust anti-cancer activity, is also reported to be a potent tyrosine kinase inhibitor. In this study, we hypothesized that the anti-EGFR potential of Curcumin might help overcome Lenvatinib resistance in HCC. We established two Lenvatinib-resistant cells and discovered that a combination of Curcumin and Lenvatinib exhibited a synergistic anti-tumor efficacy in the resistant HCC cell lines. In line with previous reports, Lenvatinib-resistant cell lines revealed significant activation of the EGFR, and genomewide transcriptomic profiling analysis identified that the PI3K-AKT pathway was associated with Lenvatinib resistance. The combination treatment with Curcumin and Lenvatinib dramatically suppressed gene and protein expression of the EGFR-PI3K-AKT pathway, suggesting Curcumin overcomes Lenvatinib resistance via inhibition of EGFR. We further validated these findings in tumor spheroids derived from resistant cell lines. In conclusion, we, for the first time, report that Curcumin reverses Lenvatinib resistance in HCC, and that their combination has clinical application potential for adjunctive treatment in HCC.

Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; ErbB Receptors; Humans; Liver Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction

Among cancer-related deaths, hepatocellular carcinoma (HCC) ranks fourth, and traditional Chinese medicine (TCM) treatment is an important complementary alternative therapy for HCC. Curcumin is a natural ingredient extracted from. Differentially expressed genes (DEGs) of curcumin treatment in PLC, KMCH, and Huh7 cells were identified, respectively. The common genes among them were then obtained to perform functional enrichment analysis and prognostic analysis. Moreover, weighted gene co-expression network analysis (WGCNA) was carried out for the construction of the co-expression network. The ferroptosis potential index (FPI) and the cuproptosis potential index (CPI) were subsequently used to quantitatively analyze the levels of ferroptosis and cuproptosis. Finally, single-cell transcriptome analysis of liver cancer was conducted.. We first identified 702, 515, and 721 DEGs from curcumin-treated PLC, KMCH, and Huh7 cells, respectively. Among them,. We developed CPI and combined it with FPI to quantitatively analyze curcumin-treated HCC cells. It was found that ferroptosis and cuproptosis, two known metal ion-mediated forms of programmed cell death, may have a vital effect in treating HCC with curcumin, and there are significant differences in various liver cancer cell types and curcumin treatment which should be considered in the clinical application of curcumin.

Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Copper; Curcumin; Ferroptosis; Humans; Liver Neoplasms

The present study aimed to construct a co-loading platform encapsulating curcumin and paclitaxel at ratios of 2:1-80:1 (w/w) designated "CU-PTX-LNP" and explored the synergistic effects of CU-PTX at different composite proportions on liver cancer cells using the combination index (CI) method.. The CU lipid nanoplatform (CU-LNP) formulation was optimized via single-factor and orthogonal experiments. Various concentrations of PTX were added to the optimal formulation of CU-LNP to generate CU-PTX-LNP and the nanoplatform characterized via differential scanning calorimetry (DSC), transmission electron microscope (TEM), X-ray diffraction (XRD), zeta potential, polydispersity index (PDI), and size analyses. The cumulative release, stability, and cytotoxicity of CU-PTX-LNP in LO2, HepG2, and SMMC-7221 cells were assessed in vitro, followed by safety investigation and pharmacokinetic studies in vivo. The anti-tumor activity of CU-PTX-LNP was also evaluated using nude mice.. CU-PTX-LNP formulations containing CU:PTX at a range of proportions (2:1-80:1; w/w) appeared as uniformly dispersed nanosized spherical particles with high entrapment efficiency (EE> 90%), sustained release and long-lasting stability. Data from in vitro cytotoxicity assays showed a decrease in the IC. The newly designed CU-PTX-LNP platform may serve as a viable technological support system for the successful production of CU-PTX composite preparations.

Topics: Animals; Carcinoma, Hepatocellular; Curcumin; Lipids; Liver Neoplasms; Mice; Mice, Nude; Paclitaxel

Constitutional

Topics: Biomarkers; BRCA1 Protein; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Curcumin; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Methylation; MicroRNAs

The objective of this study is to activate autophagy in hepatocellular carcinoma for the enhancement of its cellular degradation. Liposomes incorporated chitosan in the core used to improve the stability of lecithin and increase the niacin loading efficiency. Additionally, curcumin as a hydrophobic molecule entrapped into liposomal layers and used as a face layer to minimize the release of niacin in physiological pH 7.4. Folic acid-conjugated chitosan was used to facilitate the delivery of liposomes into a specific location of cancer cells. TEM, UV Visible spectrophotometer, and FTIR confirmed the successful liposomal formation and good encapsulation efficiency. Based on the cellular proliferation of HePG2, the results revealed that there was a significant inhibition of growth rate of HePG2 after 48 h of incubation at a concentration of 100 μg/mL by 91 % ± 1 %, P ≤ 0.002 (pure niacin), 55 % ± 3 %, P ≤ 0.001 (pure curcumin), 83 % ± 1.5 %, P ≤ 0.001 (niacin NPs), and 51 % ± 1.5 % P ≤ 0.0001 (curcumin-niacin NPs) of relative to the control. Increasingly, The expression of mRNA of mTOR was significantly increased by 0.72 ± 0.08 P ≤ 0.001, 1 ± 0.1, 0. P ≤ 0.001, 5 ± 0.07 P ≤ 0.01, and 1.3 ± 0.02 P ≤ 0.001 folds) in pure niacin, pure curcumin, niacin NPs and curcumin -niacin NPs, respectively, relative to the control with an expression of 0.3 ± 0.08. Additionally, the expression of p62 mRNA was significantly increased by 0.92 ± 0.07 P ≤ 0.05, 1.7 ± 0.07 P ≤ 0.0001, 0.72 ± 0.08 P ≤ 0.5, and 2.1 ± 0.1 P ≤ 0.0001 folds relative to that of the control with an expression of 0.72 ± 0.08. The results highlight the efficient therapies of biomaterials derived from natural sources that can be used in cancer therapies instead of traditional chemotherapies.

Topics: Autophagy; Carcinoma, Hepatocellular; Chitosan; Curcumin; Drug Carriers; Hep G2 Cells; Humans; Liposomes; Liver Neoplasms; Nanoparticles; Niacin; Particle Size

The inhibitory role of curcumin on sperm-associated antigen 5 (SPAG5) and its effects on the cancer‑related Wnt classical signaling pathway has been previously demonstrated. Nevertheless, research on the modulatory role of curcumin on the Wnt signaling pathway by acting on SPAG5 has yet to be reported. The activation of the Wnt/β‑catenin pathway is frequently observed in patients suffering from hepatocellular carcinoma (HCC), suggesting that small molecular drugs that target Wnt could present a promising therapeutic strategy. However, these drugs often result in substantial side effects. In the present study, the presence of SPAG5 in the cancer tissues of patients with HCC and cell lines was validated using immunohistochemistry, cellular immunofluorescence, reverse transcription‑quantitative polymerase chain reaction, and western blot analyses. Subsequently, the effect of SPAG5 and the regulatory role of curcumin on SPAG5 and the Wnt/β‑catenin pathway were examined using cell function tests, flow cytometry, and western blotting. Techniques of gene knockout and overexpression were employed. The findings revealed a significant overexpression of SPAG5 in the cancer tissues of patients with HCC. Both the mRNA and protein levels of SPAG5 in Huh7 and HCCLM3 cell lines were markedly elevated. Treatment with curcumin led to a decrease in SPAG5 expression, while also inhibiting cell migration and promoting apoptosis. Additionally, suppression of SPAG5 expression resulted in the decreased expression of β‑catenin. Furthermore, curcumin was observed to reduce the expression of cyclin D1 in SPAG5‑overexpressing cell lines. However, the degree of inhibition was diminished once SPAG5 expression was silenced. These initial findings indicate that SPAG5 may function as an upstream regulatory protein of the Wnt/β‑catenin pathway, hence offering a potential alternative target for HCC. Moreover, as curcumin has the capacity to inhibit Wnt via suppressing SPAG5, it could potentially serve as a natural drug component for early intervention and treatment of HCC.

Topics: beta Catenin; Carcinoma, Hepatocellular; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Wnt Signaling Pathway

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in the world. Poor prognosis of HCC patients is a major issue, thus, better treatment options for patients are required. Curcumin (Cur), hydrophobic polyphenol of the plant turmeric, shows anti-proliferative, apoptotic, and anti-oxidative properties. Boron is a trace element which is essential part of human nutrition. Sodium pentaborate pentahydrate (NaB), a boron derivative, is an effective agent against cancer. In the current study, we performed in vitro experiments and transcriptome analysis to determine the response of NaB, Cur, piperine (Pip) and their combination in two different HCC cell lines, HepG2 and Hep3B. NaB and Cur induced cytotoxicity in a dose and time dependent manner in HepG2 and Hep3B, whereas Pip showed no significant toxic effect. Synergistic effect of combined treatment with NaB, Cur and Pip on HCC cells was observed on cytotoxicity, apoptosis and cell cycle assay. Following in vitro studies, we performed RNA-seq transcriptome analysis on NaB, Cur and Pip and their combination on HepG2 and Hep3B cells. Transcriptome analysis reveals combined treatment of NaB, Cur and Pip induces anti-cancer activity in both of HCC cells.

Topics: Boron; Carcinoma, Hepatocellular; Cell Line; Curcumin; Humans; Liver Neoplasms

Curcumin (CUR) has good antitumor effects, but its poor aqueous solubility severely limits its clinical application and the systemic nonspecific distribution of the free drug in tumor patients is a key therapeutic challenge. In order to overcome the limitations of free drugs and improve the therapeutic efficacy, we developed novel galactosylated chitosan (GC)-modified nanoparticles (GC@NPs) based on poly (ethylene glycol) methyl ether-block-poly (lactide-co-glycolide) (PEG-PLGA), which can target asialoglycoprotein receptor (ASGPR) expressed on hepatocellular carcinoma cells and have excellent biocompatibility. The results showed that the drug loading (DL) of CUR was approximately 4.56 %. A favorable biosafety profile was maintained up to concentrations of 500 μg/mL. Furthermore, in vitro cellular assays showed that GC@NPs could be efficiently internalized by HepG2 cells via ASGPR-mediated endocytosis and successfully released CUR for chemotherapy. More importantly, in vivo anti-tumor experiments revealed that GC@NPs were able to accumulate effectively within tumor sites through EPR effect and ASGPR-mediated endocytosis, leading to superior inhibition of tumor growth compared to free CUR. Overall, GC@NPs are a promising CUR nanocarrier for enhanced tumor therapy with a good biosafety profile.

Topics: Carcinoma, Hepatocellular; Chitosan; Curcumin; Drug Carriers; Humans; Liver Neoplasms; Nanoparticles; Particle Size

Curcumin possesses a wide spectrum of liver cancer inhibition effects, yet it has chemical instability and poor metabolic properties as a drug candidate. To alleviate these problems, a series of new mono-carbonyl curcumin derivatives

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Liver Neoplasms; Molecular Docking Simulation

Curcumin is a chemical with various pharmacological activities used for cancer treatment. It inhibits hepatocellular carcinoma (HCC) by inducing apoptosis. Here, the mechanism underlying the effect of curcumin on the apoptosis of HCC cells was studied. Cell counting kit-8 and plate cloning assays were used to assess the proliferation of HCC cells, and acridine orange/ethidium bromide and Annexin V/PI staining were used to analyze their apoptosis. HCC xenograft tumor models were established to validate anti-cancer effects of curcumin. Expression levels of XRCC4 protein in tumor tissues were assessed by immunohistochemistry. Correlation between XRCC4 expression and the prognosis of patients with HCC was analyzed by integrating publicly available gene expression data. Curcumin inhibited HCC cells proliferation in a dose-dependent manner. Compared with the control group, curcumin significantly promoted the apoptosis of HCC cells

Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms

The aim of present study was to screen the novel and promising targets of curcumin in hepatocellular carcinoma diagnosis and chemotherapy.. Potential targets of curcumin were screened from SwissTargetPrediction, ParmMapper and drugbank databases. Potential aberrant genes of hepatocellular carcinoma were screened from Genecards databases. Fifty paired hepatocellular carcinoma patients' gene expression profiles from the GEO database were used to test potential targets of curcumin. Besides, GO analysis, KEGG pathway enrichment analysis and PPI network construction were used to explore the underlying mechanism of candidate hub genes. ROC analysis and Kaplan-Meier analysis were used to evaluate the diagnostic and prognostic value of candidate hub genes, respectively. Real-time PCR was used to verify the results of bioinformatics analysis.. Bioinformatics analysis results suggested that AURKA, CDK1, CCNB1, TOP2A, CYP2B6, CYP2C9, and CYP3A4 genes served as candidate hub genes. AURKA, CDK1, CCNB1 and TOP2A were significantly upregulated and correlated with poor prognosis in hepatocellular carcinoma, AUC values of which were 95.7, 96.9, 98.1 and 96.1% respectively. There was not significant correlation between the expression of CYP2B6 and prognosis of hepatocellular carcinoma, while CYP2C9 and CYP3A4 genes were significantly downregulated and correlated with poor prognosis in hepatocellular carcinoma. AUC values of CYP2B6, CYP2C9, and CYP3A4 were 96.0, 97.0 and 88.0% respectively. In vitro, we further confirmed that curcumin significantly downregulated the expression of AURKA, CDK1, and TOP2A genes, while significantly upregulated the expression of CYP2B6, CYP2C9, and CYP3A4 genes.. Our results provided a novel panel of AURKA, CDK1, TOP2A, CYP2C9, and CYP3A4 candidate genes for curcumin related chemotherapy of hepatocellular carcinoma.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Computational Biology; Curcumin; Data Mining; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Phytotherapy; Predictive Value of Tests; Protein Interaction Maps

Curcumin (CU) is a natural polyphenolic phytoingredient. CU has anti-inflammatory, anti-oxidant, and anticancer activities. The poor solubility, bioavailability, and stability of CU diminish its clinical application. Hence, structural modification of CU is highly recommended. The CU analog; 3,5-bis(4-bromobenzylidene)-1-propanoylpiperidin-4-one (PIP) exhibited high stability, safety, and more potent antiproliferative activity against hepatocellular carcinoma. In the present study, nano-bilosomes (BLs) were formulated to augment PIP delivery and enhance its solubility. A 2

Topics: Biological Availability; Carcinoma, Hepatocellular; Curcumin; Doxorubicin; Humans; Liver Neoplasms; Nanoparticles

Radioresistance inducing by hypoxic microenvironment of hepatocellular carcinoma is a major obstacle to clinical radiotherapy. Advanced nanomedicine provides an alternative to alleviate the hypoxia extent of solid tumor, even to achieve effective synergistic treatment when combined with chemotherapy or radiotherapy.. Herein, we developed a self-assembled nanoparticle based on hemoglobin and curcumin for photoacoustic imaging and radiotherapy of hypoxic hepatocellular carcinoma. The fabricated nanoparticles inhibited hepatoma migration and vascular mimics, and enhanced the radiosensitivity of hypoxic hepatoma cells in vitro via repressing cell proliferation and DNA damage repair, as well as inducing apoptosis. Benefit from oxygen-carrying hemoglobin combined with polyphenolic curcumin, the nanoparticles also effectively enhanced the photoacoustic contrast and the efficacy of radiotherapy for hepatocellular carcinoma in vivo.. Together, the current study offered a radiosensitization platform for optimizing the efficacy of nanomedicines on hypoxic radioresistant tumor.

Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Hemoglobins; Humans; Hypoxia; Liver Neoplasms; Nanoparticles; Tumor Microenvironment

Nanomedicine delivery systems can achieve precise drug delivery and reduce toxic side effects compared with traditional drug delivery methods, but further development is still needed to eliminate obstacles such as multiple drug co-delivery, uncontrolled drug-release, and drug-resistance. Herein, we designed a dual drug-loaded nanosystem (THCD-NPs) that selectively transports and targets tumor cells for the treatment of liver cancer. In this drug delivery system, hyaluronic acid (HA)-conjugated curcumin (Cur) and d-α-tocopherol acid polyethylene glycolsuccinate (TPGS) were used as selective drug-carrying vehicles to deliver dasatinib (DAS) to cancer cells for combined administration. The mean size of the nanoparticles was approximately 66.14 ± 4.02 nm with good

Topics: Animals; Cell Line, Tumor; Curcumin; Dasatinib; Drug Carriers; Drug Delivery Systems; Drug Liberation; Hydrogen-Ion Concentration; Liver Neoplasms; Mice; Micelles; Nanoparticles

Acrylamide (AC) is an environmental contaminant with cancer-promoting and cytotoxic properties, while curcumin (Cur.) is a phytochemical with documented anticancer and cytoprotective efficacy. Nanoparticle formulations can increase the efficacy of phytochemicals, so we examined the anticancer and hepatoprotective efficacies of nanocurcumin (N.Cur). Curcumin and nanocurcumin reduced HepG2 and Huh-7 cancer cell viability and increased apoptosis in the presence and absence of AC, while AC alone promoted proliferation. Furthermore, the anticancer efficacy of nanocurcumin was greater than that of curcumin. In mice, AC greatly increased hepatic expression of CYP2E1, P53, cleaved caspase-3, and COL1A1 as well as serum alanine aminotransferase and aspartate aminotransferase activities. These effects were reversed by nanocurcumin and curcumin. Nanocurcumin also reduced the histopathology and fibrosis caused by AC, and reversed AC-induced glycogen depletion. Nanoparticle formulation can increase the anticancer and hepatoprotective efficiencies of curcumin.

Topics: Acrylamides; Animals; Curcumin; Liver Neoplasms; Mice; Nanoparticles

The objective of this study was to develop long-circulating solid lipid nanoparticles (LSLN) containing a novel curcumin (CU) derivative (CU1), to improve CU1's pharmacokinetic behavior and its anti-cancer effects in MHCC-97H liver cancer cells.. LSLN loaded with CU1 (CU1-LSLN) was optimized and characterized. The cell biological properties and the anti-cancer mechanism of CU1-LSLN on MHCC-97H cells were evaluated by MTT, flow cytometry, Transwell, and Western blot. CU1-LSLN was further evaluated for pharmacokinetic behavior, biodistribution, and liver toxicity in SD rats.. The optimized CU1-LSLN formulation showed the ideal particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE%), and drug loading (DL%) of 122.10 ± 6.63 nm, 0.19 ± 0.02, -36.30 ± 1.25 mV, 94.98 ± 0.90% and 4.53 ± 0.69%, respectively. X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectrometry (FTIR) indicated that CU1 was well encapsulated by LSLN and existed in amorphous form. Storage stability of CU1-LSLN was up to 180 days with a sustained-release of drug over 96 h. The uptake efficiency of CU1-LSLN to MHCC-97H cells was 3.24 and 2.98 times higher than that of CU and CU1 after treatment for 3 h, which helped to enhance the inhibitive effect of CU1-LSLN on the proliferation, migration, and invasion potential of MHCC-97H cells and increased its ability to promote apoptosis. Meanwhile, the expression levels of NF-κB, COX-2, MMP-2, MMP-9, and uPA decreased significantly. In vivo, CU1-LSLN prolonged the retention time of the drug, the area under the curve (AUC) increased significantly (CU: 69.9-fold, CU1: 85.9-fold), and no significant liver toxicity was observed.. CU1-LSLN is a novel preparation with great potential for treating liver cancer.

Topics: Animals; Curcumin; Drug Carriers; Liposomes; Liver Neoplasms; Nanoparticles; Particle Size; Rats; Rats, Sprague-Dawley; Tissue Distribution

Tumor microenvironment (TME) plays a vital role in the development of hepatocellular carcinoma (HCC). Mounting evidence indicates that peripheral nerves could induce a shift from quiescent hepatic stellate cells (HSCs) to cancer-associated fibroblasts (CAFs) by secreting substance P (SP). The anti-tumor strategy by targeting "SP-HSCs-HCC" axis might be an effective therapy to inhibit tumor growth and metastasis.. In this study, we prepared novel liposomes (CUR-APR/HA&GA-LPs) modified with hyaluronic acid (HA) and glycyrrhetinic acid (GA) for co-delivery aprepitant (APR) and curcumin (CUR), in which APR was chosen to inhibit the activation of HSCs by blocking SP/neurokinin-1 receptor (NK-1R), and CUR was used to induce apoptosis of tumor cells.. To mimic the TME, we established "SP+HSCs+HCC" co-cultured cell model in vitro. The results showed that CUR-APR/HA&GA-LPs could be taken up by CAFs and HCC simultaneously, and inhibit tumor cell migration. Meanwhile, the "SP+m-HSCs+HCC" co-implanted mice model was established to evaluate the anti-tumor effect in vivo. The results showed that CUR-APR/HA&GA-LPs could inhibit tumor proliferation and metastasis, and reduce extracellular matrix (ECM) deposition and tumor angiogenesis, indicating a superior anti-HCC effect.. Overall, the combination therapy based on HA&GA-LPs could be a potential nano-sized formulation for anti-HCC therapy.

Topics: Animals; Aprepitant; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Glycyrrhetinic Acid; Hyaluronic Acid; Lipopolysaccharides; Liposomes; Liver Neoplasms; Mice; Tumor Microenvironment

Curcumin (CUR) has a bright future in the treatment of cancer as a natural active ingredient with great potential. However, curcumin has a low solubility, which limits its clinical application. In this study, IRMOF-10 was created by the direct addition of triethylamine, CUR was loaded into IRMOF-10 using the solvent adsorption method, and the two were characterized using a scanning electron microscope (SEM), X-ray diffraction (XRD), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TG) methods, and Brunauer-Emmett-Teller (BET) analysis. We also used the MTT method, 4',6-diamidino-2-phenylindole (DAPI) staining, the annexin V/PI method, cellular uptake, reactive oxygen species (ROS), and the mitochondrial membrane potential (MMP) to perform a safety analysis and anticancer activity study of IRMOF-10 and CUR@IRMOF-10 on HepG2 cells. Our results showed that CUR@IRMOF-10 had a CUR load of 63.96%, with an obvious slow-release phenomenon. The CUR levels released under different conditions at 60 h were 33.58% (pH 7.4) and 31.86% (pH 5.5). Cell experiments proved that IRMOF-10 was biologically safe and could promote curcumin entering the nucleus, causing a series of reactions, such as an increase in reactive oxygen species and a decrease in the mitochondrial membrane potential, thereby leading to cell apoptosis. In summary, IRMOF-10 is an excellent drug carrier and CUR@IRMOF-10 is an effective anti-liver cancer sustained-release preparation.

Topics: Biphenyl Compounds; Carcinoma, Hepatocellular; Curcumin; Dicarboxylic Acids; Hep G2 Cells; Humans; Liver Neoplasms; Nanoparticles; Reactive Oxygen Species

Breast cancer is a complex multifactorial disease and polymorphisms in nucleotide excision repair pathway are associated with the potential risk of breast cancer. Pathological processes linked to breast cancer are associated with oxidative stress. Catalase plays an essential role in cell defense against oxidative stress. Curcumin has antioxidant activity that can significantly reduce oxidative stress levels. The aims of this study were to determine ERCC5 rs751402 polymorphism was associated with oxidative stress in breast carcinogenesis. The impact of curcumin on catalase activity for inhibiting breast cancer progression was also studied.. The effect of ERCC5 rs751402 polymorphism on oxidative stress was studied with different H2O2 concentrations in HCC 1937 cell line for 24 h and then analysed by MTT assay. The impact of curcumin on catalase activity was studied in MCF-7 cell line treated with different curcumin concentrations for 24 h and then analysed by trypan blue exclusion assay and catalase activity assay.. It showed that this polymorphism involved in oxidative stress (p < 0.05) and curcumin caused the antiproliferative effect by the catalase activity increase (p < 0.05).. Our study indicated that ERCC5 rs751402 polymorphism may contribute to the etiology of breast carcinogenesis about the failure of oxidative stress protection and lead to breast carcinogenesis. The antiproliferative effect of curcumin may be associated with catalase activity and protect breast carcinogenesis.

Topics: Antioxidants; Breast Neoplasms; Carcinoma, Hepatocellular; Catalase; Cell Transformation, Neoplastic; Curcumin; DNA-Binding Proteins; Endonucleases; Female; Humans; Hydrogen Peroxide; Liver Neoplasms; MCF-7 Cells; Nuclear Proteins; Oxidative Stress; Polymorphism, Genetic; Transcription Factors

Currently, systemic therapies for patients with advanced-stage hepatocellular carcinoma (HCC) rely mainly on systemic drugs. However, traditional systemic drugs have a high rate of serious adverse events, and the curative effects of some potential anticancer drugs, such as curcumin (CUR) and resveratrol (RSV), are less apparent due to their poor bioavailability. Therefore, it is urgent to develop a highly effective therapy to improve patient prognosis. Herein, an injectable HCC-targeted nanoparticle (NP) was designed to deliver CUR and RSV to hepatoma cells.. The molecular self-assembled NPs showed higher tumour retention through the enhanced permeability and retention (EPR) effect of the NPs and surface modification with the HCC-specific peptide moiety SP94 to effectively treat HCC. These HCC-targeted NPs led to a significant reduction in the drug dosage, delayed the rate of drug release and improved the bioavailability of the encapsulated drugs. The drug concentrations in the vicinity of the tumour increased, and a good therapeutic effect was observed without obvious side effects.. These SP94-mediated NPs allowed large amounts of antitumor drugs to accumulate in tumours, providing a novel strategy for innovative HCC therapy. This nanoplatform also offers an idea for exploring other potential chemotherapeutics.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Drug Carriers; Humans; Liver Neoplasms; Nanoparticles; Resveratrol

Curcumin is a yellow pigment extracted from the rhizome of turmeric, a traditional Chinese medicine. Here, we tested the hypothesis that curcumin-mediated downregulation of BCLAF1 triggers mitochondrial apoptosis in hepatoma cells by inhibiting PI3K/AKT/GSK-3β signaling. Treatment of the human hepatoma cell lines, HepG2 and SK-Hep-1, with various concentrations of curcumin revealed a time-dependent and concentration-dependent inhibition of cell proliferation, increased apoptosis, cell cycle arrest at the G0/G1 phase, reduced mitochondrial membrane potential, and reduced expression levels of PI3K, p-PI3K, AKT, p-AKT, GSK-3β, and p-GSK-3β. Additionally, curcumin suppressed the levels of apoptotic factors after treating the cells with LY294002, a PI3K inhibitor. Curcumin also suppressed the expression of BCLAF1. Treating stable BCLAF1 knockout HepG2 and SK-Hep-1 cells with curcumin further enhanced apoptosis and increased the number of cells in G0/G1 cell cycle arrest, while inhibiting the downregulation of PI3K/AKT/GSK-3β pathway-related proteins. Treatment of a nude mouse xenograft model bearing HepG2 cells with curcumin inhibited tumor growth, disrupted the cellular structure of the tumor tissue, and suppressed the expression of BCLAF1 and PI3K/AKT/GSK-3β proteins. In summary, our in vitro and in vivo analyses show that curcumin downregulates BCLAF1 expression, inhibits the activation of the PI3K/AKT/GSK-3β pathway, and triggers mitochondrial apoptosis in HCC. These findings uncover a potential therapeutic strategy leveraging the antitumor effects of curcumin against HCC.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Curcumin; Glycogen Synthase Kinase 3 beta; Humans; Liver Neoplasms; Mice; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Repressor Proteins; Tumor Suppressor Proteins

To determine the potential molecular mechanisms underlying the therapeutic effect of curcumin on hepatocellular carcinoma (HCC) by network pharmacology and experimental in vitro validation.. The predictive targets of curcumin or HCC were collected from several databases. the identified overlapping targets were crossed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) platform. Two of the candidate pathways were selected to conduct an experimental verification. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium (MTT) assay was used to determine the effect of curcumin on the viability of HepG2 and LO2 cells. The apoptosis and autophagy of HepG2 cells were respectively detected by flow cytometry and transmission electron microscopy. Besides, western blot and real-time polymerase chain reaction (PCR) were employed to verify the p53 apoptotic pathway and adenosine 5'-monophosphate (AMP)‍-activated protein kinase (AMPK) autophagy pathway. HepG2 cells were pretreated with pifithrin-‍α (PFT-‍α) and GSK690693 for further investigation.. The 167 pathways analyzed by KEGG included apoptosis, autophagy, p53, and AMPK pathways. The GO enrichment analysis demonstrated that curcumin was involved in cellular response to drug, regulation of apoptotic pathway, and so on. The in vitro experiments also confirmed that curcumin can inhibit the growth of HepG2 cells by promoting the apoptosis of p53 pathway and autophagy through the AMPK pathway. Furthermore, the protein and messenger RNA (mRNA) of the two pathways were downregulated in the inhibitor-pretreated group compared with the experimental group. The damage-regulated autophagy modulator (DRAM) in the PFT-‍α-pretreated group was downregulated, and p62 in the GSK690693-pretreated group was upregulated.. Curcumin can treat HCC through the p53 apoptotic pathway and the AMPK/Unc-51-like kinase 1 (ULK1) autophagy pathway, in which the mutual transformation of autophagy and apoptosis may occur through DRAM and p62.

Topics: AMP-Activated Protein Kinases; Apoptosis; Carcinoma, Hepatocellular; Curcumin; Humans; Liver Neoplasms; Network Pharmacology; Tumor Suppressor Protein p53

The molecular mechanisms of flavonoid curcumin used in cancer treatment are not fully understood. The results of this study suggest that curcumin evidently inhibits epithelial-mesenchymal transition, cell growth, and invasion of hepatocellular carcinoma cell lines HepG2 and Huh-7, as well as the Wnt/β-catenin signal pathway. Curcumin might exert anti-tumor effect on hepatocellular carcinoma cells by regulating the TET1/Wnt/β-catenin signal pathway to inhibit the epithelial-mesenchymal transition progress.

Topics: beta Catenin; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Mixed Function Oxygenases; Proto-Oncogene Proteins; Wnt Signaling Pathway

Adipose-derived stem cells (ASCs) have been proven to have tumoricidal effects against hepatic cancer cell lines. However, it appears that exposure to oxidative microenvironment compromises the potential outcome of ASCs in real hepatoma. Herein, we aimed to examine the tumoricidal effects of ASCs under oxidative conditions and to investigate the impact of curcumin priming on ASCs' therapeutic potential.. We used human hepatoma (HepG2) cells in a coculture system with unprimed or curcumin-primed ASCs (Cur-ASCs) under H. Cur-ASCs suppressed HepG2 proliferation, migration, and invasion as well as prompted apoptosis more significantly compared to unprimed ASCs under oxidative conditions. Expressional studies also revealed an obvious decline in the BCL-2/BAX ratio in HepG2 cocultured with Cur-ASCs. In addition, we noticed a marked elevation of apoptosis and senescence in unprimed ASCs compared to Cur-ASCs after coculture experiments, which demonstrated that curcumin priming preserved the survival and growth potential of ASCs; hence, Cur-ASCs performed better tumoricidal functions under oxidative conditions.. Our findings suggest that ASCs have the intrinsic ability to induce cell death in HepG2 cells; however, their functions can be compromised under oxidative conditions. We believe that curcumin priming is an effective approach for improving the therapeutic effectiveness of ASCs in the cancerous microenvironment.

Topics: Carcinoma, Hepatocellular; Curcumin; Hep G2 Cells; Humans; Hydrogen Peroxide; Liver Neoplasms; Oxidative Stress; Stem Cells; Tumor Microenvironment

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Hep G2 Cells; HSP90 Heat-Shock Proteins; Humans; Immunoprecipitation; Liver Neoplasms; Membrane Potential, Mitochondrial; Reactive Oxygen Species

Curcumin has shown anti-tumor activity in multiple malignancies. The aim of our study was to explore the molecular mechanism behind the anti-tumor activity of curcumin in hepatocellular carcinoma (HCC).. The proliferation, migration, invasion, and apoptosis were analyzed by 5-ethynyl-2'-deoxyuridine (EDU) assay, transwell migration assay, transwell invasion assay, and flow cytometry. Western blot assay and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were conducted to analyze protein and RNA expression. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA-pull down assay were performed to confirm the interaction between microRNA-378b (miR-378b) and circular RNA_0078710 (circ_0078710) or DNA primase, polypeptide 2 (PRIM2). Tumor xenograft assay was conducted to assess the roles of curcumin and circ_0078710. Curcumin stimulation restrained the proliferation, migration, and invasion, and triggered the apoptosis of HCC cells. Curcumin down-regulated the expression of circ_0078710 in HCC cells in a dose-dependent manner. Circ_0078710 knockdown aggravated curcumin-mediated anti-tumor effects in HCC cells. Circ_0078710 acted as a molecular sponge for miR-378b. Circ_0078710 interference-induced effects in curcumin-stimulated HCC cells were partly abolished by the silence of miR-378b. MiR-378b bound to the 3' untranslated region (3'UTR) of PRIM2. PRIM2 overexpression partly reversed circ_0078710 interference-mediated influences in curcumin-treated HCC cells. Circ_0078710 silencing aggravated curcumin-mediated suppressive effect in tumor growth. Circ_0078710 silencing aggravated curcumin-mediated anti-tumor effects through mediating the miR-378b/PRIM2 signaling in HCC cells.

Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Curcumin; DNA Primase; Humans; Liver Neoplasms; MicroRNAs; RNA, Circular

Yanggan Huayu granule (YGHY) is a formula of traditional Chinese medicine that has been widely used to treat patients with liver cancer. But its working mechanism is still poorly understood.. To investigate the anti-tumor effect of YGHY and its working mechanisms in hepatocellular carcinoma (HCC).. H22 mouse xenograft model was used to detect the effect of YGHY on hepatocellular carcinoma (HCC). MTT and CCK8 assays were performed to assess the effect of YGHY on HCC cell growth. Transwell assay was performed to detect the invasion and migration activities of HCC cells. Effect of YGHY drug-contained serum on apoptosis was detected by flow cytometry. Western blot was performed to detect the protein expressions.. Results showed that YGHY inhibited tumor volume and weight, induced the apoptosis of HepG2 and SMMC-7721 cells and increased the protein expressions of Cleaved-Caspase3 and Cleaved-PARP. Furthermore, YGHY significantly down-regulated the protein expression of p-AKT. SC79, as an activator of AKT signaling, was able to increase the expression of p-AKT, and regulate the protein expressions of Cleaved-Caspase3, Cleaved-PARP, BCL-2 and BAX. YGHY drug-contained serum negated the protein expression change provided by SC79.. Taken together, this data indicates that YGHY could inhibit HCC growth by inducing apoptosis, operating through AKT signaling.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Broussonetia; Carcinoma, Hepatocellular; Cell Proliferation; Curcuma; Down-Regulation; Drugs, Chinese Herbal; Gene Expression Regulation, Neoplastic; Liver Neoplasms; Lycopus; Mice; Plants, Medicinal; Proto-Oncogene Proteins c-akt; Signal Transduction; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Line; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Liver Neoplasms; Molecular Structure; NF-kappa B; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Structure-Activity Relationship

Hepatocellular carcinoma (HCC) is one of the most common cause of cancer-related death worldwide. Curcumin (C) has been extensively investigated in different types of malignancies, including hepatocellular carcinoma, but its physicochemical properties have significantly influenced its clinical use. Several approaches are being explored to enhance curcumin's therapeutic response, including its combination with various drugs.. This study aimed to evaluate the anti-tumor effect of curcumin (C) in combination with F2 (N-n-butyl haloperidol iodide) on hepatocellular carcinoma and its potential underlying mechanism in vitro and in vivo.. Cell proliferation was evaluated by CCK-8 and colony formation assays, and apoptosis was measured by flow cytometry. The migratory and invasive abilities of Hep3B and SMMC-7721 cells were measured by wound-healing and matrigel transwell assays. In order to investigate the molecular pathways, various experiments such as western blotting, qPCR, RNA-seq, immunostaining and transfection were performed. To evaluate the anti-HCC effects in vivo, a xenograft tumor model was used.. Our findings showed that the combination of curcumin (C) & F2 (F2C) strongly inhibited malignant proliferation and migration in SMMC-7721 and Hep3B cells. The F2C treatment downregulates enhancer of zeste homolog 2 (EZH2) transcription and protein expression, which is key epigenetic regulator responsible for HCC development. Moreover, the inhibition of EZH2 by F2C led to Wnt/β-catenin signaling inhibition by decreasing tri-methylation of histone H3 at lysine 27 (H3K27me3) and long non-coding RNA H19 expression. The inhibition of F2C was associated with the suppression of tumorigenicity in xenograft HCC models.. These findings suggested that, F2C inhibited HCC formation, migration and its modulatory mechanism seemed to be associated with downregulation of EZH2, silencing Wnt/β-catenin signaling by interacting with H19, suggesting that F2C may be a promising drug in the clinical treatment of HCC.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Curcumin; Enhancer of Zeste Homolog 2 Protein; Gene Expression Regulation, Neoplastic; Haloperidol; Humans; Liver Neoplasms; Mice, Nude; RNA, Long Noncoding; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Objective To investigate the effect of curcumin combined with 5-FU on autophagy and Yes-associated protein (YAP) expression in hepatocellular carcinoma cells. Methods HepG2 cells, HepG2 cells with stable YAP overexpression, and HepG2 cells with stable YAP knockdown were treated with 10 μmol/L of curcumin and 10 μg/mL of 5-FU alone and in combination for 24 hours. The proliferation of cells was detected by MTT assay. The expression changes of autophagy markers microtubule-associated protein LC3II and YAP were detected by Western blotting. Results When the two agents were used in combination, the inhibition rate of tumor cell proliferation was significantly higher than that of each single agent group. Compared with the control group, group with curcumin, group with 5-FU, and combination group could increase the expression level of LC3II protein and decrease that of YAP in HepG2 cells, HepG2 cells with stable YAP overexpression, and HepG2 cells with stable YAP knockdown. Conclusion The combination of curcumin and 5-FU induces autophagy and down-regulates the expression of YAP in hepatocellular carcinoma cells.

Topics: Apoptosis; Autophagy; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Fluorouracil; Humans; Liver Neoplasms

Hydrazinocurcumin (HZC), a synthetic derivative of curcumin (CUR), has been documented to show anticancer potential in impeding tumor growth in several cancers, including hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms remain unclear. This study aimed to explore the function and underlying mechanisms of HZC on HCC cells, which may involve the p38 mitogen activated protein kinase (MAPK) pathway. HZC was first purified and identified. HepG2 cells were then subjected to treatment with HZC or CUR of different concentrations and p38 MAPK signaling inhibitor (SB203580) to verify their effects on HCC cell apoptosis and proliferation. Furthermore, the functional relevance between HZC and the p38 MAPK pathway in HCC was examined. It was observed that 40 μM HZC exhibited the best pro-apoptosis effect in HCC cells. HZC was found to inhibit HCC cell proliferation and promote apoptosis, the effect of which was stronger than 5-fluorouracil (5-FU). More importantly, the anti-oncogenic effect of HZC and 5-FU was implicated with activation of the p38 MAPK pathway. In vivo experimental results showed that HZC inhibited tumor growth more effectively than 5-FU through the p38 MAPK pathway. These results provide evidence that HZC exerted anti-oncogenic and pro-apoptosis effects in HCC cells through activation of the p38 MAPK pathway.

Topics: Animals; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Hep G2 Cells; Humans; Hydrazines; Imidazoles; Liver Neoplasms; Male; MAP Kinase Signaling System; p38 Mitogen-Activated Protein Kinases; Pyridines; Rats; Toxicity Tests, Subacute; Xenograft Model Antitumor Assays

Using natural polysaccharides from Traditional Chinese Medicine as nanodrug delivery systems have considerable potential for tumor diagnostics and therapeutics.. On the basis of targeted therapy and combining the advantages of natural polysaccharides (angelica polysaccharide, APS) and natural Chinese medicine (curcumin, Cur) to design functionalized nanoparticles to improve the therapeutic through cell membrane encapsulation and immunotherapy.. Cur-loaded, glycyrrhetic acid (GA)-APS-disulfide bond (DTA)-Cur nanomicelle (GACS-Cur), which were prepared by the dialysis method. GACS-Cur was encapsulated with the membranes from red blood cells (RBCm) termed GACS-Cur@RBCm, which were prepared by the principle of extrusion using a miniature extruder. The developed formulations were subjected to various in vitro and in vivo evaluation tests.. The resulting APS nanocarriers supported a favorable drug-loading capacity, biocompatibility, and enhanced synergistic anti-hepatoma effects both in vitro and in vivo. After administration in mice, in vivo imaging results showed that the GACS-Cur and RBCm-coated groups had an obvious stronger tumor tissue targeting ability than the control treatment groups. Additionally, the immunomodulatory effect increased IL-12, TNF-α and IFN-γ expression and CD8+ T cell infiltration (1.9-fold) than that of the saline group. Notably, in comparison with hyaluronic acid (HA) nanocarriers, APS nanocarriers possess higher anti-hepatoma efficiency and targeting capabilities and, thus, should be further studied for a wide range of anti-cancer applications.. Our data demonstrated that APS nanocarriers encapsulated with erythrocyte membrane mighty be a promising clinical method in the development of efficacy, safety and targeting of liver cancer therapy.

Topics: Angelica; Animals; Antineoplastic Agents, Phytogenic; Biomimetics; Carcinoma, Hepatocellular; Curcumin; Drug Carriers; Drug Delivery Systems; Female; Hep G2 Cells; Humans; Immunologic Factors; Liver Neoplasms; Mice, Nude; Micelles; Nanoparticles; Polysaccharides; Tissue Distribution; Xenograft Model Antitumor Assays

More effective strategies are needed to improve the treatment of liver cancer. Sono-photodynamic therapy (SPDT) has a more obvious antitumor effect than sonodynamic therapy (SDT) or photodynamic therapy (PDT). We aimed to investigate Glypican-3-targeted, curcumin-loaded microbubbles (GPC3-CUR-MBs)-mediated SPDT in liver cancer cells in vitro and in vivo. GPC3-CUR-MBs were prepared by streptavidin-biotin interactions and the immune ligation method. The characterization and toxicity of GPC3-CUR-MBs and the anti-liver cancer effects of GPC3-CUR-MB-mediated SPDT in vitro and in vivo were studied. We synthetized GPC3-CUR-MBs and found that GPC3-CUR-MBs had no significant toxicity to HepG2 liver cancer cells. In terms of the anti-liver cancer effects in vitro and in vivo, when we used CUR, CUR-MBs or GPC3-CUR-MBs as the sono/photosensitizers, the outcome of SPDT was superior to that of SDT or PDT alone. The outcomes with GPC3-CUR-MBs were better than those with CUR or CUR-MBs in the SDT, PDT or SPDT groups. During the treatment period, the weight of the HepG2 tumor-bearing mice did not decrease significantly, and no significant evidence of lung, heart, liver, spleen and kidney damage was found with H&E staining. Our results indicated that the anti-liver tumor effect of SPDT was better than that of SDT and PDT and that GPC3-CUR-MBs were promising sono/photosensitizers.

Topics: Animals; Cell Line, Tumor; Curcumin; Glypicans; Liver Neoplasms; Mice; Microbubbles; Phospholipids; Photochemotherapy

Hepatocellular carcinoma (HCC) ranks near the top in the global list of malignancies causing cancer-related death. Recently, combination therapy has gained popularity in treating this cancer. We tried to investigate the efficacy of combined treatment with curcumin and anti-programmed cell death-1 (anti-PD-1) in HCC. Hep3B cells were treated with different concentrations of curcumin, followed by determination of Hep3B cell proliferation and programmed cell death ligand-1 (PD-L1) expression. Then, Hep3B cells were co-cultured with peripheral blood mononuclear cells (PBMCs), after which the Hep3B cell growth and immune activity were detected following treatment with curcumin and/or anti-PD-1. Besides, we investigated the effect of transforming growth factor beta 1 (TGF-β1) on lymphocyte activation and the interaction between E1A binding protein P300 (P300), histone acetylation, TGF-β1, and thrombin. Additionally, the synergistic role of curcumin and anti-PD-1 in mouse models of HCC was studied. Curcumin retarded Hep3B cell growth and reduced surface PD-L1 expression in Hep3B cells. After co-culture of Hep3B cells and PBMCs, curcumin had a synergistic effect with anti-PD-1 to slow Hep3B cell proliferation, activate lymphocytes, inhibit immune evasion, and down-regulate TGF-β1 expression. Functionally, curcumin inhibited thrombin to reduce P300-induced histone acetylation in the TGF-β1 promoter region, and anti-PD-1 suppressed binding of PD-1 and PD-L1 to promote immune activity; the combination of the two showed better in vitro anti-cancer effects. In vivo, curcumin combined with anti-PD-1 also lowered HCC growth rate and improved the tumor microenvironment. In conclusion, the combination of curcumin and anti-PD-1 is synergistically effective in the treatment of HCC treatment.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Drug Synergism; E1A-Associated p300 Protein; Female; Humans; Leukocytes, Mononuclear; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Programmed Cell Death 1 Receptor; Transforming Growth Factor beta1; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays

Curcumin can induce cancer cell apoptosis through lysosomal permeabilization pathway. However, the poor selectivity of curcumin restricts its use in the therapy of hepatocellular carcinoma. Because galactose group can recognize ASGPR overexpressed on hepatoma cells and morpholine group can target to the lysosome, they are integrated into a dual-targeted lipid material with low toxicity. The corresponding galactose-morpholine modified liposomes loaded with curcumin (Gal-Mor-LPs) were prepared and evaluated in comparison with conventional liposomes (LPs) and galactose modified liposomes (Gal-LPs). The in vitro and in vivo hepatic targeting capacity of liposomes followed a trend of LPs < Gal-LPs < Gal-Mor-LPs. The endocytosis of Gal-Mor-LPs was competitively inhibited by galactose, which confirmed the galactose modified liposomes entered hepatoma cells via ASGPR-mediated pathway. Gal-Mor-LPs displayed more excellent lysosomal targeting efficacy than LPs and Gal-LPs due to the attraction of acidic lysosome on basic morpholine group of Gal-Mor-LPs. The in vivo tumor inhibition effects of formulations also followed a trend of free curcumin < LPs < Gal-LPs < Gal-Mor-LPs, confirming that hepatic and lysosomal dual-targeting vehicle can improve the antitumor efficacy of curcumin. Moreover, the curcumin-loaded liposomes modified with galactose and morpholine moieties show good biocompatibility in vivo.

Topics: Carcinoma, Hepatocellular; Curcumin; Galactose; Humans; Liposomes; Liver Neoplasms; Lysosomes

(1E,4E)-1,5-bis(2-bromophenyl) penta-1,4-dien-3-one (GL63) is a curcumin analog that can protect against carcinogenesis in hepatocellular carcinoma (HCC). The aim of this study was to explore the molecular mechanism of GL63 in HCC.. Cell viability was examined by cell counting kit-8 (CCK-8) assay. Circular RNA zinc finger protein 83 (circZNF83), microRNA-324-5p (miR-324-5p), and cyclin-dependent kinase 16 (CDK16) levels were measured via the quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was assessed using colony formation assay. Flow cytometry was performed for detecting cell cycle and apoptosis. Protein analysis was conducted by western blot. Cell migration and invasion were determined using transwell assay. Target relation was analyzed using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The function of GL63 in vivo was researched by xenograft model in mice.. GL63 inhibited the circZNF83 expression in HCC cells. CircZNF83 overexpression attenuated the inhibitory effects of GL63 on HCC cell growth, cell cycle progression, migration, and invasion but the promoting effect on cell apoptosis. CircZNF83 served as a sponge of miR-324-5p and circZNF83/miR-324-5p axis was involved in the functional regulation of GL63 in HCC progression. Moreover, CDK16 was a downstream target of miR-324-5p and circZNF83 could regulate the CDK16 expression by sponging miR-324-5p. The anti-tumor function of GL63 was also related to the miR-324-5p/CDK16 axis. In addition, GL63 inactivated the JAK2/STAT3 pathway via downregulating circZNF83 to mediate the miR-324-5p/CDK16 axis. GL63 also repressed tumor growth in vivo through the circZNF83/miR-324-5p/CDK16-mediated JAK2/STAT3 signal inhibition.. This study suggested GL63 impeded the HCC development by blocking the JAK2/STAT3 signaling pathway via mediating the circZNF83/miR-324-5p/CDK16 axis.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Cyclin-Dependent Kinases; Liver Neoplasms; Mice; MicroRNAs; RNA, Circular; Signal Transduction; Zinc Fingers

Tumor angiogenesis has been proven to potentiate tumor growth and metastasis; therefore, the strategies targeting tumor-related angiogenesis have great potentials in antitumor therapy.. Here, the GA&Gal dual-ligand-modified liposomes co-loaded with curcumin and combretastatin A-4 phosphate (CUCA/GA&Gal-Lip) were prepared and characterized. A novel "BEL-7402+HUVEC" co-cultured cell model was established to mimic tumor microenvironment. The cytotoxicity and migration assays were performed against the novel co-cultured model. Angiogenesis ability was evaluated by tube formation test, and in vivo metastatic ability was evaluated by lung metastasis test.. The result demonstrated that dual-ligand-modified liposomes showed greater inhibition of tumor angiogenesis and metastasis in comparison with other combined groups. Significantly, the mechanism analysis revealed that curcumin and combretastatin A-4 phosphate could inhibit tumor angiogenesis and metastasis via down-regulation of VEGF and VEGFR2 expression, respectively, and that GA&Gal-Lip could improve antitumor effect by GA/Gal-mediated active-targeting delivery.. CUCA/GA&Gal-Lip hold great potentials in hepatoma-targeting delivery of antitumor drugs and can achieve anti-angiogenic and anti-metastatic effects by simultaneously blocking VEGF/VEGFR2 signal pathway, therefore exhibiting superior anti-hepatoma efficacy.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Drug Liberation; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Ligands; Liposomes; Liver Neoplasms; Lung Neoplasms; Mice, Inbred BALB C; Neovascularization, Pathologic; Stilbenes; Xenograft Model Antitumor Assays

Topics: Apoptosis; Biological Availability; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Curcumin; Fluorouracil; Gastrointestinal Microbiome; Humans; Liver Neoplasms; Phosphatidylinositol 3-Kinases

The effects of two-drug combination, all-trans retinoic acid (ATRA) and bisdemethoxycurcumin (BDMC), on apoptosis induction of liver cancer cells were investigated in human liver Hep 3B cells. Two-drug combination caused a more effective decrease in cell viability and in induction of S phase arrest, DNA damage, and cell apoptosis than that of ATRA or BDMC only. Also, the two-drug combination caused more cells to undergo significantly increased ROS productions when compared to that of ATRA or BDMC only. Results of Western blotting demonstrated that two-drug combination increased expressions of Fas, pro-apoptotic proteins, and active form of caspase-3 and -9, but decreased that of anti-apoptotic proteins and XIAP than that of ATRA or BDMC only in Hep 3B cells. In conclusion, ATRA combined with BDMC enhance cell apoptosis and associated protein expression in Hep 3B cells. PRACTICAL APPLICATIONS: Bisdemethoxycurcumin (BDMC) derived from natural plants, turmeric (Curcuma longa), which had been used for Asia food for thousands of years. All-trans retinoid acid (ATRA) is currently used as a primary treatment for patients with acute promyelocytic leukemia. In previous study, ATRA and BDMC were reported to have anti-inflammatory and anticancer effects. Our results showed that treatment of ATRA combined with BDMC showed more effectively apoptosis than that of ATRA or BDMC only in Hep 3B cells. The findings also provided possible pathways concerning the induction of liver cancer cell apoptosis. We conclude that ATRA combined with BDMC may be potent anticancer agents or adjuvants for liver cancer therapy in the future.

Topics: Apoptosis; Cell Line, Tumor; Curcumin; Diarylheptanoids; Humans; Liver Neoplasms; Tretinoin

Curcumin is a lipophilic anti-cancer compound extracted from turmeric. Our previous study demonstrated that the curcumin-loaded nanostructured lipid carrier (Cur-NLC) exhibits superior anti-cancer activity in inhibiting proliferation as well as inducing apoptosis of human HepG2 cells compared to native curcumin. This study aims to unveil the mechanisms underlying the pro-apoptotic effect of Cur-NLC on HepG2 cells. Evidence indicates that low expression of death receptors (DRs) on cancer cell membranes leads to attenuated apoptosis signaling. This study showed that Cur-NLC significantly increased total expression of DR5 protein while simultaneously upregulated cell membrane expression of DR5. Cur-NLC significantly increased caspase-8 and caspase-3 activities, accompanied by increased apoptosis. Furthermore, enhanced apoptosis was inhibited in the presence of a pan-caspase inhibitor, Z-VAD-FMK. Therefore, Cur-NLC induced activation of the extrinsic apoptosis pathway via modulating the DR5/caspase-8/-3 mediated apoptosis pathway in HepG2 cells, suggesting that Cur-NLC is a promising therapeutic agent or supplement for the treatment of hepatocellular carcinoma.

Topics: Apoptosis; Carcinoma, Hepatocellular; Caspases; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Drug Carriers; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Lipids; Liver Neoplasms; Nanostructures; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction

Hepatocellular carcinoma (HCC) is a leading cancer worldwide. In the present investigation, sorafenib (SFN) and curcumin (CCM) were co-delivered using pH-sensitive lactosylated nanoparticles (LAC-NPs) for targeted HCC treatment.. pH-responsive lactosylated materials were synthesized. SFN and CCM co-delivered, pH-responsive lactosylated nanoparticles (LAC-SFN/CCM-NPs) were self-assembled by using the nanoprecipitation technique. The nanoparticles were characterized in terms of particle size, charge and drug release profile. The anti-cancer effects of the nanoparticles were evaluated in human hepatic carcinoma cells (HepG2) cells and HCC tumor xenograft models.. In summary, LAC-SFN/CCM-NPs was proved to be a promising system for targeted HCC therapy.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line; Cell Proliferation; Curcumin; Drug Delivery Systems; Drug Screening Assays, Antitumor; Drug Tolerance; Hep G2 Cells; Humans; Injections, Intravenous; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Particle Size; Sorafenib; Surface Properties

Curcumin has been demonstrated to affect the chemoresistance in cancer cells of various origins. However, its ability to modulate lactate-induced chemoresistance remains unclear. The Present investigation demonstrates that curcumin inhibits the survival of HepG2 and HuT78 cells and can modulate chemo-susceptibility of HepG2 cells. Experimental simulation of simultaneous and pre-treatment suggest cooperatively between curcumin and anticancer drugs as well as the modulation of molecular regulators. Inhibition of glucose consumption, lactate production, extracellular acidity and augmented level of Nitric oxide were observed. DAPI staining revealed hyper condensation of chromatin in curcumin-treated HepG2 cells. Curcumin also diminished the lactate-induced chemoresistance against doxorubicin in hepatic cancer cells along with down regulation of lactate receptor (hydroxycarboxylic acid receptor-1; HCAR-1/GPR81). Alteration of the extracellular milieu along with inhibited expression of genes (hif-1α, ldh-a, mct-1, mdr-1 and stat-3) and proteins (HIF-1α and HCAR-1) are indicated to be involved in curcumin-induced reversal of chemoresistance in HepG2 cells. Findings of present investigation contribute to knowledge of curcumin mediated chemosensitization and its mechanism.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Survival; Chromatin; Cisplatin; Curcumin; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; Glucose; Hep G2 Cells; Hepatocytes; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lactate Dehydrogenase 5; Lactic Acid; Liver Neoplasms; Monocarboxylic Acid Transporters; Nitric Oxide; Rats; Receptors, G-Protein-Coupled; STAT3 Transcription Factor; Symporters

A multistep process with an accumulation of epigenetic alterations of tumor suppressor genes (TSGs) can induce cancer. Abnormal regional hypermethylation and histone deacetylation of several TSGs has been observed in hepatocellular carcinoma (HCC). Acetylation and deacetylation of histone are carried out by histone acetyltransferase (HAT) and histone deacetylase (HDAC) respectively. Besides, DNA methylation is carried out by DNA methyltransferases (DNMTs). Previously, we evaluated the effect of DNA demethylating agents and histone deacetylase inhibitors on HCC and colon cancer. This study aimed to evaluate the effect of curcumin (CUR) in comparison with trichostatin A (TSA) on estrogen receptor alpha (ERα) reactivation, apoptotic induction, and cell growth inhibition in HCC.. the cells were cultured and treated with various concentrations of CUR and TSA and the MTT assay, flow cytometry assay and Real-Time RT-PCR were achieved to determine cell viability, cell apoptosis, and ERα gene expression respectively.. CUR indicated dose and time-dependent antiproliferative effects (P < 0.035). A similar antiproliferative effect was observed by TSA (P < 0.001). Both compounds indicated significant apoptotic effects in all different periods (P < 0.001), CUR indicated a more significant apoptotic effect than TSA (P < 0.001). The ERα gene expression quantity was increased significantly by treatment with CUR and TSA (P <0.012).. CUR and TSA play important roles in restoring the ERα resulting in cell growth inhibition and apoptosis induction. Therefore, ERα may be a potential target for therapeutic intervention in the treatment of HCC.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Estrogen Receptor alpha; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Liver Neoplasms; Tumor Cells, Cultured

Current direct-acting antiviral agents for treatment of hepatitis C virus genotype 4a (HCV-4a) have been reported to cause adverse effects, and therefore less toxic antivirals are needed. This study investigated the role of curcumin chitosan (CuCs) nanocomposite as a potential anti-HCV-4a agent in human hepatoma cells Huh7.. Docking of curcumin and CuCs nanocomposite and binding energy calculations were carried out. Chitosan nanoparticles (CsNPs) and CuCs nanocomposite were prepared with an ionic gelation method and characterized with TEM, zeta size and potential, and HPLC to calculate encapsulation efficiency. Cytotoxicity studies were performed on Huh7 cells using MTT assay and confirmed with cellular and molecular assays. Anti-HCV-4a activity was determined using real-time PCR and Western blot.. The strength of binding interactions between protein ligand complexes gave scores with NS3 protease, NS5A polymerase, and NS5B polymerase of -124.91, -159.02, and -129.16, for curcumin respectively, and -68.51, -54.52, and -157.63 for CuCs nanocomposite, respectively. CuCs nanocomposite was prepared at sizes 29-39.5 nm and charges of 33 mV. HPLC detected 4% of curcumin encapsulated into CsNPs. IC50 was 8 µg/mL for curcumin and 25 µg/mL for the nanocomposite on Huh7 but was 25.8 µg/mL and 34 µg/mL on WISH cells. CsNPs had no cytotoxic effect on tested cell lines. Apoptotic genes' expression revealed the caspase-dependent pathway mechanism. CsNPs and CuCs nanocomposite demonstrated 100% inhibition of viral entry and replication, which was confirmed with HCV core protein expression.. CuCs nanocomposite inhibited HCV-4a entry and replication compared to curcumin alone, suggesting its potential role as an effective therapeutic agent.

Topics: Antiviral Agents; Cell Line; Chitosan; Curcumin; Genotype; Hepacivirus; Humans; Liver Neoplasms; Nanoparticles; Viral Core Proteins; Viral Nonstructural Proteins; Virus Internalization; Virus Replication

PTEN exerts tumor suppressor role through inhibiting PI3K/AKT signaling. DJ-1 plays an oncogenic role through negatively regulation of PTEN expression. Curcumin (Cur) is a phenolic compound extracted from a variety of plant roots, with multiple anti-tumor pharmacological effects. This study aims to investigate whether Cur plays a role in the regulation of DJ-1-PENT/PI3K/AKT signaling as well as the proliferation and apoptosis of hepatocellular carcinoma cells. Normal human hepatocyte HL-7702 and hepatocellular carcinoma cell lines SMMC-7721 and HepG2 were cultured followed by analysis of the expression of DJ-1 and PTEN. SMMC-7721 and HepG2 cells were treated with different concentrations of Cur (0, 5, 10 μM) followed by measuring cell proliferation by CCK-8, caspase-3 activity as well as DJ-1 expression by western blot. In addition, SMMC-7721 or HepG2 cells were divided into two groups: Cur+pcDNA3.1-Blank and Cur+pcDNA3.1-DJ-1 for analysis of the expression of DJ-1, PTEN and p-AKT, cell apoptosis and proliferation. Compared with HL-7702, SMMC-7721 and HepG2 cells displayed significantly higher DJ-1 expression and lower PTEN expression. Cur treatment significantly inhibited proliferation of SMMC-7721 and HepG2 cells, increased caspase-3 activity and downregulated DJ-1 expression. Transfection of pcDNA3.1-DJ-1 significantly increased DJ-1 and p-AKT expression, promoted cell proliferation, but decreased PTEN expression and cell apoptosis. In conclusion, Cur inhibits proliferation of hepatocellular carcinoma cells and PTEN/PI3K/AKT signaling pathway via the reduction of DJ-1 expression, which provides new insights to the anticancer effects of curcumin in hepatocellular carcinoma.

Topics: Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Phosphatidylinositol 3-Kinases; Protein Deglycase DJ-1; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction

Sono-photodynamic therapy (SPDT) activates the same photo-/sonosensitizer and exerts more marked antitumor effects than sonodynamic therapy or photodynamic therapy. We aimed to explore the utilization of curcumin (CUR)-loaded poly(L-lactide-co-glycolide) microbubble (MB)-mediated SPDT (CUR-PLGA-MB-SPDT) in HepG2 liver cancer cells. The cytotoxicity and intracellular accumulation of CUR were determined. We used 40 µM CUR as the photo-/sonosensitizer for 3 h. In a comparison of CUR-SDT or CUR-PDT, HepG2 cell viability decreased and apoptotic rate increased in CUR-SPDT. The CUR-PLGA MBs had round spheres with smooth surfaces and an average size of 3.7 µm. In CUR-PLGA MBs, drug entrapment efficiency and drug-loading capacity were 74.29 ± 2.60% and 17.14 ± 0.60%, respectively. CUR-loaded PLGA MBs (CUR-PLGA MBs) had good biocompatibility with normal L02 cells and were almost non-cytotoxic to HepG2 cells. Among CUR-SDT, CUR-PDT, CUR-SPDT or CUR-PLGA-MB-SDT, the cell CUR-PLGA-MB-SPDT had the lowest viability. Transmission electron microscopy revealed pyroptosis and apoptosis in the CUR-PLGA-MB-SPDT group; the potential mechanism was related to the mitochondrial membrane potential loss and increased production of intracellular reactive oxygen species. These findings suggested that CUR-PLGA-MB-SPDT may be a promising treatment for liver cancer.

Topics: Antineoplastic Agents; Curcumin; Drug Delivery Systems; Hep G2 Cells; Humans; Liver Neoplasms; Microbubbles; Microscopy, Confocal; Photochemotherapy; Polylactic Acid-Polyglycolic Acid Copolymer; Spectrometry, Fluorescence; Ultrasonic Therapy

Hydrazinocurcumin (HZC), a curcumin analogue, serves as a tumor suppressor in breast cancer and lung cancer. In this study, we investigate the role and mechanism of HZC in regulating HepG2 cell apoptosis and tumorigenicity, and its synergistic effects with 5-fluorouracil (5-Fu). HepG2 cells were treated with HZC and/or 5-Fu to analyze the possible synergistic effects on cell proliferation, apoptosis and cell cycle distribution in vitro using EdU staining, Hoechst staining and flow cytometry, respectively. For mechanistic investigation we used pic, a phosphatase and tensin homolog (PTEN) inhibitor, and in other studies assessed the expression pattern of PTEN and PI3K/Akt signaling pathway-related genes. Additionally, we tested in vivo effects of HZC and 5-Fu treatment on growth of HepG2 cell tumors in nude mice. We found that HZC or 5-Fu induced apoptosis and repressed proliferation of HepG2 cells by upregulating the expression of PTEN and disrupting the PI3K/Akt signaling pathway activation. Moreover, HZC had a higher pro-apoptotic effect than 5-Fu. HZC and 5-Fu induced HepG2 cell apoptosis and inhibited their tumorigenicity in vivo. Inhibition of PTEN expression activated the PI3K/Akt signaling pathway and reversed the protective effects of HZC or 5-Fu. Thus, HZC and 5-Fu increase PTEN, which blocks the PI3K/Akt signaling pathway, ultimately inducing HepG2 cell apoptosis. Importantly, the synergistic combination of HZC and 5-Fu may present promising strategy for the treatment of HCC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Drug Synergism; Fluorouracil; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Hydrazines; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Curcumin, the main active ingredient of turmeric, is widely used as a kind of food additive and also displays a range of pharmacological activities, such as anti-inflammation, anti-tumor, liver and kidney protection, and so forth. Sorafenib was the first targeted agent against hepatocellular carcinoma (HCC), whose intolerance is related to the promotion of lipid synthesis and epithelial-to-mesenchymal transition (EMT) formation. In this study, biochemical analysis, immune cells composition, the tumor microenvironment, metabolomics, and relative metabolic enzymes and transporters were detected in H22-bearing mice treated with curcumin combined with sorafenib vs. control groups. It was found that curcumin protected against liver cancer progression through reducing the level of alpha fetoprotein in liver tissues, increasing the number of immune cells, like NK cells, inhibiting EMT via the regulation of IL-6/JAK/STAT3 and IL-1β/NF-κB pathways, suppressing anaerobic glycolysis through the inhibition of LDH and HIF-1α, and decreasing the lipid synthesis via the downregulation of FASN, and upregulated the serum HDL-C and mRNA levels of apoA1 in the sorafenib-treated mice. Furthermore, curcumin regulation of the disorder of glycolipid metabolism and EMT was also based on the PI3K/AKT pathway. A docking study was performed and proved the strong affinity between curcumin and the proteins of STAT3, FASN, and AKT. All in all, this experiment provided evidence for the addition of curcumin in the diet to enhance the antitumor efficacy of sorafenib through activating immune function, downregulating EMT, and reversing disorders of the metabolism.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Disease Models, Animal; Drug Synergism; Functional Food; Liver Neoplasms; Mice; Mice, Inbred Strains; Sorafenib; Tumor Microenvironment

Curcumin is a more efficient polyphenol than many chemotherapeutics. It can inhibit many signaling pathways at the same time resulting in modulation and down regulation for many oncogenic activities, tumor suppressor genes, several transcription factors and their signaling pathways. However it is still not employed as a potential therapeutic tool for cancer treatment. This is due to its hydrophobicity, its hypersensitivity and its poor adsorption. Many trials have been applied for encapsulating curcumin as a delivery system thinking to save its biological benefits. In our recent work, encapsulated curcumin was successfully used to produce bio cross-linkers for mucoadhesive polymer forming multi branched or flower like shape. Moreover, this strategy is not used only to save its biological function, but also to provide a novel bio cross-linker for hydrogel system. This study was investigated by using scanning electron microscopy, FTIR, U-V Visible Spectroscopy. Encapsulated curcumin provides promising bio safe cross-linker for optimizing hydrogel system, since carboxymethyl cellulose raises its ability to penetrate mucus layer. Additionally, flow cytometry and cytotoxicity show ability of encapsulated curcumin to inhibit proliferation of liver cancer cells.

Topics: Carboxymethylcellulose Sodium; Curcumin; Drug Carriers; Humans; Liver Neoplasms; Nanoparticles

Mitochondrial malfunction plays a crucial role in cancer development and progression. Cancer cells show a substantially higher mitochondrial activity and greater mitochondrial transmembrane potential than normal cells. This concept can be exploited for targeting cytotoxic drugs to the mitochondria of cancer cells using mitochondrial-targeting compounds. In this study, a polyamidoamine dendrimer-based mitochondrial delivery system was prepared for curcumin using triphenylphosphonium ligands to improve the anticancer efficacy of the drug in vitro and in vivo. For the in vitro evaluations, various methods, such as viability assay, confocal microscopy, flow cytometry, reactive oxygen species (ROS), and real-time polymerase chain reaction analyses, were applied. Our findings showed that the targeted-dendrimeric curcumin (TDC) could successfully deliver and colocalize the drug to the mitochondria of the cancer cells, and selectively induce a potent apoptosis and cell cycle arrest at G2/M. Moreover, at a low curcumin dose of less than 25 μM, TDC significantly reduced adenosine triphosphate and glutathione, and increased the ROS level of the isolated rat hepatocyte mitochondria. The in vivo studies on the Hepa1-6 tumor-bearing mice also indicated a significant tumor suppression effect and the highest median survival days (Kaplan-Meier survival estimation and log-rank test) after treatment with the TDC construct compared to the free curcumin and untargeted construct. Besides its targeted nature and safety, the expected improved solubility and stability represent the prepared targeted-dendrimeric construct as an up-and-coming candidate for cancer treatment. The results of this study emphasize the promising route of mitochondrial targeting as a practical approach for cancer therapy, which can be achieved by optimizing the delivery method.

Topics: Animals; Carcinoma, Hepatocellular; Cell Fractionation; Cell Line, Tumor; Curcumin; Dendrimers; Drug Carriers; Drug Stability; Hepatocytes; Humans; Liver Neoplasms; Male; Membrane Potential, Mitochondrial; Mice; Mitochondria; Polyamines; Primary Cell Culture; Rats; Solubility; Xenograft Model Antitumor Assays

Zinc(II) complexes of curcumin display moderate cytotoxicity towards cancer cells at low micromolar concentrations. However, the clinical use of zinc(II) complexes is hampered by hydrolytic insolubility and poor bioavailability and their anticancer mechanisms remain unclear. Here, we investigated the efficacy and mechanism of action of a polyvinylpyrrolidone (PVP-k30)-based solid dispersion of Zn(II)-curcumin (ZnCM-SD) against hepatocellular carcinoma (HCC) in vitro and in vivo. In vitro assays revealed ZnCM-SD not only reduced the viability of HepG2 cells and SK-HEP1 cells in a dose-dependent manner, but also potently and synergistically enhanced cell growth inhibition and cell death in response to doxorubicin by regulating cellular zinc homeostasis. ZnCM-SD was internalized into the cells via non-specific endocytosis and degraded to release curcumin and Zn

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Curcumin; Doxorubicin; Drug Synergism; Fecal Microbiota Transplantation; Female; Gastrointestinal Microbiome; Homeostasis; Humans; Ileum; Liver; Liver Neoplasms; Male; Mice, Inbred BALB C; Rats, Sprague-Dawley; RNA, Ribosomal, 16S; Zinc

Liver cancer is a major health problem facing mankind. Currently, the focus of research is to improve the treatment of liver cancer using a variety of treatment options such as providing chemotherapy drugs through nanocarriers.. The aim of this study was to prepare a curcumin-loaded (PLGA/TPGS) NPs delivery system by the emulsification-solvent evaporation method in order to achieve synergistic antitumor activity against liver cancer.. Curcumin-loaded (PLGA/TPGS) NPs were prepared by the emulsification and solvent evaporation method. The physical and chemical characteristics of NPs such as size, morphology, and release profiles were discussed. In vitro and in vivo studies were carried out to evaluate its anti-tumor activity in target cells.. Curcumin-loaded (PLGA/TPGS) NPs could be successfully internalized by HepG2 cells and play a synergistic role in inhibiting the growth of hepatocellular carcinoma cells. They exhibited high target organ accumulation, superior antitumor efficiency, and lower toxicity in vivo.. The present study indicates that the curcumin-loaded (PLGA/TPGS) NPs provide a promising platform for the treatment of liver cancer.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Compounding; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred Strains; Molecular Structure; Polylactic Acid-Polyglycolic Acid Copolymer; Structure-Activity Relationship; Vitamin E

Curcumin has been used as a traditional medicine and/or functional food in several cultures because of its health benefits including anticancer properties. However, poor oral bioavailability of curcumin has limited its oral usage as a food supplement and medical food. Here we formulated curcumin pellets using a solid dispersion technique. The pellets had the advantages of reduced particle size, improved water solubility, and particle porosity. This pellet form led to an improvement in curcumin's oral bioavailability. Additionally, we used the C-Map and Library of Integrated Network-Based Cellular Signatures (LINCS) Unified Environment (CLUE) gene expression database to determine the potential biological functions of formulated curcumin. The results indicated that, similar to conventional curcumin, the formulated curcumin acted as an NF-κB pathway inhibitor. Moreover, ConsensusPathDB database analysis was used to predict possible targets and it revealed that both forms of curcumin exhibit similar biological functions, including apoptosis. Biochemical characterization revealed that both the forms indeed induced apoptosis of hepatocellular carcinoma (HCC) cell lines. We concluded that the formulated curcumin increases the oral bioavailability in animals, and, as expected, retains characteristics similar to conventional curcumin at the cellular level. Our screening platform using big data not only confirms that both the forms of curcumin have similar mechanisms but also predicts the novel mechanism of the formulated curcumin.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Aurora Kinase A; Biological Availability; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Delivery Systems; Humans; Liver Neoplasms; Male; Rats; Rats, Sprague-Dawley; Sorafenib

The aim of this study is to investigate the role of glypican-3(GPC3)/wnt/β-catenin signaling pathway and autophagy in the regulation of hepatocellular carcinoma (HCC) growth mediated by curcumin.. HepG2 cells were treated with various concentrations of curcumin and/or GPC3-targeting siRNA in the presence or absence of 3-MA. Cell proliferation and apoptosis were determined by MTT and TUNEL assay, respectively. Expression of GPC3, β-catenin, c-myc, LC3, and Beclin1 was determined by western blotting. In addition, curcumin was tested in tumor xenografts mice model, Caliper IVIS Lumina II was used to monitor the tumor growth, and GPC3/wnt/β-catenin signaling proteins were determined by western blotting.. Curcumin treatment led to proliferation inhibition and apoptosis induction in HepG2 cells in a concentration-dependent manner, and suppressed HCC tumor growth in vivo. Further analysis showed that curcumin treatment inactivated Wnt/β-catenin signaling and decreased GPC3 expression, silencing of GPC3 expression promoted the effects of curcumin on Wnt/β-catenin signaling. In addition, inhibiting autophagy by 3-MA relieved curcumin-dependent down-regulation of GPC3.. Curcumin suppressed HCC tumor growth through down-regulating GPC3/wnt/β-catenin signaling pathway, which was partially mediated by activation of autophagy.

Topics: Animals; Apoptosis; beta Catenin; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Down-Regulation; Gene Expression Regulation, Neoplastic; Glypicans; Hep G2 Cells; Humans; Liver Neoplasms; Mice; Mice, Nude; Real-Time Polymerase Chain Reaction; Wnt3 Protein

Chemotherapy has been the standard for cancer therapy, but the nonspecific cytotoxicity of chemotherapeutic agents and drug resistance of tumor cells has limited its efficacy. However, multidrug combination therapy and targeting therapy have resulted in enhanced anticancer effects and have become increasingly important strategies in clinical applications. In this study, a biotin-/lactobionic acid-modified poly(ethylene glycol)-poly(lactic-co-glycolic acid)-poly(ethylene glycol) (BLPP) copolymer was synthesized, and curcumin- and 5-fluorouracil-loaded nanoparticles (BLPPNPs/C + F) were prepared to enhance the treatment of hepatocellular carcinoma. Blank BLPPNPs were shown to have great biocompatibility via both in vitro and in vivo studies. Good targeting of tumor cells of BLPPNPs was confirmed by flow cytometry, fluorescence microscopy, and biodistribution. The synergistic anticancer effects of BLPPNPs/C + F were demonstrated by cytotoxicity and animal studies, while western blotting was used to further verify the synergistic effect of curcumin and 5-fluorouracil. The dual-targeting and drug-loaded codelivery nanosystem demonstrated higher cellular uptake and stronger cytotoxicity for tumor cells. Therefore, these dual-targeting NPs are a promising codelivery carrier that could be made available for cellular targeting of anticancer drugs to achieve better intracellular delivery and synergistic anticancer efficacy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biotin; Carcinoma, Hepatocellular; Curcumin; Disaccharides; Drug Carriers; Drug Liberation; Drug Synergism; Fluorouracil; Hep G2 Cells; Humans; Liver Neoplasms; Mice; Nanoparticles; Polyethylene Glycols; Polyglactin 910; Tissue Distribution; Xenograft Model Antitumor Assays

Hypoxia may affect the therapeutic efficacy of transcatheter arterial embolization (TAE), which is widely used in nonsurgical hepatocellular carcinoma (HCC). Liposomal curcumin can exert anticancer effect. Our purpose is to explore the antitumor effect of liposomal curcumin on the HCC after TAE.. The HepG2 cells were cultured under hypoxic condition (1% O. By regulating the apoptosis-related molecules, curcumin liposome obviously inhibited the cell viability and promoted the apoptosis in G1 phase. Curcumin liposome reduced the tumor size and alleviated neoplasia in VX2 rabbits. Curcumin liposome decreased the expressions of MVD and VEGF and increased the apoptosis of liver tissues. The levels of hypoxia-inducible factor-1α (HIF-1α) and survivin were suppressed by curcumin liposome both in hypoxic cells and liver tissues in the VX2 rabbits.. Curcumin liposome exerted antitumor effect by regulating the proliferation- and apoptosis-related molecules. Curcumin liposome suppressed the HIF-1α and survivin levels and inhibited the angiogenesis in VX2 rabbits after TAE.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Hypoxia; Cell Proliferation; Combined Modality Therapy; Curcumin; Disease Models, Animal; Embolization, Therapeutic; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liposomes; Liver Neoplasms; Rabbits; Survivin

Microenvironment plays a vital role in tumor progression; we focused on elucidating the role of hepatic stellate cells (HSCs) in hepatocarcinoma (HCC) aggressiveness and investigated the potential protective effect of curcumin on HSC-driven hepatocarcinoma angiogenesis and invasion. Our data suggest that HSCs increase HCC reactive oxygen species (ROS) production to upregulate hypoxia-inducible factor-1

Topics: Carcinoma, Hepatocellular; Chemokine CXCL12; Connective Tissue Growth Factor; Curcumin; Down-Regulation; Epithelial-Mesenchymal Transition; Glutathione; Hep G2 Cells; Hepatic Stellate Cells; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-6; Liver Neoplasms; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neovascularization, Pathologic; NF-E2-Related Factor 2; Vascular Endothelial Growth Factor A

Primary gastric cancer (PGC) is the fourth most common malignant human cancer and the second leading cause of death worldwide. The majority of the subjects of PGC is diagnosed at a late stage, resulting in poor prognosis and therapeutic outcome, largely attributable to dissemination of tumor cells into circulation as circulating tumor cells (CTCs) and their formation of distal tumor. Curcumin is an active ingredient from the rhizome of the plant Curcuma longa. Here, we assessed whether treatment with Curcumin may reduce the incidence of metastatic tumor formation in liver in mice carrying PGC. We found that Curcumin treatment significantly reduced the presence of CTCs and formation of liver tumor. Mechanistically, Curcumin reduced CXCR4 expression in PGCs in vitro and in vivo, and thus likely inhibited metastasis of PGC through suppression of stromal cell -derived factor-1/CXCR4 signaling. Thus, our study suggests that Curcumin may inhibit liver metastasis of PGC through reducing CTCs.

Topics: Animals; Antineoplastic Agents; Curcumin; Gene Expression Regulation, Neoplastic; Liver Neoplasms; Mice; Mice, Inbred NOD; Mice, Transgenic; Neoplastic Cells, Circulating; Receptors, CXCR4; Stomach Neoplasms

Dysregulation of cellular energy metabolism is closely linked to cancer development and progression. Calorie or glucose restriction (CR or GR) inhibits energy-dependent pathways, including IGF-1/PI3K/Akt/mTOR, in cancer cells. However, alterations in proton dynamics and reversal of the pH gradient across the cell membrane, which results in intracellular alkalinization and extracellular acidification in cancer tissues, have emerged as important etiopathogenic factors. We measured glucose, lactate, and ATP production after GR, plant-derived CR-mimetic curcumin treatment, and curcumin plus GR in human hepatoma cells. Intracellular pH regulatory effects, in particular, protein-protein interactions within mTOR complex-1 and its structural change, were investigated. Curcumin treatment or GR mildly inhibited Na+/H+ exchanger-1 (NHE1). vATPase, monocarboxylate transporter (MCT)-1, and MCT4 level. Combination treatment with curcumin and GR further enhanced the inhibitory effects on these transporters and proton-extruding enzymes, with intracellular pH reduction. ATP and lactate production decreased according to pH change. Modeling of mTOR protein revealed structural changes upon treatments, and curcumin plus GR decreased binding of Raptor and GβL to mTOR, as well as of Rag A and Rag B to Raptor. Consequently, 4EBP1 phosphorylation was decreased and cell migration and proliferation were inhibited in a pH-dependent manner. Autophagy was increased by curcumin plus GR. In conclusion, curcumin treatment combined with GR may be a useful supportive approach for preventing intracellular alkalinization and cancer progression.

Topics: Alkalies; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line; Cell Proliferation; Curcumin; Glucose; Hep G2 Cells; Humans; Liver Neoplasms; Monocarboxylic Acid Transporters; Regulatory-Associated Protein of mTOR; Vacuolar Proton-Translocating ATPases

Hepatocellular carcinoma (HCC) is a common cancer type throughout the world. Due to the high occurrence rate and mortality, liver cancer is one of the leading causes of cancer associated death. With the development of monoclonal antibodies and immunotherapy, the mortality of HCC cancer patients has reduced. However, the recurrence and outcomes of patients remain poor. Therefore, there is an urgent need to develop more effective drugs for HCC therapy. WZ35, a novel curcumin derivative, exhibits potential anti-tumor activity in gastric cancer cells by regulating ROS dependent JNK activation and ER stress. Here, we evaluated the tumor suppressive activity of WZ35 in hepatocellular carcinoma in vitro and in vivo. CCK-8 was used to detect cell viability with or without curcumin or WZ35; cell apoptosis was determined by flow cytometry analysis; GFP-LC3 plasmids were used to investigate the level of autophagy-associated LC3; siRNA transfection was applied to silence endogenous YAP; and western blot was performed to detect the alteration of indicated molecules. Bioinformatics analysis and IHC assay were applied to evaluate the YAP level in normal and liver cancer tissues. In this study, we found that WZ35 effectively suppresses HCC cancer cell growth in vitro and in vivo by promoting cell apoptosis. Importantly, downregulation of YAP contributes to WZ35 caused autophagy inhibition which is different from that of curcumin. We also confirmed that WZ35 is more effective at suppressing HCC cell growth in vivo. Finally, we confirmed that YAP was significantly overexpressed in liver cancer tissues. Collectively, these data indicate that WZ35 could be considered as a promising compound for HCC therapy.

Topics: Adaptor Proteins, Signal Transducing; Animals; Autophagy; Carcinoma, Hepatocellular; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Reactive Oxygen Species; YAP-Signaling Proteins

Curcumin, a natural polyphenol extracted from a perennial herb

Topics: Antineoplastic Agents; Antioxidants; Carcinoma, Hepatocellular; Cell Death; Curcumin; HeLa Cells; Hep G2 Cells; HT29 Cells; Humans; Liver Neoplasms; MCF-7 Cells; Nanoparticles; Silicon Dioxide

The combination of traditional Chinese medicines can improve the efficacy of cancer treatment. Furthermore, the combination of the traditional Chinese medicine curcuma zedoary and kelp was used to enhance the effect of the dissipation of blood stasis in pediatrics during the Song Dynasty. Curcumenol and laminarin, the main components of curcuma zedoary and kelp, are also reported to have a wide range of biological activities. Therefore, we hypothesize that the combination of curcuma zedoary and kelp may prevent the development of cancer. The aim of this research was to confirm whether a combination of curcuma zedoary and kelp could inhibit the proliferation and metastasis of hepatoma cells and consequently improve prognosis. In this study, we firstly found in H22-bearing mice that the combination of curcuma zedoary and kelp inhibited tumor growth and the expression of metastasis-related proteins (MMPs, VEGF, pAkt, pERK1/2). Meanwhile, the decreased cystathionine beta synthase (CBS, an endogenous hydrogen sulfide (H2S) synthetase) level was also observed in H22-bearing mice admistrated with the combination of curcuma zedoary and kelp. It was also observed that the combination of curcumenol and laminarin inhibited the proliferation, migration and invasion in human hepatoma HepG2 cells. Furthermore, we investigated the potential inhibiting mechanism of the combination of curcumenol and laminarin on HepG2 cell proliferation and metastasis. Our previous research showed that a CBS/H2S system was vital for maintaining the proliferation in hepatoma cells. Here, we found that the levels of pSTAT3 and BCL-2 were decreased in CBS knockdown HepG2 cells and the combination of curcumenol and laminarin significantly decreased the H2S level in a dose-dependent manner and down-regulated the levels of pSTAT3 and BCL-2 in HepG2 cells. Angiogenesis, positively regulated by the vascular endothelial growth factor (VEGF), is essential for human cancer metastasis. In the present study, we found that the combination of curcumenol and laminarin could significantly down-regulate the expression levels of VEGF and its downstream key genes pAkt and pERK1/2. Furthermore, previous research showed that hydrogen sulfide could stimulate angiogenesis. Here, we also observed the reduction of the VEGF, Akt, pAkt, ERK1/2 and pERK1/2 proteins levels and the inhibition of proliferation and metastasis in CBS knockdown HepG2 cells. Moreover, exogenous H2S rescued the cytological results caused by

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcuma; Drugs, Chinese Herbal; Female; Humans; Hydrogen Sulfide; Kelp; Liver Neoplasms; Male; Mice; Neoplasm Metastasis; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; STAT3 Transcription Factor; Vascular Endothelial Growth Factor A

The aim of the present study was to investigate the vascular normalization effect of traditional Chinese medicine Astragalus membranaceus (AM) and Curcuma wenyujin (CW) on tumor-derived endothelial cells (TECs).. TECs were isolated from the xenografted HCC cell line HepG2 expressing red fluorescent protein (RFP). The effect of AM and CW on TECs proliferation was measured using the CCK8 assay. The vascular normalization potential of AM and CW was assessed using a tube formation assay. Immunocytochemistry was performed to assess the effect of AM and CW on the expression of angiogenic maker CD34 and hypoxia-inducible factor HIF1a.. The isolated TECs and endothelioma (EOMA) cells did not differ with regard to the expression levels of endothelial markers CD34, VEGFR-1, VEGFR-2, PDGFR-α and PDGFR-β. All AM, CW, AM+CW and Nintedanib (Nin) showed a dose-dependent increasing inhibition effect on either TECs or EOMA cells. AM, CW and AM+CW significantly reduced HIF1a expression, increased CD34 expression and enhanced endothelial network formation in TECs or EOMA cells compared to the control.. AM and CW promoted vascular normalization in tumor-derived endothelial cells of HCC, through increased expression of CD34 and reduced expression of HIF1a.

Topics: Animals; Antigens, CD34; Astragalus propinquus; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcuma; Drugs, Chinese Herbal; Endothelial Cells; Female; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Medicine, Chinese Traditional; Mice; Neoplasm Transplantation; Signal Transduction

Hepatocellular carcinoma (HCC) has poor prognosis due to the advanced disease stages by the time it is diagnosed, high recurrence rates and metastasis. In the present study, we investigated the effects of metformin (a safe anti-diabetic drug) and curcumin (a turmeric polyphenol extracted from rhizome of Curcuma longa Linn.) on proliferation, apoptosis, invasion, metastasis, and angiogenesis of HCC in vitro and in vivo. It was found that co-treatment of metformin and curcumin could not only induce tumor cells into apoptosis through activating the mitochondria pathways, but also suppress the invasion, metastasis of HCC cells and angiogenesis of HUVECs. These effects were associated with downregulation of the expression of MMP2/9, VEGF, and VEGFR-2, up-regulation of PTEN, P53 and suppression of PI3K/Akt/mTOR/NF-κB and EGFR/STAT3 signaling. Co-administration of metformin and curcumin significantly inhibited HCC tumor growth than administration with metformin or curcumin alone in a xenograft mouse model. Thus, metformin and curcumin in combination showed a better anti-tumor effects in hepatoma cells than either metformin or curcumin presence alone and might represent an effective therapeutic strategy for HCC treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Line; Cell Proliferation; Cells, Cultured; Curcumin; Female; Hep G2 Cells; Humans; Liver Neoplasms; Metformin; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Neovascularization, Pathologic; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

This study aimed to explore crucial genes, transcription factors (TFs), and microRNAs (miRNAs) associated with the effects of curcumin against hepatocellular carcinoma (HCC). We downloaded data (GSE59713) from Gene Expression Omnibus to analyze differentially expressed genes (DEGs) between curcumin-treated and untreated HCC cell lines. Then, we identified the disease ontology (DO) and functional enrichment analysis of these DEGs and analyzed their protein-protein interactions (PPIs). Additionally, we constructed TF-target gene and miRNA-target gene regulatory networks and explored the potential functions of these DEGs. Finally, we detected the expression of CDKN1A, CTGF, LEF1 TF and MIR-19A regulated by curcumin in PLC/PRF/5 cells using RT-PCR. In total, 345 upregulated and 212 downregulated genes were identified. The main enriched pathway of upregulated genes was the TNF signaling pathway. The downregulated genes were significantly enriched in TGF-beta signaling pathway. In addition, most DEGs were significantly enriched in DO terms such as liver cirrhosis, hepatitis, hepatitis C and cholestasis (eg., CTGF). In the constructed PPI network, CDKN1A and CTGF were the key proteins. Moreover, LEF1, CDKN1A, and miR-19A that regulated CTGF were highlighted in the regulatory networks. Furthermore, the expression of CDKN1A, CTGF, LEF1 TF and miR-19A regulated by curcumin in PLC/PRF/5 cells was consistent with the aforementioned bioinformatics analysis results. To conclude, curcumin might exert its protective effects against HCC tumorigenesis by downregulating LEF1 and downregulating CTGF regulated by MIR-19A and upregulating CDKN1A expression.

Topics: Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Connective Tissue Growth Factor; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Databases, Genetic; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Lymphoid Enhancer-Binding Factor 1; MicroRNAs; Neoplasm Proteins; Protein Interaction Maps

Worldwide, hepatocellular carcinoma (HCC) is the major subtype of primary liver cancers. HCC is typically diagnosed late in its course. With respect to cancer, the genomic actions of vitamin D are mediated through binding to the Vitamin D Receptor (VDR), which allows it to modulate the expression of genes in a cell-and tissue-specific manner. Epigenetics is a rapidly evolving field of genetic study applicable to HCC. Changes in DNA methylation patterns are thought to be early events in hepatocarcinogenesis. Curcumin has great potential as an epigenetic agent. Accordingly, the current study has been designed to study the methylation status of VDR gene promoter for the first time in HCC aiming to find its clinical significance and potential screening role in chronic Liver Disease (CLD). Additionally, we aimed to investigate, the effect of Curcumin on HCC cell line, aiming to discover new therapeutic targets through epigenetics. This study was conducted on 45 formalin-fixed, paraffin-embedded liver tissue blocks including 15 HCC samples (group A), 15 CLD samples (group B) and 15 apparently normal tissue taken from around benign lesions (group C). Methylation Specific Restriction Digestion and qPCR were done on all samples after DNA extraction. The percentage of VDR gene promoter methylation was significantly higher in the HCC group compared to both CLD and control groups (p < 0.01). VDR promoter methylation by (MS-qPCR) was decreased and the relative expression of VDR by (qRT-PCR) was markedly increased in a dose-dependent fashion in cells grown in Curcumin-adequate medium. In conclusion, this study may open a new gate for the use of VDR promoter methylation as a potential biomarker in HCC.

Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Curcumin; DNA Methylation; Epigenesis, Genetic; Female; Hep G2 Cells; Humans; Liver Neoplasms; Male; Polymerase Chain Reaction; Prognosis; Promoter Regions, Genetic; Receptors, Calcitriol; ROC Curve; Sensitivity and Specificity

To investigate thymoquinone, curcumin and a combination of these two drugs were effective or not at the growth of liver.. Forty female Wistar-Albino rats distributed into five groups of eight rats each, control, thymoquinone, curcumin, and thymoquinone/curcumin groups. Pathological specimens were studied using the Ki-67 Proliferation Index(PI); and arginase(Arg), tissue plasminogen activator(tPA), ceruloplasmin(Cer) and nitric oxide(NO) were studied in biochemical analysis.. Our results showed that Ki-67 proliferation index was low in Groups 1. The proliferation coefficient was significantly higher in the Group 2 and Group 4 than in the Group 1 and Group 3.(P < 0.001 between Groups 1 and 2, 1 and 4, and 3 and 4). There was no difference between Groups 2 and 4 (P = 1). The results of the biochemical Arg, tPA and Cer test showed statistically between the Group 1 and Group 2. NO showed significant differences Group 1 and 3.. Thymoquinone and curcumin both have known positive effects on the organism. Histological and biochemical tests showed that thymoquinone is more effective than curcumin.

Topics: Animals; Antineoplastic Agents; Antioxidants; Arginase; Benzoquinones; Biomarkers; Cell Proliferation; Ceruloplasmin; Curcumin; Female; Hepatectomy; Ki-67 Antigen; Liver; Liver Neoplasms; Liver Regeneration; Liver Transplantation; Nitric Oxide; Rats; Rats, Wistar; Tissue Plasminogen Activator

This study was focused on developing a drug carrier system composed of a polymer containing hydroxyapatite (HAp) shell and a magnetic core of iron oxide nanoparticles. Doxorubicin and/or curcumin were loaded into the carrier via a simple diffusion deposition approach, with encapsulation efficiencies (EE) for curcumin and doxorubicin of 93.03 ± 0.3% and 97.37 ± 0.12% respectively. The co-loading of curcumin and doxorubicin led to a total EE of 76.02 ± 0.48%. Release studies were carried out at pH 7.4 and 5.3, and revealed a greater extent of release at pH 5.3, showing the formulations to have potential applications in tumor microenvironments. Cytotoxicity assays, fluorescence imaging and flow cytometry demonstrated that the formulations could effectively inhibit the growth of MCF-7 (breast) and HEpG2 (liver) cancer cells, being more potent than the free drug molecules both in terms of dose and duration of action. Additionally, hemolysis tests and cytotoxicity evaluations determined the drug-loaded carriers to be non-toxic towards non-cancerous cells. These formulations thus have great potential in the development of new cancer therapeutics.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Curcumin; Doxorubicin; Drug Carriers; Durapatite; Female; Ferric Compounds; Flow Cytometry; Hemolysis; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Liver Neoplasms; Male; MCF-7 Cells; Nanoparticles; Optical Imaging; Polymers; Rats, Wistar

Topics: Animals; Antineoplastic Agents, Phytogenic; Carbocyanines; Cell Line, Tumor; Contrast Media; Curcumin; Delayed-Action Preparations; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Drug Liberation; Dynamic Light Scattering; Humans; Hydrogen-Ion Concentration; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron, Transmission; Molecular Imaging; Nanoparticles; Particle Size; Polyethylene Glycols; Polylysine; Proton Magnetic Resonance Spectroscopy; Technology, Pharmaceutical; Theranostic Nanomedicine; Tissue Distribution; Tumor Burden; Xenograft Model Antitumor Assays

In recent years, actively targeted drug delivery systems have been utilized in pre-clinical studies for site-specific delivery of drugs, which reduces toxicities associated with chemotherapy. This study reports the preparation of the tumor homing ligand, transferrin (Tf) anchored methoxy-polyethylene glycol-poly(d,l-Lactide) polymeric micelles (Tf-PP). Curcumin which possess wide anti-cancer activity was loaded into the micelles. Tf-PPC with average particle size of 132.16 ± 1.37 nm and encapsulation efficiency of 88.27 ± 2.53% showed a sustained drug release. The efficacy of Tf-PPC was studied in vitro in Tf-overexpressing human cervical carcinoma (HeLa) and human hepatoma (HepG2) cells. The mouse embryo fibroblast (NIH-3T3) cells were used as control cells. Tf-PPC showed higher internalization compared to non-targeted micelles (PPC). The curcumin-mediated cytotoxicity increased significantly following Tf-PPC treatment in both the tested cell lines. In NIH-3T3 cells, Tf conjugation did not differ in comparison to the non-targeted micelles. Further, the efficiency of Tf-PPC was studied in three-dimensional (3D) HeLa tumor spheroids. The Tf-PPC was efficiently internalized by the spheroidal structures, causing higher cytotoxicity and apoptosis compared to PPC. These results reveal that the newly developed, Tf-PPC could be employed as an effective chemotherapy in the treatment of Tf- overexpressing cancers.

Topics: Animals; Antineoplastic Agents, Phytogenic; Curcumin; Drug Delivery Systems; Female; HeLa Cells; Hep G2 Cells; Humans; Liver Neoplasms; Mice; Micelles; NIH 3T3 Cells; Polyesters; Spheroids, Cellular; Transferrin; Uterine Cervical Neoplasms

Tumor metastasis is the leading cause of cancer death; due to the progress made in the elucidation of the mechanism of cancer cell metastasis, there is hope for patients with severe stages of cancer. Curcumin, as a novel anti-cancer drug, has been applied in cancer therapy; however, the toxicity of curcumin hinders its application. Herein, we constructed a novel derivative, WZ35, and evaluated its metastatic inhibition properties in vitro and in vivo. CCK-8 assay was performed to evaluate the tumor suppressive activity of WZ35. Cell apoptosis was detected by flow cytometry analysis. Transwell cell migration assay and RTCA were used to detect cell migration in mock and WZ35-treated cells. Western blotting was performed to analyze molecular alteration with different treatments. In this study, we found that curcumin and its derivative WZ35 could dramatically suppress proliferation, invasion, and migration of the hepatocellular HCCLM3, HepG2, and Huh7 cancer cells. Moreover, the cancer cell metastatic markers MMP-2, MMP-9, and N-cadherin were decreased, and E-cadherin was up-regulated. In addition, our data show that WZ35 promotes ROS-dependent JNK activation that is essential for WZ35-caused cell metastasis suppression. Moreover, the NAC and JNK inhibitor SP600125 could dramatically reverse WZ35-caused MMP-2, MMP-9, and N-cadherin reduction and E-cadherin up-regulation. We have also found that WZ35 exhibits powerful anti-metastasis activity of HCCLM3 in vivo. In conclusion, our data indicated that WZ35 could be a candidate for the treatment of metastatic liver cancer patients.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Movement; Curcumin; Female; Humans; Liver Neoplasms; MAP Kinase Kinase 4; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Reactive Oxygen Species

Curcumin has been revealed to inhibit liver cancer, however, no studies have reported that the mechanism of curcumin's action on liver cancer is related to damage-associated molecular pattern (DAMP) molecules heat shock protein 70 (HSP70) and the toll-like receptor 4 (TLR4) signaling. This study aimed to investigate whether the activation of TLR4 signaling by HSP70 could be inhibited by curcumin, thus investigating the possible mechanism of curcumin in the inhibition of liver cancer. Western blotting was used to evaluate the expression of the HSP70 and TLR4 in HepG2 cells and ELISA was used to detect the concentration of HSP70 in cell culture medium. A thermal tolerance HepG2 (HepG2TT) cell model was established to simulate HSP70 accumulation in the microenvironment. A certain concentration of curcumin was co-cultured with HepG2 and HepG2TT cells to observe the changes of HSP70 and TLR4. Our results revealed that heat stress significantly increased the expression of extracellular HSP70 (eHSP70) and TLR4 (P<0.01), but significantly reduced the expression of intracellular HSP70 (P<0.01). Curcumin inhibited proliferation, invasion, and metastasis of HepG2 cells, caused cells to remain in the DNA S phase, promoted apoptosis, and significantly reduced intracellular HSP70, eHSP70 and TLR4 levels of HepG2TT cells. Following the removal of curcumin, eHSP70 increased again. In summary, our results demonstrated that the antitumor effect of curcumin was related to the inhibition HSP70-TLR4 signaling.

Topics: Alarmins; Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Hep G2 Cells; HSP72 Heat-Shock Proteins; Humans; Liver Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; S Phase; Toll-Like Receptor 4; Tumor Microenvironment

The main objective of this study was to develop novel BSA nanoparticles (BSA NPs) for improving the bioavailability of curcumin as an anticancer drug, and those BSA NPs were galactosylated for forming the curcumin-loaded galactosylated BSA nanoparticles (Gal-BSA-Cur NPs), thus enhancing their ability to target asialoglycoprotein receptor (ASGPR) overexpressed on hepatocellular carcinoma (HCC) cells.. Gal-BSA-Cur NPs were prepared by the desolvation method and showed a spherical shape and well distribution with the average particle size of 116.24 nm.. In vitro drug release assay exhibited that Gal-BSA-Cur NPs had higher release rates and improved the curcumin solubility. Cell uptake studies confirmed that Gal-BSA-Cur NPs could selectively recognize receptors on the surface of HCC (HepG2) cells and improve internalization ability of drug compared with BSA NPs-loaded curcumin (BSA-Cur NPs), which might be due to high affinity to galactose. Further, the effects of Gal-BSA-Cur NPs were evaluated by cytotoxicity assay, crystal violet assay, cell apoptosis assay, and wound healing assay, respectively, which revealed that Gal-BSA-Cur NPs could inhibit HepG2 cells proliferation, induce cell apoptosis, and inhibit cell migration.. Immunofluorescence staining has proved that the effects of Gal-BSA-Cur NPs related to the suppression of the nuclear factor κB-p65 (NF-κB-p65) expression in HepG2 cell nucleus. Therefore, these results indicate that novel Gal-BSA-Cur NPs are potential candidates for targeted curcumin delivery to HCC cells.

Topics: Antineoplastic Agents; Apoptosis; Binding, Competitive; Carcinoma, Hepatocellular; Cell Movement; Cell Proliferation; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Endocytosis; Galactose; Hep G2 Cells; Humans; Liver Neoplasms; Nanoparticles; Particle Size; Serum Albumin, Bovine; Spectroscopy, Fourier Transform Infrared; Transcription Factor RelA

Overexpression of MDA-9/Syntenin occurs in multiple human cancer cell lines and is associated with higher grade of tumor classification, invasiveness and metastasis. In some cases, its role in cancer biology depends on relationships between MDA-9/Syntenin and NF-κB.. This study aims to analyze the presence of a regulation loop like that between MDA-9/Syntenin - NF-κB - RKIP in human liver carcinoma.. Transient transfection was performed with siRNA anti-MDA-9/Syntenin. Expression of different factors was evaluated by Real time-PCR and Western blotting, while NF-κB activation by TransAM assay. Invasion capacity was analyzed by Matrigel Invasion Assay and the effects of agents on cell viability were examined by MTS assay.. We have examined basal expression of MDA-9/Syntenin in three cell lines of human liver carcinoma (HA22T/VGH, Hep3B and HepG2). In all cell lines there was an inverse relationship between MDA-9/Syntenin and RKIP expression levels, and a positive correlation between MDA-9/Syntenin expression and NF-κB activation levels. By silencing with a siRNA anti-MDA-9/Syntenin we observed in all cell lines a very strong increase of RKIP at mRNA level. Interestingly, in all cell lines, inhibition of MDA- 9/Syntenin expression induced NF-κB downregulation and contemporary a reduction in invasion ability MMP-2 dependent. Finally, we showed a good additive effect of MDA- 9/Syntenin siRNA when associated with Curcumin or Doxorubicin on cell growth inhibition.. Our data confirm the key role of MDA-9/Syntenin in HCC biology. The presence of a regulation loop among MDA-9/Syntenin, NF-κB and RKIP provide new pharmacological approaches.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Curcumin; Doxorubicin; Hep G2 Cells; Humans; Liver Neoplasms; Neoplasm Invasiveness; Neoplasm Proteins; NF-kappa B; Phosphatidylethanolamine Binding Protein; Signal Transduction; Syntenins

We have synthesized bioactive 1,4-disubstituted 1,2,3-triazole analogues containing 2H-1,4-benzoxazin-3-(4H)-one derivatives via 1,3-dipolar cycloaddition in the presence of CuI. All the reactions proceeded smoothly and afforded its desired products in excellent yields. Among these analogues, 3y exhibited a better cytotoxic effect on human hepatocellular carcinoma (HCC) Hep 3B cells and displayed less cytotoxicity on normal human umbilical vein endothelial cells, compared with Sorafenib, a targeted therapy for advanced HCC. 3y also induced stronger apoptosis and autophagy. Addition of curcumin enhanced 3y-induced cytotoxicity by further induction of autophagy. Using gene expression signatures of 3y to query Connectivity Map, a glycogen synthase kinase-3 inhibitor (AR-A014418) was predicted to display similar molecular action of 3y. Experiments further demonstrate that AR-A014418 acted like 3y, and vice versa. Overall, our data suggest the chemotherapeutic potential of 3y on HCC.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Carcinoma, Hepatocellular; Cell Line, Tumor; Copper; Curcumin; Databases, Genetic; Glycogen Synthase Kinase 3; Humans; Liver Neoplasms; Structure-Activity Relationship; Thiazoles; Triazoles; Urea

Liver cancer is a common malignant tumor in the digestive system. Curcumin is a kind of phenolic pigment, which is extracted from herbage and has a plenty of physiological roles in anti-inflammation, anti-oxidation and anti-tumor. In our study, human hepatoma SMMC-7721 cell lines were selected and treated with curcumin to detect its effects on the apoptosis and AMPK signaling pathway.. Human liver cancer cell strain SMMC-7721 was cultured and treated with different curcumin concentrations for different times followed by measuring the changes of cell proliferation activity and cycle by MTT and flow cytometry, respectively. Protein expression of Bcl-2, Bax and Caspase-3 were tested by Western blot, and the activation level of AMPK was also detected.. Different concentrations of curcumin could inhibit the proliferation of tumor cells in a dose-dependent manner. After 48 h inhibition by curcumin with a concentration of 40 mmol/L, the inhibitory effect was more obvious with statistically significant (p<0.05). The number of human liver cancer SMMC-7721 cells increased in G1 stage and decreased in S stage after treated with different concentrations of curcumin. During the G1 stage to the S stage, inhibition occurred and the effect of curcumin intervention group with 40 mmol/L was more evident than that of 10 mmol/L group, 20 mmol/L group and the control group with statistically significant (p<0.05). SMMC-7721 cell stains had been intervening by curcumin with concentrations of 10 mmol/L, 20 mmol/L and 40 mmol/L for 12 h, 24 h and 48 h, as the drug concentration increased, the reaction time prolonged, the protein expressions of Bcl-2 and Survivin were significantly decreased and Bax protein expression was significantly increased (p<0.05).. Curcumin decreased the proliferation activity of tumor cells, increased the cell quantities in G1 stage and decreased the cell numbers in S stage in human liver cancer SMMC-7721 cells. The Bcl-2 and Survivin proteins were downregulated and Bax protein was upregulated; furthermore, the AMPK signaling pathway was activated.

Topics: AMP-Activated Protein Kinases; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Liver Neoplasms

Sirtuin 3 (SIRT3) regulates mitochondrial antioxidant (AO) defense and improves mitochondrial disorders. Curcumin protects mitochondria; however, the mechanisms need investigation. We postulated that curcumin increases AO defense under hyperglycemic conditions in HepG2 cells through SIRT3-mediated mechanisms. Cell viability was determined in HepG2 cells cultured with 5 mM glucose, 19.9 mM mannitol, vehicle control, 10 mM glucose, and 30 mM glucose in the absence or presence of curcumin for 24 h. SIRT3, nuclear factor-kappa B (NF-κB), heat-shock protein 70 (Hsp70), and Lon protein expressions were determined using western blot. Transcript levels of SIRT3, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), cAMP response element-binding protein (CREB), glutathione peroxidase 1 (GPx1), and superoxide dismutase 2 (SOD2) were measured by quantitative polymerase chain reaction. Cell viability, SIRT3 protein expression, transcript levels of SIRT3, PGC-1α, CREB, GPx1, and SOD2 and protein expressions of NF-κB, Lon, and Hsp70 were significantly increased in the curcumin-treated hyperglycemic groups. Since curcumin and SIRT3 both improve mitochondrial function and AO defense, SIRT3 may be involved in the protective effects of curcumin.

Topics: Antioxidants; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Glutathione Peroxidase; Glutathione Peroxidase GPX1; HSP70 Heat-Shock Proteins; Humans; Liver Neoplasms; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Protease La; Sirtuin 3; Superoxide Dismutase; Up-Regulation

Co-delivery of multiple drugs with complementary anticancer mechanisms by nano-carriers offers an effective strategy to treat cancer. The combination of drugs with pro-apoptotic and anti-angiogenic activities is potentially effective in treating human hepatocellular carcinoma (HCC). Herein, we developed a co-delivery system for doxorubicin (Dox), a pro-apoptotic drug, and curcumin (Cur), a potent drug for antiangiogenesis, in pH-sensitive nanoparticles (NPs) constituted with amphiphilic poly(β-amino ester) copolymer. Dox & Cur co-loaded NPs ((D+C)/NPs) were prepared with optimized drug ratio, showing low polydispersity, high encapsulation efficiency, and enhanced release in the acidic environment of cancer cells. Furthermore, enhanced cellular internalization of cargoes delivered from (D+C)/NPs were observed in human liver cancer SMMC 7721 cells and human umbilical vein endothelial cells (HUVECs) compared to the use of free drugs. The (D+C)/NPs induced a high rate of apoptosis in SMMC 7721 cells through decreased mitochondrial membrane potential. Additionally, (D+C)/NPs exhibited stronger anti-angiogenic effects including inhibition of HUVEC proliferation, migration, invasion, and tube formation mediated VEGF pathway modulation in vitro and in vivo. Taken together, encapsulation of the pro-apoptotic drug Dox and antiangiogenic agent Cur in pH-sensitive NPs provides a promising strategy to effectively inhibit HCC progression in a synergistic manner.. The combination of multiple drugs has been demonstrated to be more effective than single treatment. However, the different physicochemical and pharmacokinetic profiles of each drug render optimal delivery challenging. In view of the great delivery advantage of nanocarriers to unify the multiple drugs in vivo, stimulus-responsive nano-carriers are more crucial to increase efficacy and reduce toxicity from off-target exposure. Therefore, herein the pH-sensitive nanoparticles, composed by d-α-tocopheryl polyethylene glycol 1000-block-poly (β-amino ester) (TPGS-PAE) polymers, have been fabricated for doxorubicin (Dox) and curcumin (Cur) co-delivery, which exhibited diverse anticancer approaches, i.e. pro-apoptosis and antiangiogenesis. The precise intracellular target site and effective drug combination concentration result in the enhanced antitumor efficiency and the reduced systematic toxicity of Dox. The co-encapsulation of the pro-apoptotic drug and antiangiogenic agent in pH-sensitive NPs provides a promising strategy to effectively inhibit malignant neoplasm progression in a synergistic manner.

Topics: Apoptosis; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Delivery Systems; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen-Ion Concentration; Liver Neoplasms; Nanoparticles; Neovascularization, Pathologic

In this study, a glycyrrhetinic acid-functionalized mesoporous silica nanoparticle (MSN-GA) was prepared for active tumor targeting. MSN-GA exhibited satisfactory loading capacity for insoluble drugs, uniform size distribution, and specific tumor cell targeting. Glycyrrhetinic acid, a hepatocellular carcinoma-targeting group, was covalently decorated on the surface of MSN via an amido bond. The successful synthesis of MSN-GA was validated by the results of Fourier transform infrared spectroscopy, transmission electron microscopy (TEM), and zeta potential measurement. TEM images revealed the spherical morphology and uniform size distribution of the naked MSN and MSN-GA. Curcumin (CUR), an insoluble model drug, was loaded into MSN-GA (denoted as MSN-GA-CUR) with a high-loading capacity (8.78%±1.24%). The results of the in vitro cellular experiment demonstrated that MSN-GA-CUR significantly enhanced cytotoxicity and cellular uptake toward hepatocellular carcinoma (HepG2) cells via a specific GA receptor-mediated endocytosis mechanism. The results of this study provide a promising nanoplatform for the targeting of hepatocellular carcinoma.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Curcumin; Drug Carriers; Dynamic Light Scattering; Glycyrrhetinic Acid; Hep G2 Cells; Humans; Liver Neoplasms; Microscopy, Electron, Transmission; Nanoparticles; Silicon Dioxide; Spectroscopy, Fourier Transform Infrared

Curcumin (CUR), a widely used food additive, is derived mainly from Curcuma species that has been applied traditionally for the treatment of various diseases, including hepatocellular carcinoma (HCC). However, its poor systemic bioavailability hampers its clinical application, which may be related to its wide metabolism. Tetrahydrocurcumin (THC) is a major metabolite of CUR and has been reported to have multiple biologic activities. We investigated, for the first time, the efficacy and associated mechanism of action of THC and CUR in a H22 ascites tumor-bearing model in mice. THC evoked a significant dose-dependent promotion of survival and was significantly more effective than CUR in inhibiting tumor growth, including increased body weight, abdominal circumference, ascites volume, and the viability of cancer cells. Experiments on essential immune organs indicated that THC had a more favorable margin of safety than the reference drug cyclophosphamide. THC induced the apoptosis of H22 cells obviously by increasing the level of p53 and decreasing the level of murine double minute 2. THC also decreased the expression of Bcl-2 significantly and increased the expression of Bcl2-associated X, resulting in the release of cytochrome C. THC significantly activated and induced cleavage of caspase-3 and caspase-9 to induce the apoptosis of H22 cells. Taken together, these results indicate that THC was more effective than CUR in inhibiting the apoptosis of H22-induced ascites tumor cells and achieved it via regulation of a mitochondrial apoptosis pathway. THC might be a bioactive anti-tumor form of CUR and represented a potentially effective agent for HCC treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Ascites; Cell Line, Tumor; Curcumin; Cytochromes c; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Mice; Mitochondria

Curcumin, a phenolic compound, has a wide spectrum of therapeutic effects such as antitumor, anti-inflammatory, anti-cancer and so on. The study aimed to investigate the underlying mechanisms of curcumin to protect liver damage and progression of non-alcoholic steatohepatitis (NASH) in a novel NASH-hepatocellular carcinoma (HCC) mouse model. To induce this model neonatal C57BL/6J male mice were exposed to low-dose streptozotocin and were fed a high-fat diet (HFD) from the age of 4weeks to 14weeks. Curcumin was given at 100mg/kg dose daily by oral gavage started at the age of 10weeks and continued until 14weeks along with HFD feeding. We found that curcumin improved the histopathological changes of the NASH liver via reducing the level of steatosis, fibrosis associated with decreasing serum aminotransferases. In addition, curcumin treatment markedly reduced the hepatic protein expression of oxidative stress, pro-inflammatory cytokines, and chemokines including interferon (IFN) γ, interleukin-1β and IFNγ-inducible protein 10, in NASH mice. Furthermore, curcumin treatment significantly reduced the cytoplasmic translocation of high mobility group box 1 (HMGB1) and the protein expression of toll like receptor 4. Nuclear translocation of nuclear factor kappa B (NF-κB) was also dramatically attenuated by the curcumin in NASH liver. Curcumin treatment effectively reduced the progression of NASH to HCC by suppressing the protein expression of glypican-3, vascular endothelial growth factor, and prothrombin in the NASH liver. Our data suggest that curcumin reduces the progression of NASH and liver damage, which may act via inhibiting HMGB1-NF-κB translocation.

Topics: Active Transport, Cell Nucleus; Animals; Animals, Newborn; Carcinoma, Hepatocellular; Curcumin; Disease Models, Animal; Fibrosis; HMGB1 Protein; Humans; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Streptozocin

Topics: Animals; Antioxidants; Carcinogens; Cells, Cultured; Curcuma; Curcumin; Epithelial Cells; Ferric Compounds; Iron; Iron Overload; Liver; Liver Neoplasms; Oxidative Stress; Plant Extracts; Quaternary Ammonium Compounds; Rats

The aim of the present study was to investigate the efficacy of the traditional Chinese medicine (TCM), astragaloside IV (AS-IV) and curcumin on tumor growth and angiogenesis in an orthotopic nude-mouse model of human hepatocellular carcinoma (HCC). We have previously shown the usefulness of orthotopic models of human cancer for evaluation of the efficacy of TCM.. Nude mice with orthotopic HepG2 HCC were treated with vehicle control (0.01 ml/g normal saline), cisplatinum (2 mg/kg), AS-IV (20 mg/kg), curcumin (100 mg/kg) or AS-IV plus curcumin (20 mg/kg + 100 mg/kg). Tumor inhibition in each group was evaluated by tumor weight at autopsy. The effect of AS-IV and curcumin on tumor angiogenesis was assessed by CD34 staining and expression of fibroblast growth factor-2 (FGF2), matrix metalloproteinase 2 (MMP2), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), thrombosis-related factor tissue factor (TF) and coagulation factor VII (FVII), as well as microRNAs miR-122 and miR-221.. AS-IV and curcumin alone and in combination significantly reduced mean tumor weight compared to vehicle control (p<0.05). Tumor microvessel count was reduced by AS-IV and curcumin alone. Expression of FGF2, MMP2, VEGF, HGF, TF and FVII was reduced by AS-IV and curcumin alone. AS-IV and curcumin alone up-regulated expression of miR-122 and down-regulated that of miR-221. The combination of AS-IV and curcumin demonstrated significant synergistic effects on microvessel count as well as on expression of angiogenic and thrombosis-related factors and microRNAs.. The present study indicates future clinical potential of combination therapy with AS-IV and curcumin for HCC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Growth Processes; Curcumin; Disease Models, Animal; Down-Regulation; Drug Synergism; Hep G2 Cells; Heterografts; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Random Allocation; Saponins; Triterpenes

In this paper, we synthesized a series of curcumin analogs and evaluated their cytotoxicity against HepG2 cells. The results exhibited that the hydroxyl group at 3,3'-position play an essential role in enhancing their anti-proliferation activity. More importantly, 3,3'-hydroxy curcumin (1b) caused apoptosis in HepG2 cells with the ROS generation, which may be mainly composed of hydroxyl radicals (HO) and H2O2. The more cytotoxic activity and ROS-generating ability of 1b may be due to the more stable in (RPMI)-1640 medium and more massive uptake than curcumin. Then the generation of ROS can disrupt the intracellular redox balance, induce lipid peroxidation, cause the collapse of the mitochondrial membrane potential and ultimately lead to apoptosis. The results not only suggest that 3,3'-hydroxy curcumin (1b) may cause HepG2 cells apoptosis through ROS-mediated pathway, but also offer an important information for design of curcumin analog.

Topics: Antineoplastic Agents; Apoptosis; Curcumin; Hep G2 Cells; Humans; Hydroxyl Radical; Liver; Liver Neoplasms; Reactive Oxygen Species

At present, the therapeutic treatment strategies for patients with hepatocellular carcinoma (HCC) remain unsatisfactory, and novel methods are urgently required to treat this disease. Members of the B cell lymphoma (Bcl)-2 family are anti‑apoptotic proteins, which are commonly expressed at high levels in certain HCC tissues and positively correlate with the treatment resistance of patients with HCC. ABT-737, an inhibitor of Bcl-2 anti-apoptotic proteins, has been demonstrated to exhibit potent antitumor effects in several types of tumor, including HCC. However, treatment with ABT-737 alone also activates certain pro-survival signaling pathways, which attenuate the antitumor validity of ABT-737. Curcumin, which is obtained from Curcuma longa, is also an antitumor potentiator in multiple types of cancer. In the present study, the synergistic effect of curcumin and ABT-737 on HCC cells was investigated for the first time, to the best of our knowledge. It was found that curcumin markedly enhanced the antitumor effects of ABT-737 on HepG2 cells, which was partially dependent on the induction of apoptosis, according to western blot analysis and flow cytometric apoptosis analysis. In addition, the sustained activation of the ROS-ASK1-c-Jun N-terminal kinase pathway may be an important mediator of the synergistic effect of curcumin and ABT-737. Collectively, these results indicated that the combination of curcumin and ABT-737 can efficaciously induce the death of HCC cells, and may offer a potential treatment strategy for patients with HCC.

Topics: Apoptosis; Biphenyl Compounds; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; MAP Kinase Kinase 4; MAP Kinase Kinase Kinase 5; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver making up more than 80 percent of cases. It is known to be the sixth most prevalent cancer and the third most frequent cause of cancer related death worldwide. Epigenetic regulation constitutes an important mechanism by which dietary components can selectively activate or inactivate target gene expression. The miR-34 family members including mir-34a, mir-34b and mir-34c are tumor suppressor micro RNAs, which are expressed in the majority of normal tissues. Several studies have indicated silencing of miR-34 expression via DNA methylation in multiple types of cancers. Bioactive nutrients like curcumin (Cur) have excellent anticarcinogenic activity and minimal toxic manifestations in biological systems. This compound has recently been determined to induce epigenetic changes. However, Cur is lipophilic and has a poor systemic bioavailability and poor absorption. Its bioavailability is increased through employing dendrosome nanoparticles. The aim of the current study was to investigate the effect of dendrosomal nanocurcumin (DNC) on expression of mir-34 family members in two HCC cell lines, HepG2 and Huh7. We performed the MTT assay to evaluate DNC and dendrosome effects on cell viability. The ability of DNC to alter expression of the mir-34 family and DNA methyltransferases (DNMT1, DNMT3A and 3B) was evaluated using semi-quantitative and quantitative PCR. We observed the entrance of DNC into HepG2 and Huh7 cells. Gene expression assays indicated that DNC treatment upregulated mir34a, mir34b and mir34c expression (P<0.05) as well as downregulated DNMT1, DNMT3A and DNMT3B expression (P<0.05) in both HepG2 and Huh7 cell lines. DNC also reduced viability of Huh7 and HepG2 cells through restoration of miR-34s expression. We showed that DNC could awaken the epigenetically silenced miR-34 family by downregulation of DNMTs. Our findings suggest that DNC has potential in epigenetic therapy of HCC.

Topics: Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; DNA Methyltransferase 3B; Drug Carriers; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; MicroRNAs; Nanoparticles; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Photoactivated therapy has become a complementary and attractive modality for traditional cancer treatment. Herein, we demonstrated a novel single-stimulus dual-drug sensitive nanoplatform, Cur-loaded Dex-Pt(N3) nanoparticles (Cur@DPNs) for enhanced photoactivated therapy. The developed Cur@DPNs could be photoactivated by UVA light to simultaneously generate instant reactive oxygen species from Cur for fast photodynamic therapy and release lasting Pt(II) from Pt(N3) for long-acting photochemotherapy. Compared with small free drugs and individual photoactivated therapy, Cur@DPNs exhibited enhanced photoactivated cytotoxicity and in vivo antitumor efficacy with low systemic toxicity accompanied. Therefore, the single-stimulus dual-drug sensitive nanoplatform is convinced to be a promising strategy for multidrug delivery, site-selective and combinational photoactivated therapy in the near future.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cisplatin; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Liver Neoplasms; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The side-effects observed in conventional therapies have made them unpromising in curing Hepatocellular carcinoma; therefore, developing novel treatments can be an overwhelming significance. One of such novel agents is curcumin which can induce apoptosis in various cancerous cells, however, its poor solubility is restricted its application. To overcome this issue, this paper employed dendrosomal curcumin (DNC) was employed to in prevent hepatocarcinoma in both RNA and protein levels. Hepatocarcinoma cells, p53 wild-type HepG2 and p53 mutant Huh7, were treated with DNC and investigated for toxicity study using MTT assay. Cell cycle distribution and apoptosis were analyzed using Flow-cytometry and Annexin-V-FLUOS/PI staining. Real-time PCR and Western blot were employed to analyze p53, BAX, Bcl-2, p21 and Noxa in DNC-treated cells. DNC inhibited the growth in the form of time-dependent manner, while the carrier alone was not toxic to the cell. Flow-cytometry data showed the constant concentration of 20μM DNC during the time significantly increases cell population in SubG1 phase. Annexin-V-PI test showed curcumin-induced apoptosis was enhanced in Huh7 as well as HepG2, compared to untreated cells. Followed by treatment, mRNA expression of p21, BAX, and Noxa increased, while the expression of Bcl-2 decreased, and unlike HepG2, Huh7 showed down-regulation of p53. In summary, DNC-treated hepatocellular carcinoma cells undergo apoptosis by changing the expression of genes involved in the apoptosis and proliferation processes. These findings suggest that DNC, as a plant-originated therapeutic agent, could be applied in cancer treatment.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Chemistry, Pharmaceutical; Curcumin; Down-Regulation; G1 Phase; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Nanoparticles; RNA, Messenger; Solubility

We developed Cur nanosuspension (Cur-NS) with PVPK30 and SDS as stabilizers to improve poor water solubility and short biological half-time of Cur.. Physicochemical characterization of Cur-NS was characterized systematically. The in-vitro dissolution, cytotoxicity and in-vivo pharmacokinetic experiments of Cur-NS were also evaluated.. Scanning electron microscope indicated that the morphologies of Cur-NS were spherical or ellipsoidal in shape. X-ray diffraction verified that Cur was successfully developed as nanoparticles with an amorphous phase in Cur-NS. Fourier transform infrared spectroscopy suggested there was no degradation about Cur in the Cur-NS. Furthermore, the in-vitro study showed that the cumulative release of the Cur-NS was 82.16 ± 2.62% within 34 h and the cytotoxicity of the Cur-NS against HepG2 cells was much better than raw Cur. Besides, in-vivo pharmacokinetics in rats by intravenous injection displayed that the in-vivo process of Cur-NS pertained to two-compartment model. Meanwhile, the t1/2 and AUC0-t of Cur-NS were enhanced by 11.0-fold and 4.2-fold comparing to Cur solution.. The Cur-NS significantly increased the water solubility and half-time of Cur, suggesting its potential as a nanocarrier in the delivery of Cur for future clinical application.

Topics: Animals; Antineoplastic Agents, Phytogenic; Area Under Curve; Biological Availability; Curcuma; Curcumin; Drug Delivery Systems; Female; Hep G2 Cells; Hepatoblastoma; Humans; Liver Neoplasms; Male; Nanoparticles; Particle Size; Pharmaceutical Solutions; Polyvinyls; Rats, Sprague-Dawley; Sodium Dodecyl Sulfate; Solubility; Spectroscopy, Fourier Transform Infrared; Water; X-Ray Diffraction

Curcumin (CUM) is a promising agent in complementary oncology. The present study analyzed the photoactive properties of curcumin on pediatric epithelial liver tumor cell lines.. Hepatoblastoma cell lines (HuH6, HepT1) and hepatocellular carcinoma cell lines (HepG2, HC-AFW1) were treated with curcumin and exposed to blue light (phototherapy, 480 nm, 300 W). Cell viability (MTT tests), cellular oxidative stress (production of reactive oxygen species (ROS)) and cellular uptake/degradation of curcumin were analyzed.. Significant loss of viability resulted from 24-48 h incubation with curcumin. With photodynamic therapy (PDT), even short time incubation (1 h) with curcumin resulted in significantly lower half maximal inhibitory concentration (IC50) (p<0.001, two-way ANOVA). Significant ROS production was observed with PDT and curcumin.. Phototherapy strongly enhances the anticancer properties of curcumin in pediatric solid liver tumors in vitro.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Child; Curcumin; Drug Screening Assays, Antitumor; Drug Synergism; Hep G2 Cells; Humans; Liver Neoplasms; Photochemotherapy

The present study was designed to identify the chemical constituents of the methanolic extract of Curcuma longa L. rhizomes and their inhibitory effect on a hepatoma cell line. The methanolic extract was subjected to GC-MS analysis to identify the volatile constituents and the other part of the same extract was subjected to liquid column chromatographic separation to isolate curcumin. The inhibition of cell growth in the hepatoma cell line and the cytopathological changes were studied. GC-MS analysis showed the presence of fifty compounds in the methanolic extract of C. longa. The major compounds were ar-turmerone (20.50 %), β-sesquiphellandrene (5.20 %) and curcumenol (5.11 %). Curcumin was identified using IR, 1H and 13C NMR. The inhibition of cell growth by curcumin (IC50 = 41.69 ± 2.87 μg mL-1) was much more effective than that of methanolic extract (IC50 = 196.12 ± 5.25 μg mL-1). Degenerative and apoptotic changes were more evident in curcumin- treated hepatoma cells than in those treated with the methanol extract. Antitumor potential of the methanolic extract may be attributed to the presence of sesquiterpenes and phenolic constituents including curcumin (0.051 %, 511.39 μg g-1 dried methanol extract) in C. longa rhizomes.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Cell Survival; Chromatography, High Pressure Liquid; Chromatography, Liquid; Curcuma; Curcumin; Cyclohexane Monoterpenes; Cyclohexenes; Drug Discovery; Gas Chromatography-Mass Spectrometry; Hep G2 Cells; Humans; Inhibitory Concentration 50; Ketones; Liver Neoplasms; Monoterpenes; Plant Extracts; Rhizome; Sesquiterpenes; Volatile Organic Compounds

This study was designed to investigate the role of curcumin against hepatocellular carcinoma (HCC) induced in rats. Forty rats were divided into five groups. Group (1) was negative control. Groups (2), (4), and (5) were orally administrated N-nitrosodiethylamine for HCC induction, then group (2) was left untreated, and group (4) was treated orally with curcumin, while group (5) was intraperitoneally injected with doxorubicin. Group (3) was served as curcumin control group. Serum alpha-fetoprotein, alpha L-fucosidase and vascular endothelial growth factor levels were analyzed. Gamma glutamyl transferase (GGT) and heat shock protein gp96 (HSPgp96) gene expressions were detected by RT-PCR. The immunohistochemical analysis of proliferating cell nuclear antigen (PCNA) and Ki-67 expressions was performed. Apoptosis was detected using DNA fragmentation assay. Also, histological investigation of liver tissue was achieved. Untreated HCC group showed significant elevation in the studied biochemical markers and significant upregulation in GGT and HSPgp96 gene expression as well as marked increase in PCNA and Ki-67 expression. Furthermore, this group revealed no DNA fragmentation. Histological investigation of liver tissue sections in HCC group revealed a typical anaplasia. On the other hand, the curcumin-treated group showed a significant depletion in the studied tumor markers and a significant downregulation in GGT and HSPgp96 gene expression. Also, this group displayed remarkable decrease in PCNA and Ki-67 expression. Moreover, this group revealed an obvious DNA fragmentation. Interestingly, treatment with curcumin showed remarkable improvement in the histological features of liver tissue. This study revealed the promising therapeutic role of curcumin against hepatocellular carcinoma owing to its antiangiogenic, antiproliferative, and apoptotic effects.

Topics: alpha-Fetoproteins; Angiogenesis Inhibitors; Animals; Antioxidants; Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; DNA Fragmentation; Down-Regulation; gamma-Glutamyltransferase; Heat-Shock Proteins; Ki-67 Antigen; Liver; Liver Neoplasms; Male; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Up-Regulation

MiRNAs are an emerging type of biomarker for diagnostics and prognostics. A reliable sensing strategy that can monitor miRNA expression in living cancer cells would be critical in view of its extensive advantages for fundamental research related to miRNA-associated bioprocesses and biomedical applications. Conventional miRNA sensing methods include northern blot, microarrays and real-time quantitative PCR. However, none of them is able to monitor miRNA levels expressed in living cancer cells in a real-time fashion. Some fluorescennt biosensors developed recently from carbon nanomaterials, such as single-walled carbon nanotubes (SWNTs), graphene oxide (GO), and carbon nanoparticles, have been successfully used for assaying miRNA in vitro; however the preparation processes are often expensive, complicated and time-consuming, which have motivated the research on other substitute and novel materials. Herein we present a novel sensing strategy based on peptide nucleic acid (PNA) probes labeled with fluorophores and conjugated with an NMOF vehicle to monitor multiplexed miRNAs in living cancer cells. The NMOF works as a fluorescence quencher of the labelled PNA that is firmly bound with the metal center. In the presence of a target miRNA, PNA is hybridized and released from the NMOF leading to the recovery of fluorescence. This miRNA sensor not only enables the quantitative and highly specific detection of multiplexed miRNAs in living cancer cells, but it also allows the precise and in situ monitoring of the spatiotemporal changes of miRNA expression.

Topics: Biosensing Techniques; Cell Line, Tumor; Cell Survival; Curcumin; Flow Cytometry; Fluorescent Dyes; Graphite; Humans; Liver Neoplasms; MCF-7 Cells; MicroRNAs; Microscopy, Fluorescence; Nanoparticles; Nanostructures; Nanotubes, Carbon; Organometallic Compounds; Oxides; Peptide Nucleic Acids; Real-Time Polymerase Chain Reaction

Bisdemethoxycurcumin (BDCur) has been found widely in foods such as cheese, butter, etc., and in curry (powder) as a spice. It has been reported to possess anticancer activity. However, its poor absorption limited its application. Natural borneol (NB) has been used as a promoter of drug absorption and widely used in candies, beverages, baked goods, chewing gum and other foods. Thus, we investigated whether NB could potentiate the cellular uptake of BDCur, and elucidated the molecular mechanisms of their combined inhibitory effects on HepG2 cells. Our results demonstrate that NB significantly enhanced the cellular uptake of BDCur. Induction of cell cycle arrest in HepG2 cells by NB and BDCur in combination was evidenced by accumulation of the G2/M cell population. Further investigation on the molecular mechanism showed that NB and BDCur in combination resulted in a significant decrease in the expression level of Cdc2 and cyclin B. Moreover, studies also found that ROS acted as an upstream mediator in NB/BDCur-induced HepG2 cell growth inhibition and led to DNA damage with up-regulation of the expression level of phosphorylated ATM and p53. Our findings suggest that the strategy of using NB and BDCur in combination may have promising potential applications in cancer chemoprevention.

Topics: Absorption, Physiological; Antineoplastic Agents, Phytogenic; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Camphanes; Carcinoma, Hepatocellular; CDC2 Protein Kinase; Curcuma; Curcumin; Cyclin B; Diarylheptanoids; Drug Synergism; Food Additives; G2 Phase; Hep G2 Cells; Humans; Liver Neoplasms; Neoplasm Proteins; Phosphorylation; Protein Processing, Post-Translational; Reactive Oxygen Species; Rhizome; Tumor Suppressor Protein p53

Liver cancer is a leading cause of cancer deaths worldwide. The combination therapy of cytotoxic and chemosensitizing agents loaded in nanoparticles has been highlighted as an effective treatment for different cancers. However, such studies in liver cancer remain very limited. In our study, we aim to develop a novel lipid nanoparticles loaded with doxorubicin (DOX) (an effective drug for liver cancer) and curcumin (Cur) (a chemosensitizer) simultaneously, and we examined the efficacy of chemotherapy in liver cancer. DOX and Cur codelivery lipid nanoparticles (DOX/Cur-NPs) were successfully prepared using a high-pressure microfluidics technique, showing a mean particle size of around 90 nm, a polydispersity index <0.3, and a zeta potential <-10 mV. The encapsulation efficacy was >90% for both DOX and Cur. The blank lipid nanoparticles were nontoxic, as determined by a cell cytotoxicity study in human normal liver cells L02 and liver cancer cells HepG2. In vitro DOX release studies revealed a sustained-release pattern until 48 hours in DOX/Cur-NPs. We found enhanced cytotoxicity and decreased inhibitory concentration (IC)50 in HepG2 cells and reduced cytotoxicity in L02 cells treated with DOX/Cur-NPs, suggesting the synergistic effects of DOX/Cur-NPs compared with free DOX and DOX nanoparticles (NPs). The optimal weight ratio of DOX and Cur was 1:1. Annexin-V-fluorescein isothiocyanate/propidium iodide double staining showed enhanced apoptosis in HepG2 cells treated with DOX/Cur-NPs compared with free DOX and DOX-NPs. An in vivo experiment showed the synergistic effect of DOX/Cur-NPs compared with DOX-NPs on liver tumor growth inhibition. Taken together, the simultaneous delivery of DOX and Cur by DOX/Cur-NPs might be a promising treatment for liver cancer.

Topics: Animals; Apoptosis; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Delivery Systems; Hep G2 Cells; Humans; Liver Neoplasms; Male; Mice; Nanoparticles; Particle Size

Curcumin is widely used as a traditional medicine. This work was aimed to investigate its possible protective effect against chemically induced hepatocellular carcinoma (HCC) in rats. Fifty male albino rats were divided into five groups (n=10, each). The control group received a single dose of normal saline, the diethylnitrosamine (DENA) group received a single intra-peritoneal dose at 200mg/kg body weight, and the 3rd, 4th and 5th groups were given DENA and daily administrated curcunine (CUR) via intra-gastric intubation in doses of 300,200 and 100 mg/kg b.wt. respectively for 20 weeks. Serum, and liver samples were used for determination of alpha feto-protein (AFP), interleukin-2 (IL-2), interleukine-6 (IL-6), serum liver enzymes (AST, ALT, ALP and GGT) levels as well the activities and gene expression of glutathione peroxidise (GPx), glutathione reductase (GR), catalase (CAT) and super oxide dismutase (SOD). Curcumin significantly lowered the serum levels of AFP, IL-2 and IL-6, ALT, ALT, and malondialdehyde (MDA) as well gene expression of IL-2 and IL-6. In contrast it increased the gene expression and activities of Gpx, GRD, CAT and SOD. The protective effect of CUR against DEN-induced hepatocarcinogenesis in albino rats was proven.

Topics: alpha-Fetoproteins; Animals; Antioxidants; Carcinoma, Hepatocellular; Catalase; Chemical and Drug Induced Liver Injury; Curcumin; Diethylnitrosamine; Glutathione Peroxidase; Glutathione Reductase; Interleukin-2; Interleukin-6; Liver; Liver Neoplasms; Male; Malondialdehyde; Rats; Superoxide Dismutase

Application of nanoparticles has recently promising results for water insoluble agents like curcumin. In this study, we synthesized polymeric nanoparticle-curcumin (PNPC) and then showed its efficiency, drug loading, stability, and safety. Therapeutic effects of PNPC were also assessed on two cell lines and in an animal model of breast cancer. PNPC remarkably suppressed mammary and hepatocellular carcinoma cells proliferation (P < 0.05). Under the dosing procedure, PNPC was safe at 31.25 mg/kg and lower doses. Higher doses demonstrated minimal hepatocellular and renal toxicity in paraclinical and histopathological examinations. Tumor take rate in PNPC-treated group was 37.5% compared with 87.5% in control (P < 0.05). Average tumor size and weight were significantly lower in PNPC group than control (P < 0.05). PNPC increased proapoptotic Bax protein expression (P < 0.05). Antiapoptotic Bcl-2 protein expression, however, was lower in PNPC-treated animals than the control ones (P < 0.05). In addition, proliferative and angiogenic parameters were statistically decreased in PNPC-treated animals (P < 0.05). These results highlight the suppressing role for PNPC in in vitro and in vivo tumor growth models. Our findings provide credible evidence for superior biocompatibility of the polymeric nanocarrier in pharmacological arena together with an excellent tumor-suppressing response.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Line; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Carriers; Drug Stability; Female; Humans; Liver Neoplasms; Mice; Mice, Inbred BALB C; Micelles; Nanoparticles; Polymers

The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently activated in liver CSCs is NF-κB signaling.. We evaluated the CSCs-depleting potential of NF-κB inhibition in liver cancer achieved by the IKK inhibitor curcumin, RNAi and specific peptide SN50. The effects on CSCs were assessed by analysis of side population (SP), sphere formation and tumorigenicity. Molecular changes were determined by RT-qPCR, global gene expression microarray, EMSA, and Western blotting.. HCC cell lines exposed to curcumin exhibited differential responses to curcumin and were classified as sensitive and resistant. In sensitive lines, curcumin-mediated induction of cell death was directly related to the extent of NF-κB inhibition. The treatment also led to a selective CSC-depletion as evidenced by a reduced SP size, decreased sphere formation, down-regulation of CSC markers and suppressed tumorigenicity. Similarly, NF-κB inhibition by SN50 and siRNA against p65 suppressed tumor cell growth. In contrast, curcumin-resistant cells displayed a paradoxical increase in proliferation and expression of CSC markers. Mechanistically, an important component of the CSC-depleting activity of curcumin could be attributed to a NF-κB-mediated HDAC inhibition. Co-administration of the class I/II HDAC inhibitor trichostatine sensitized resistant cells to curcumin. Further, integration of a predictive signature of curcumin sensitivity with human HCC database indicated that HCCs with poor prognosis and progenitor features are most likely to benefit from NF-κB inhibition.. These results demonstrate that blocking NF-κB can specifically target CSC populations and suggest a potential for combined inhibition of NF-κB and HDAC signaling for treatment of liver cancer patients with poor prognosis.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Histone Deacetylases; Humans; Hydroxamic Acids; Liver Neoplasms; Mice; Neoplastic Stem Cells; NF-kappa B; Signal Transduction

Although paclitaxel is an effective chemotherapeutic drug used in the treatment of many tumors, hepatoma cells, in particular, are known to be highly resistant to it. Previously, we discovered that Lin28 was closely associated with resistance to paclitaxel in Hep3B cells. The nuclear factor-kappa B (NF-κB) transcription factor, which plays an important role in tumor survival, directly activates Lin28 expression through a binding site on the first intron. Curcumin, a non-toxic anti-inflammatory agent, inhibits NF-κB activity in vitro. In this study, we reported that a combination of curcumin and paclitaxel exhibited synergistic anti-proliferative and pro-apoptosis effects on Hep3B cells, and curcumin down-regulated paclitaxel-induced enhanced expression of Lin28 and NF-κB activation. Furthermore, our results revealed that curcumin reduced Lin28 levels via mechanisms directly mediated by inhibition of NF-κB activity. These mechanism-based observations evidence that curcumin enhances the sensitivity of hepatoma cells to paclitaxe, and strongly support the notion that paclitaxel in combination with curcumin may provide a superior therapeutic index for HCC chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; NF-kappa B; Paclitaxel; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA-Binding Proteins; RNA, Messenger; Tumor Cells, Cultured

Galactosylated pullulan-curcumin conjugate (LANH2-Pu Ald-Cur SA) is developed for target specific delivery of curcumin to hepatocarcinoma cells by five step synthetic strategy, which includes oxidation of pullulan (Pu Ald), introduction of amino group to the targeting ligand (LANH2), grafting of the LANH2 to Pu Ald, modification of curcumin (Cur SA) and conjugation of Cur SA to pullulan. Nongalactosylated pullulan-curcumin conjugate (Pu-Cur SA) is also prepared to compare the enhancement in cytotoxicity offered by the targeting group. Both LANH2-Pu Ald-Cur SA and Pu-Cur SA conjugates could self assemble to micelle in water with hydrodynamic diameters of 355±9nm and 363±10nm, respectively. Both conjugates show spherical morphology and enhance stability of curcumin in physiological pH. Compared to Pu-Cur SA, LANH2-Pu Ald-Cur SA exhibits higher toxicity and internalization towards HepG2 cells. This indicates the enhanced uptake of LANH2-Pu Ald-Cur SA conjugate via ASGPR (asialoglycoprotein receptor) mediated endocytosis into HepG2 cells.

Topics: Antineoplastic Agents; Curcumin; Drug Stability; Galactose; Glucans; Hep G2 Cells; Humans; Liver Neoplasms; Magnetic Resonance Spectroscopy; Micelles; Microscopy, Electron, Scanning

The present study was planned to investigate the role of sex hormone receptor gene expression in the pathogenesis of hepatocellular carcinoma (HCC). Adult male Wistar rats were divided into seven groups. Group (1) was negative control. Groups (2), (5), (6), and (7) were orally administered with N-nitrosodiethylamine for the induction of HCC, then group (2) was left untreated, group (5) was orally treated with curcumin, group (6) was orally treated with carvacrol, and group (7) was intraperitoneally injected with doxorubicin, whereas groups (3) and (4) were orally administered only curcumin and carvacrol, respectively. The HCC group showed significant upregulation in the androgen receptor (AR) and the estrogen receptor-alpha (ERα) gene expression levels in the liver tissue. On the contrary, HCC groups treated with either curcumin or carvacrol showed significant downregulation in AR and ERα gene expression levels in the liver tissue. In conclusion, the obtained data highlight that both AR and ERα but not estrogen receptor-beta (ERβ) gene expression may contribute to the male prevalence of HCC induced in male rats. Interestingly, both curcumin and carvacrol were found to have a promising potency in alleviating the male predominating HCC.

Topics: Animals; Biological Products; Carcinoma, Hepatocellular; Curcumin; Cymenes; Diethylnitrosamine; Down-Regulation; Estrogen Receptor alpha; Estrogen Receptor beta; Gene Expression; Gonadal Steroid Hormones; Liver Neoplasms; Male; Monoterpenes; Rats; Rats, Wistar; Receptors, Androgen; Up-Regulation

Curcumin has been reported to suppress different types of clinical and experimentally-induced tumors, but due to less absorption and quick metabolism it show poor bioavailability. The present study was envisaged to investigate the possible synergistic effect of combined treatment of curcumin with piperine in suppression of diethylnitrosamine (DENA)-induced hepatocellular carcinoma (HCC) in rats, owing to permeability enhancing effect of latter. HCC was induced by supplying DENA (0.01%) in drinking water for 10 weeks. The rats were treated with curcumin (100mg/kg; p.o.) per se and curcumin along with piperine (20mg/kg; p.o.) for 4 weeks post HCC induction. The combined treatment significantly attenuated the morphological, histopathological, biochemical, apoptotic and proliferative changes in the liver and serum in comparison to curcumin per se and vehicle control group. The results of present study concluded that curcumin in combination with piperine shows better suppression of DENA-induced HCC in contrast to curcumin per se.

Topics: Alkaloids; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzodioxoles; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Diethylnitrosamine; Drug Administration Schedule; Drug Synergism; Lipid Peroxidation; Liver Neoplasms; Male; Neoplasms, Experimental; Piperidines; Polyunsaturated Alkamides; Rats

Hepatocellular carcinoma is the fifth most common cancer worldwide, with poor prognosis and resistance to chemotherapy. This gives novel cancer treatment methods an overwhelming significance. Epigenetic therapy of cancer is useful in reversing some of the cancer defects because of reversibility of the epigenetic alterations. Non-protein coding transcripts are the major part of our transcriptome. MEG3 is a tumor suppressor long non-coding RNA being expressed in many normal tissues. Methylation of MEG3 promoter region elicits the decrease in its expression in hepatocellular cancer cells. Bioactive nutrients including curcumin offer great potential in altering DNA methylation status which is catalyzed via DNMT1, DNMT3A and 3B.. Herein, we aimed to study RNA-based epigenetic effects of dendrosomal curcumin (DNC) on hepatocellular cancer (HCC).. To this end miRNA-dependent regulation of MEG3 expression under treatment with DNC was studied by evaluating the modulatory involvement of miR-29a for DNMT3A and 3B and miR-185 for DNMT1.. We evaluated DNC entrance to HCC cells with the use of fluorescent characteristics of curcumin. Next we performed the MTT assay to evaluate DNC and dendrosome effects on HCC cell viability. The coding and non-coding genes expression analyses were done using quantitative-PCR.. In result we found that the DNC dependent overexpression of miR-29a and miR-185 (P < 0.01) can down-regulate the expression of DNMT1, 3A and 3B (P < 0.05) and subsequently overexpresses MEG3 (P < 0.05).. DNC potentially can induce DNA hypomethylation and reexpression of silenced tumor suppressor genes in HCC. These data suggest that DNC could be an effective choice for epigenetic therapy of HCC.

Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; DNA Methyltransferase 3B; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; MicroRNAs; Promoter Regions, Genetic; RNA, Long Noncoding; Up-Regulation

We have designed and developed curcumin (Ccn)-loaded albumin nanoparticles (BNPs) surface-functionalized with glycyrrhetinic acid (Ccn-BNP-GA) for GA receptor-mediated targeting. Ccn-BNP-GA was prepared by conjugating GA as a hepatoma cell-specific binding molecule onto the surface of BNPs. Ccn-BNP-GA showed a narrow distribution with an average size of 258.8±6.4 nm, a regularly spherical shape, an entrapment efficiency of 88.55%±5.54%, and drug loading of 25.30%±1.58%. The density of GA as the ligand conjugated to BNPs was 140.48±2.784 μg/g bovine serum albumin. Cytotoxicity assay results indicated that Ccn-BNP-GA was significantly more cytotoxic to HepG2 cells and in a concentration-dependent manner. Ccn-BNP-GA also appeared to be taken up to a greater extent by HepG2 cells than undecorated groups, which might be due to the high affinity of GA for GA receptors on the HepG2 cell surface. These cytotoxicity assay results were corroborated by analysis of cell apoptosis and the cell cycle. Further, Ccn-BNP-GA showed an approximately twofold higher rate of cell apoptosis than the other groups. Moreover, proliferation of HepG2 cells was arrested in G2/M phase based on cell cycle analysis. These results, which were supported by the GA receptor-mediated endocytosis mechanism, indicate that BNPs surface-functionalized with GA could be used in targeted cancer treatment with high efficacy, sufficient targeting, and reduced toxicity.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cattle; Cell Cycle; Curcumin; Glycyrrhetinic Acid; Hep G2 Cells; Humans; Liver Neoplasms; Microscopy, Electron, Transmission; Nanomedicine; Nanoparticles; Particle Size; Serum Albumin, Bovine; Spectroscopy, Fourier Transform Infrared; Surface Properties

Anticancer activity of a novel curcumin analog (E)-2-(4-hydroxy-3-methoxybenzylidene)-5-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)cyclopentanone (CUR3d) was studied using a human hepatocellular carcinoma cell line (HepG2). The results showed that CUR3d completely inhibits the tumor cell proliferation in a dose- and time-dependent manner. CUR3d at 100 μmol/L activated the pro-apoptotic caspase-3 along with downregulation of anti-apoptotic BIRC5 and Bcl2. CUR3d treatment controlled the cancer cell growth by downregulating the expression of PI3K/Akt (Akt1, Akt2) pathway along with NF-κB. CUR3d down-regulated the members of epidermal growth receptor family (EGFR, ERBB3, ERBB2) and insulin like growth receptors (IGF1, IGF-1R, IGF2). This correlated with the downregulation of G-protein (RHOA, RHOB) and RAS (ATF2, HRAS, KRAS, NRAS) pathway signaling. CUR3d also arrested cell cycle via inhibition of CDK2, CDK4, CDK5, CDK9, MDM2, MDM4 and TERT genes. Cell cycle essential aurora kinases (AURKα, AURKβ) and polo-like kinases (PLK1, PLK2, PLK3) were also modulated by CUR3d. Topoisomerases (TOP2α, TOP2β), important factors in cancer cell immortality, as well as HIF-1α were downregulated following CUR3d treatment. The expression of protein kinase-C family (PRKC-A, PRKC-D, PRKC-E) was also attenuated by CUR3d. The downregulation of histone deacetylases (Class I, II, IV) and PARP I further strengthened the anticancer efficacy of CUR3d. Downregulation of carcinogenic cathepsins (CTSB, CTSD) and heat shock proteins exhibited CUR3d's potency as a potential immunological adjuvant. Finally, the non-toxic manifestation of CUR3d in healthy liver and lung cells along with downregulation of drug resistant gene ABCC1 further warrant need for advance investigations.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Cell Cycle; Cell Proliferation; Curcumin; DNA Fragmentation; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Rats

Curcumin is conjugated to gum arabic, a highly water soluble polysaccharide to enhance the solubility and stability of curcumin. Conjugation of curcumin to gum arabic is confirmed by (1)H NMR, fluorescence and UV spectroscopy studies. The conjugate self assembles to spherical nano-micelles (270 ± 5 nm) spontaneously, when dispersed in aqueous medium. Spherical morphology of the self assembled conjugate is evidenced by field emission scanning electron microscopy and transmission electron microscopy. The self assembly of the amphiphilic conjugate into micelle in aqueous medium significantly enhances the solubility (900 fold of that of free curcumin) and stability of curcumin in physiological pH. The anticancer activity of the conjugate micelles is found to be higher in human hepatocellular carcinoma (HepG2) cells than in human breast carcinoma (MCF-7) cells. The conjugate exhibits enhanced accumulation and toxicity in HepG2 cells due to the targeting efficiency of the galactose groups present in gum arabic.

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma, Hepatocellular; Curcumin; Drug Carriers; Female; Gum Arabic; Hep G2 Cells; Humans; Liver; Liver Neoplasms; MCF-7 Cells; Micelles

Cucurbitacin B is a plant-derived tetracyclic triterpenoid, which has been used for a variety of cancers, especially human hepatoma. Curcumin, isolated from a plant Curcuma longa also has found the anti-tumor property. In the present study, the synergistic effect of cucurbitacin B and curcumin was studied on BEL7402/5-Fu cells in vitro and BEL7402 tumor-bearing mice in vivo. The synergistic anticancer activity of these two compounds involves the two mechanisms. Firstly, curcumin synergistically enhanced the apoptosis of BEL7402/5-Fu cells induced by cucurbitacin B in the optimal mass ratio of 2:1 (cucurbitacin B:curcumin). The mechanism may result from the cell arresting in different phases of cell cycles and the apoptotic change of ultrastructure in BEL7402/5-Fu cells. Secondly, curcumin reversed the multidrug resistance (MDR) caused by cucurbitacin B in the optimized concentration of 67.9μM (25μg/ml). The mechanism was associated with the P-gp reduction, ΔΨm collapse and mitochondrial colocalization in BEL7402/5-Fu cells. The findings were consistent with the changes of the body weight and tumor volume, caspase3 activation and ATP down-regulation in vivo. In conclusion, cucurbitacin B in the combination with curcumin could serve as a novel, promising approach for human hepatoma.

Topics: Adenosine Triphosphate; Animals; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Body Weight; Carcinoma, Hepatocellular; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Activation; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Intracellular Space; Liver Neoplasms; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Triterpenes; Xenograft Model Antitumor Assays

Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primary liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Curcumin; Diffusion; Drug Synergism; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nanocapsules; Niacinamide; Phenylurea Compounds; Polymers; Sorafenib; Treatment Outcome

In children with hepatocellular carcinoma (pHCC) the 5-year overall survival rate is poor. Effects of cytostatic therapies such as cisplatin and doxorubicin are limited due to chemoresistance and tumor relapse. In adult HCC, several antitumor properties are described for the use of curcumin. Curcumin is one of the best-investigated phytochemicals in complementary oncology without relevant side effects. Its use is limited by low bioavailability. Little is known about the influence of curcumin on pediatric epithelial hepatic malignancies. We investigated the effects of curcumin in combination with cisplatin on two pediatric epithelial liver tumor cell lines. As mechanisms of action inhibition of NFkappaB, beta-catenin, and decrease of cyclin D were identified. Using a mouse xenograft model we could show a significant decrease of alpha-fetoprotein after combination therapy of oral micellar curcumin and cisplatin. Significant concentrations of curcuminoids were found in blood samples, organ lysates, and tumor tissue after oral micellar curcumin administration. Micellar curcumin in combination with cisplatin can be a promising strategy for treatment of pediatric HCC.

Topics: alpha-Fetoproteins; Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Child; Curcumin; Female; Humans; Immunoenzyme Techniques; In Vitro Techniques; Liver Neoplasms; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neovascularization, Pathologic; NF-kappa B; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The effects and possible underlying mechanism of curcumin combined with radiation in human hepatocellular carcinoma (HCC) cells in vitro were evaluated. The effects of curcumin, radiation, and combination of both on cell viability, apoptosis, NF-κB activation, and expressions of NF-κB downstream effector proteins were investigated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), NF-κB reporter gene, mitochondrial membrane potential (MMP), electrophoretic mobility shift (EMSA), and Western blot assays in Huh7-NF-κB-luc2, Hep3B, and HepG2 cells. Effect of I kappa B alpha mutant (IκBαM) vector, a specific inhibitor of NF-κB activation, on radiation-induced loss of MMP was also evaluated. Results show that curcumin not only significantly enhances radiation-induced cytotoxicity and depletion of MMP but inhibits radiation-induced NF-κB activity and expressions of NF-κB downstream proteins in HCC cells. IκBαM vector also shows similar effects. In conclusion, we suggest that curcumin augments anticancer effects of radiation via the suppression of NF-κB activation.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; I-kappa B Proteins; Liver Neoplasms; Membrane Potential, Mitochondrial; Mice; NF-kappa B; NF-KappaB Inhibitor alpha; Xenograft Model Antitumor Assays

Recent evidence indicating that phthalates promote cancer development, including cell proliferation, migration, and invasion, has raised public health concerns. Here, we show that bis(2-ethylhexyl) phthalate promotes the migration, invasion, and epithelial-mesenchymal transition of hepatocellular carcinoma cells. In addition, bis(2-ethylhexyl) phthalate increased the proportion of cancer stem cell (CSC)-like cells and stemness maintenance in vitro as well as tumor growth and metastasis in vivo. The various activities of curcumin, including anticancer, anti-inflammation, antioxidation, and immunomodulation, have been investigated extensively. Curcumin suppressed phthalate-induced cell migration, invasion, and epithelial-mesenchymal transition, decreased the proportion of CSC-like cells in hepatocellular carcinoma cell lines in vitro, and inhibited tumor growth and metastasis in vivo. We also reveal that curcumin suppressed phthalate-induced migration, invasion, and CSC-like cell maintenance through inhibition of the aryl hydrocarbon receptor/ERK/SK1/S1P3 signaling pathway. Our results suggest that curcumin may be a potential antidote for phthalate-induced cancer progression.

Topics: Animals; Carcinoma, Hepatocellular; Cell Movement; Curcumin; Extracellular Signal-Regulated MAP Kinases; Humans; Liver Neoplasms; Male; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplastic Stem Cells; Phthalic Acids; Receptors, Aryl Hydrocarbon; Signal Transduction; Small-Conductance Calcium-Activated Potassium Channels

Rhizoma Paridis saponins combined with turmeric (RT) showed well anti-hepatocarcinoma activities in our previous research. The aim of this study was to investigate the progression of the biochemical response to RT and capture metabolic variations during intragastric administration of their compatibility. In the experiment, histopathological examination and (1)H NMR method were developed and validated for the metabolic profiling of RT intervention in H22 tumor growth. Data were analyzed with principal components analysis (PCA) and partial least-squares discrimination analysis (PLS-DA). As a result, Rhizoma paridis saponins (RPS) or RT induced inflammatory cell infiltration in tumors. RT also mediated the tumor microenvironment to promote anti-tumor immunity of mice. RT significantly inhibited tumor growth rate through suppressing levels of amino acids containing alanine, asparagine, glutamine, putrescine, and sarcosine, lipid compounds, and carbohydrates like myo-inositol and arabinose in the tumor tissues. In conclusion, these results uncovered unexpectedly poor nutritional conditions in the RT-treated tumor tissues whose effect was stronger than RPS's. Therefore, RT could be a novel anticancer agent that targets on cancer metabolism through starving tumors reducing viability of cancer cells.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Curcuma; Disease Models, Animal; Female; Liver Neoplasms; Magnetic Resonance Spectroscopy; Mice; Phytotherapy; Plant Extracts; Principal Component Analysis; Rhizome; Saponins

Fatty acid synthase (FAS) is highly expressed in many kinds of human cancers, including liver cancer. Curcumin is the major active ingredient of Curcuma longa and has long been used to treat a variety of maladies. In the present study, we investigated the potential use of curcumin as a kind of FAS inhibitor for chemoprevention of liver cancer. Curcumin induced HepG2 cell apoptosis with the IC50 value of 8.84 μg/ml. It inhibited intracellular FAS activity, and downregulated expression and mRNA level of FAS in a dose-dependent manner. In addition, sodium palmitate could rescue cell apoptosis induced by curcumin. Further studies reviewed that siRNA of FAS showed similar results as curcumin. These findings suggested that curcumin might be useful for preventing or treating liver cancer.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Fatty Acid Synthases; Hep G2 Cells; Humans; Liver Neoplasms; RNA, Messenger; Transfection

No effective chemopreventive agent has been approved against hepatocellular carcinoma (HCC) to date. Since HCC is one of the hypervascular solid tumors, blocking angiogenesis represents an intriguing approach to HCC chemoprevention. The aim of the current study was to examine the combined effect of the anti-angiogenic agents: leflunomide; a disease modifying antirheumatic drug, perindopril; an angiotensin converting enzyme inhibitor (ACEI) and curcumin; the active principle of turmeric, on diethylnitrosamine (DEN)-induced HCC in mice. Eight weeks following DEN administration, there was a significant rise in immunohistochemical staining of CD31-positive endothelial cells and consequently hepatic microvessel density (MVD) as compared to normal liver. DEN treatment was associated with elevation in hepatic vascular endothelial growth factor (VEGF) level as compared to normal controls (P<0.05, 3842±72pg/ml and 2520.8±97pg/ml, respectively). Similarly, increased hepatic expression of hypoxia inducible growth factor-1α (HIF-1α) was observed in 100% of the DEN-treated animals compared to 0% in their normal counterparts. Treatment with leflunomide, perindopril or curcumin alone abrogated the DEN-induced increased MVD as well as the elevated expression of VEGF, while only curcumin inhibited HIF-1α hepatic expression. Combination of these agents showed further inhibitory action on neovascularization and synergistic attenuation of hepatic VEGF (1954.27±115pg/ml) when compared to each single agent. Histopathological examination revealed a more beneficial chemopreventive activity in the combination group compared to each monotherapy. In conclusion, the combination treatment of leflunomide, perindopril and curcumin targeting different angiogenic pathways, resulted in synergistic inhibition of angiogenesis and consequently more effective chemoprevention of HCC.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antineoplastic Agents; Antirheumatic Agents; Carcinogens; Carcinoma, Hepatocellular; Curcumin; Diethylnitrosamine; Drug Therapy, Combination; Hypoxia-Inducible Factor 1, alpha Subunit; Isoxazoles; Leflunomide; Liver; Liver Neoplasms; Male; Mice; Neovascularization, Pathologic; Perindopril; Platelet Endothelial Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

Curcumin is a yellow pigment found in turmeric (Curcuma Longa L.), and is reported, in recent studies, to have several pharmacological effects, including anti-oxidant, anti-inflammatory, anti-tumour and lipid-lowering properties. However, as most curcumin is conjugated when absorbed through the intestine, free curcumin is present at extremely low levels inside the body. Therefore, curcumin metabolites have been presumed to be responsible for the curcumin bioactivity. In this study, we first confirmed that curcumin glucuronide is the major metabolite of curcumin found in the plasma after oral administration of curcumin in rats. Next, we synthesised curcumin glucuronide and compared the effects of curcumin and curcumin glucuronide on gene expression in a human hepatoma cell line (HepG2). We found that the effects of curcumin glucuronide are weaker than those of curcumin and that this difference is related to relative absorption rates of curcumin and curcumin glucuronide into HepG2 cells.

Topics: Animals; Anti-Inflammatory Agents; Carcinoma, Hepatocellular; Curcuma; Curcumin; Hep G2 Cells; Humans; Liver Neoplasms; Male; Rats; Rats, Sprague-Dawley

Vasculogenic mimicry (VM) refers to the process in which highly invasive cancer cells mimic endothelial cells by forming blood channels. In the present study, we investigated the effect of curcumin, a natural product from turmeric, on VM of SK-Hep-1 human hepatocellular carcinoma (HCC) cells.. In vitro VM, cell migration, and matrix metalloproteinase-9 (MMP9) production of HCC cells were determined by Matrigel tube formation assay, Transwell cell migration assay, and gelatin zymography, respectively. Effects of curcumin on AKT, signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK) and nuclear factor-κB (NF-κB) signaling pathways were determined by immunoblot analysis.. At non-cytotoxic concentrations, curcumin inhibited VM, reduced cell migration and MMP9 production of the HCC cells. Further study revealed that the anti-VM effect of curcumin was due to inhibition of AKT and STAT3 phosphorylation, as confirmed by specific inhibitors.. Curcumin presents proven potential as an anti-VM agent in HCC cells, through down-regulation of STAT3 and AKT signaling pathways.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; Humans; Liver Neoplasms; Matrix Metalloproteinase 9; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; STAT3 Transcription Factor

The purpose of the present study was to evaluate the preventive effects of hydrazinocurcumin (HZC) on diethylnitrosamine (DEN)-induced hepatocarcinogenesis in a male Sprague Dawley (SD) rat model. One hundred and twenty male SD rats used in this study were divided into six groups. Those receiving DEN with curcumin (CUR) or HZC were studied compared with the DEN-alone group. The study demonstrated that DEN induced severe histological and immunohistochemical changes in liver tissues, significantly increasing the levels of liver marker enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT) and total bilirubin level (TBL)). The hepatocarcinoma incidences were 100.0%, 36.7% and 20.0% in the DEN-alone, DEN-CUR and DEN-HZC groups, respectively. Although macroscopic and microscopic features suggested that both CUR and HZC were effective in inhibiting DEN- induced hepatocarcinogenesis, HZC was exerted a stronger influence. Immunohistochemical analysis with PCNA demonstrated significantly differences among the groups (all P < 0.05). Taken together, the results suggested application of CUR and HZC could prevent the occurrence of carcinogenesis and HZC may be a more potent compound for prevention of DEN-induced hepatocarcinogenesis in rats than CUR.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Carcinogenesis; Carcinoma, Hepatocellular; Curcumin; Diethylnitrosamine; gamma-Glutamyltransferase; Hydrazines; Liver; Liver Function Tests; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Rats; Rats, Sprague-Dawley

Curcumin can inhibit proliferation of liver cancer cells by inducing apoptosis, but the specific signaling pathways involved are not completely clear. Here, we report that curcumin inhibited proliferation of MHCC97H liver cancer cells by induction of apoptosis in a concentration dependent manner via stimulating intracellular reactive oxygen species (ROS) generation. Also, we showed that increased intracellular ROS formation activated the TLR-4/MyD-88 signaling pathway, resulting in activation of caspase-8 and caspase-3, which eventually led to apoptosis in MHCC97H cells. These results showed that as an prooxidant, curcumin exerts anti-cancer effects by inducing apoptosis via the TLR-4/MyD-88 signaling pathway.

Topics: Apoptosis; Caspase 3; Caspase 8; Cell Line, Tumor; Curcumin; Humans; Liver Neoplasms; Myeloid Differentiation Factor 88; Reactive Oxygen Species; Signal Transduction; Toll-Like Receptor 4

Curcumin has been reported to be effective as a cancer therapy. However, the anti-metastatic effect and molecular mechanism(s) of curcumin in hepatocellular carcinoma (HCC) remain poorly understood. The purpose of this study was to test the effects of curcumin on HCC and its putative mechanism(s). Curcumin inhibited the proliferation of HCC cells and inhibited the migration and invasion of these cells at sub-cytotoxic concentrations. Curcumin also decreased the expression and activity of matrix metalloproteinases (MMP)-2 and MMP-9, and reduced p38 phosphorylation. Combination treatment of HCC cells with curcumin and SB203580 (a p38 signaling pathway inhibitor), generated a synergistic effect on the expression of MMP-2 and MMP-9, suggesting that the anti-metastatic effect of curcumin on HCC may involve a p38 signaling pathway.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Drug Synergism; Humans; Imidazoles; Liver Neoplasms; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Phosphorylation; Pyridines

Hepatocellular carcinoma (HCC) accounts for the majority of liver cancers. A hypoxic microenvironment is a common feature of HCC, and is associated with malignant invasion, metastasis and epithelial-mesenchymal transition (EMT) changes. Curcumin is a botanical agent derived from the dried rhizome of Curcuma longa. Although a number of preclinical studies have shown that curcumin has anticancer properties when administered in a normoxic microenvironment, no studies have directly examined the effect of curcumin on preventing HCC invasion and metastasis under hypoxic conditions. This study aimed to determine whether curcumin has effects on the hypoxia-induced malignant biological behavior of HCC. CoCl2 was used to establish a hypoxia model in vitro. The results showed that curcumin significantly decreased hypoxia-induced hypoxia inducible factor-1α (HIF-1α) protein level in HepG2 cells. Furthermore, cell proliferation, migration and invasiveness, as well as EMT changes associated with HIF-1α accumulation generated by a hypoxic microenvironment, were eliminated by curcumin. In conclusion, these data indicate that curcumin may be a viable anticancer agent in the treatment of HCC.

Topics: Antigens, CD; Antineoplastic Agents; Cadherins; Carcinoma, Hepatocellular; Cell Hypoxia; Cell Movement; Cell Proliferation; Curcumin; Drug Screening Assays, Antitumor; Epithelial-Mesenchymal Transition; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Snail Family Transcription Factors; Transcription Factors; Vimentin

Curcumin, a spice component as well as a traditional Asian medicine, has been reported to inhibit proliferation of a variety of cancer cells but is limited in application due to its low potency and bioavailability. Here, we have assessed the therapeutic effects of a novel and water soluble curcumin analog, 3,5-bis(2-hydroxybenzylidene)tetrahydro-4H-pyran-4-one glutathione conjugate [EF25-(GSH)2], on hepatoma cells. Using the MTT and colony formation assays, we determined that EF25-(GSH)2 drastically inhibits the proliferation of hepatoma cell line HepG2 with minimal cytotoxicity for the immortalized human hepatic cell line HL-7702. Significantly, EF25-(GSH)2 suppressed growth of HepG2 xenografts in mice with no observed toxicity to the animals. Mechanistic investigation revealed that EF25-(GSH)2 induces autophagy by means of a biphasic mechanism. Low concentrations (<5 µmol/L) induced autophagy with reversible and moderate cytoplasmic vacuolization, while high concentrations (>10 µmol/L) triggered an arrested autophagy process with irreversible and extensive cytoplasmic vacuolization. Prolonged treatment with EF25-(GSH)2 induced cell death through both an apoptosis-dependent and a non-apoptotic mechanism. Chloroquine, a late stage inhibitor of autophagy which promoted cytoplasmic vacuolization, led to significantly enhanced apoptosis and cytotoxicity when combined with EF25-(GSH)2. Taken together, these data imply a fail-safe mechanism regulated by autophagy in the action of EF25-(GSH)2, suggesting the therapeutic potential of the novel curcumin analog against hepatocellular carcinoma (HCC), while offering a novel and effective combination strategy with chloroquine for the treatment of patients with HCC.

Topics: Androstadienes; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Protein 5; Beclin-1; Carcinoma, Hepatocellular; Cell Proliferation; Cell Shape; Curcumin; G2 Phase Cell Cycle Checkpoints; HCT116 Cells; HEK293 Cells; HeLa Cells; Hep G2 Cells; Humans; Liver Neoplasms; Membrane Proteins; Microtubule-Associated Proteins; Tumor Burden; Wortmannin; Xenograft Model Antitumor Assays

Malignant transformation of hepatocellular carcinoma (HCC) occurs through repetitive liver injury in a context of inflammation and oxidative DNA damage. A spectrum of natural sesquiterpenoids from curcuma oil has displayed antioxidant, anti-inflammatory and anti-carcinogenic properties. The aim of the study was to investigate the hepatoprotective and anti-HCC effects of curcuma oil in vivo and in vitro. Mice were pretreated with curcuma oil (100 mg/kg) for 3 days, then treated with Concanavalin A (30 mg/kg). The hepatic tissue was evaluated for histology, CD4+ cell, interferon-γ, apoptosis, lipid peroxidation, 8-hydroxy-deoxyguanosine and MnSOD. C57L/J mice were treated with curcuma oil and 107 Hepa1-6 cells directly inoculated into liver lobes. The effects of curcuma oil on cell growth and cell death were evaluated. In addition, MnSOD, HSP60, catalase, NF-κB and caspase-3 were also investigated in the Hepa1-6 cells treated with curcuma oil. Pretreatment with curcuma oil significantly attenuates inflammation and oxidative damage by Concanavalin A. Treatment with curcuma oil can decrease the incidence of HCC. Curcuma oil inhibits cell growth and induces cell death in Hepa1-6 cells. Curcuma protected mice with hepatic injury from inflammatory and oxidative stress. Curcuma oil can inhibit hepatoma cell growth in vivo and in vitro.

Topics: Animals; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Chemical and Drug Induced Liver Injury; Concanavalin A; Curcuma; Fluorescent Antibody Technique; Gas Chromatography-Mass Spectrometry; Humans; Immunoenzyme Techniques; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Mitogens; Oxidative Stress; Plant Extracts; Tumor Cells, Cultured

Ethanol consumption induces hepatocellular carcinoma (HCC) cell metastasis by changing the extracellular matrix (ECM). Lysyl oxidase (LOX) catalyzes the cross-linkage of collagen or elastin in the ECM. LOX protein and mRNA overexpression (>21-fold compared with controls, n = 6) was detected in cirrhotic HCC patients with a history of alcoholism. LOX protein expression was induced in HCC cells after long-term treatment with ethanol (10 mM) for 20-40 passages (denoted E20-E40 cells). Pterostilbene (PSB, 1 μM) displayed significant potency to reduce LOX-mediated activity in E40 cells when combined with curcumin and its analogues. The ability of E40 cells to form colonies in soft agar was reduced by both genetic depletion of LOX and by chemical inhibitors of LOX expression. This study suggests that targeting LOX expression with food components such as PSB and curcumin may be a novel strategy to overcome ethanol-induced HCC cell metastasis in liver cancer patients.

Topics: Adult; Aged; Alcoholism; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Collagen; Curcumin; Elastin; Ethanol; Extracellular Matrix; Female; Gene Expression Regulation; Humans; Laser Capture Microdissection; Liver Neoplasms; Male; Middle Aged; Protein-Lysine 6-Oxidase; Real-Time Polymerase Chain Reaction; RNA, Messenger; Stilbenes

Hepatitis C virus (HCV) has been reported to regulate cellular microRNAs. The HCV core protein is considered to be a potential oncoprotein in HCV-related hepatocellular carcinoma, but HCV core-modulated cellular microRNAs are unknown. The HCV core protein regulates p21(Waf1/Cip1) expression. However, the mechanism of HCV core-associated p21(Waf1/Cip1) regulation remains to be further clarified. Therefore, we attempted to determine whether HCV core-modulated cellular microRNAs play an important role in regulating p21(Waf1/Cip1) expression in human hepatoma cells.. Cellular microRNA profiling was investigated in core-overexpressing hepatoma cells using TaqMan low density array. Array data were further confirmed by TaqMan real-time qPCR for single microRNA in core-overexpressing and full-length HCV replicon-expressing cells. The target gene of microRNA was examined by reporter assay. The gene expression was determined by real-time qPCR and Western blotting. Apoptosis was examined by annexin V-FITC apoptosis assay. Cell cycle analysis was performed by propidium iodide staining. Cell proliferation was analyzed by MTT assay.. HCV core protein up- or down-regulated some cellular microRNAs in Huh7 cells. HCV core-induced microRNA-345 suppressed p21(Waf1/Cip1) gene expression through targeting its 3' untranslated region in human hepatoma cells. Moreover, the core protein inhibited curcumin-induced apoptosis through p21(Waf1/Cip1)-targeting microRNA-345 in Huh7 cells.. HCV core protein enhances the expression of microRNA-345 which then down-regulates p21(Waf1/Cip1) expression. It is the first time that HCV core protein has ever been shown to suppress p21(Waf1/Cip1) gene expression through miR-345 targeting.

Topics: Apoptosis; Base Sequence; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Down-Regulation; Gene Expression Regulation, Neoplastic; Hepacivirus; Humans; Liver Neoplasms; MicroRNAs; Molecular Targeted Therapy; Viral Core Proteins

Curcumin, the major phytochemical in turmeric, exerts anti‑proliferative, anticancer and anti‑inflammatory activities in various types of cancer cells. Curcumin has been demonstrated to induce apoptosis through multiple signaling pathways; however, its association with survival pathways, including the Wnt signaling pathway, is not fully understood. The Wnt signaling pathway is involved in diverse functions, including cell development, growth and proliferation. This pathway is important for cancer cell survival and metastasis. β‑catenin and GSK3β play a key role in the Wnt signaling pathway and therefore, various members of the Wnt signaling pathway have been hypothesized to represent potential targets for anticancer therapy. In the present study, the effect of curcumin on the suppression of migration and proliferation of Hep3B hepatocarcinoma cells was investigated via suppression of Wnt signaling in vitro and in vivo. 12‑O‑tetradecanoylphorbol‑13‑acetate (TPA)‑induced cell migration was observed to be suppressed by curcumin treatment. In addition, curcumin suppressed TPA‑induced activation of Wnt signaling. These results indicate that curcumin induces anti‑migratory activity, which functions via the Wnt signaling pathway.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Humans; Liver Neoplasms; Mice; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

MicroRNAs (miRNAs) play an essential role in regulating gene expression in normal and malignant cells. Expression of the microRNA-200 (miR-200) family has been correlated with malignancy in cancers. However, whether miR-200a/b plays a role in curcumin-mediated treatment of hepatocellular carcinoma (HCC) is unknown. We performed miRNA array analyses in two different HCC cell lines (HepG2 and HepJ5). The expression patterns of miR-200 family members were assessed with real-time PCR. We overexpressed miR-200 family members using a lentiviral system and selected stably transduced clones with antibiotics. The anticancer effects of curcumin on J5-200a, J5-200b, and J5-control cells were assessed by MTT assay, flow cytometry cell cycle analysis, and TUNEL assay. We found that HepG2 cells, which were more resistant to curcumin treatment than HepJ5 cells, expressed higher levels of miR-200a/b. The MTT assay revealed that the overexpression of miR-200a/b in HepJ5 cells conferred enhanced resistance to curcumin treatment compared with the control cells. By cell cycle analysis and TUNEL assay, we found that apoptosis was increased dramatically in J5-control cells compared with J5-200a and J5-200b cells after curcumin treatment. Finally, we evaluated the levels of Bcl-2, Bax, and Bad, and found a decrease of Bcl-2 levels and increase of Bad levels in the J5-control cells treated with curcumin. The expression levels of miR-200a/b might determine the therapeutic efficacy of curcumin on HCC cells.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; bcl-Associated Death Protein; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Gene Expression; Hep G2 Cells; Humans; Liver Neoplasms; MicroRNAs; Proto-Oncogene Proteins c-bcl-2

Curcumin and 5-Fluorouracil (5-Fu) have been reported to have anticancer potentials and show certain synergetic effect on some cancer cell lines. However, the poor bioavailability and rapid metabolism limited their medical application. In this study, we encapsulated curcumin with solid lipid nanoparticles (SLN), 5-Fu with Layered double hydroxides (LDHs) separately and tested its properties and anticancer potentials. SLN-curcumin and LDH-5-Fu were determined to be 100 and 60 nm by Transmission Electron Microscopy detection, and the loading efficiency were 28%±2.5% and 16.7%±1.8%, individually. Furthermore, SLN-curcumin and LDH-5-Fu showed a significantly synergetic effect on SMMC-7721 cell stronger than plain drugs together, of which the Idrug loaded nano-carriers was only 0.315. FACS analysis revealed that the combination of SLN-curcumin and LDH-5-Fu induced 80.1% apoptosis in SMMC-7721 cells, which were 1.7-folds of the sum of the two plain drug loaded carriers. The results demonstrated the significant synergetic anticancer potentials of nano-encapsulated curcumin and 5-Fu, which could be further explored for the treatment of other carcinoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Drug Synergism; Fluorouracil; Humans; Hydroxides; Lipids; Liver Neoplasms; Nanoparticles

Liver cancer, one of the most common cancers in China, is reported to feature relatively high morbidity and mortality. Curcumin (Cum) is considered as a drug possessing anti-angiogenic, anti-inflammation and anti-oxidation effect. Previous research has demonstrated antitumor effects in a series of cancers.. In this study the in vitro cytotoxicity of Cum was measured by MTT assay and pro-apoptotic effects were assessed by DAPI staining and measurement of caspase-3 activity. In vivo anti-hepatoma efficacy of Cum was assessed with HepG2 xenografts.. It is found that Cum dose-dependently inhibited cell growth in HepG2 cells with activation of apoptosis. Moreover, Cum delayed the growth of liver cancer in a dose-dependent manner in nude mice.. Cum might be a promising phytomedicine in cancer therapy and further efforts are needed to explore this therapeutic strategy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Cell Proliferation; Curcumin; Enzyme Activation; Female; Flow Cytometry; Humans; Liver Neoplasms; Male; Mice; Mice, Nude; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

This study was conducted to evaluate the effect of mesenchymal stem cells (MSCs) and a novel curcumin derivative (NCD) on HepG2 cells (hepatoma cell line) and to investigate their effect on Notch1 signaling pathway target genes. HepG2 cells were divided into HepG2 control group, HepG2 cells treated with MSC conditioned medium (MSCs CM), HepG2 cells treated with a NCD, HepG2 cells treated with MSCs CM and NCD, and HepG2 cells treated with MSCs CM (CM of MSCs pretreated with a NCD). Expression of Notch1, Hes1, VEGF, and cyclin D1 was assessed by real-time, reverse transcription-polymerase chain reaction (RT-PCR) in HepG2 cells. In addition, HepG2 proliferation assay was performed in all groups. Notch1 and its target genes (Hes1 and cyclin D1) were downregulated in all treated groups with more suppressive effect in the groups treated with both MSCs and NCD. Also, treated HepG2 cells showed significant decrease in cell proliferation rate. These data suggest that modulation of Notch1 signaling pathway by MSCs and/or NCD can be considered as a therapeutic target in HCC.

Topics: Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Cyclin D1; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Homeodomain Proteins; Humans; Liver Neoplasms; Mesenchymal Stem Cells; Receptor, Notch1; Signal Transduction; Transcription Factor HES-1; Vascular Endothelial Growth Factor A

Curcumin from the rhizome of Curcuma longa (zingiberaceae) has been reported to be a chemopreventive agent that affects cell proliferation by arresting the cell cycle in G2 and modulating the wnt signaling pathway. We found that curcumin inhibits proliferation and induces apoptosis of human hepatocellular carcinoma (HCC) cells in a concentration-dependent manner. We identified that curcumin interrupts wnt signaling by decreasing β-catenin activity, which in turn suppresses the expression of β-catenin target genes (c-myc, VEGF and cyclin D1). Our results from molecular simulation of curcumin binding to Dvl2 protein and from binding free energy calculations suggest that curcumin may prevent axin recruitment to cellular membrane in order to maintain the functional β-catenin destruction complex in normal cells. This results in β-catenin being unable to accumulate in the nucleus, depriving the protein of its ability to bind with lymphoid enhancer factor/T cell-specific transcription factor (Lef/Tcf) and repressing its activation of target gene transcription. This may be one mechanism through which curcumin inhibits proliferation and induces apoptosis of HCC cells.

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Apoptosis; Axin Protein; Axin Signaling Complex; beta Catenin; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Cyclin D1; Dishevelled Proteins; Down-Regulation; Enzyme Inhibitors; Humans; Liver Neoplasms; Molecular Docking Simulation; Phosphoproteins; Protein Binding; Proto-Oncogene Proteins c-myc; TCF Transcription Factors; Transcription, Genetic; Vascular Endothelial Growth Factor A; Wnt Proteins; Wnt Signaling Pathway

Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic syndromes and is characterized by the accumulation of hepatic triglycerides (TG), which result from an imbalance between uptake, synthesis, export, and oxidation of fatty acids. Curcumin is a polyphenol derived from the herbal remedy and dietary spice turmeric, was found to prevent obesity and diabetes in mouse models. However, a hypolipidemic effect of curcumin in oleic acid- induced hepatocarcinoma cells has not been reported. In this study, we examined the effect of curcumin on reducing lipid accumulation in hepatic cells.. Hepatocytes were treated with oleic acid (OA) containing with or without curcumin to observe the lipid accumulation by Oil Red O stain. We also tested the effects of curcumin on triglycerides (TG) and total cholesterol (TC) in HepG2 cells. Western blot and reverse transcription polymerase chain reaction (RT-PCR) was used to measure sterol regulatory element binding proteins-1 (SREBP-1), fatty acid synthase (FAS), peroxisome proliferator-activated receptor (PPAR)-α, and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) expression.. Curcumin suppressed OA-induced lipid accumulation and TG and TC levels. Also, curcumin decreased hepatic lipogenesis such as SREBP-1, and FAS. Besides, we also found out the antioxidative effect of curcumin by increasing the expression of PPARα. Curcumin increased AMPK phosphorylation in hepatocytes.. These results indicated that curcumin has the same ability to activate AMPK and then reduce SREBP-1, and FAS expression, finally leading to inhibit hepatic lipogenesis and hepatic antioxidative ability. In this report, we found curcumin exerted a regulatory effect on lipid accumulation by decreasing lipogenesis in hepatocyte. Therefore, curcumin extract may be active in the prevention of fatty liver.

Topics: AMP-Activated Protein Kinases; Carcinoma, Hepatocellular; Curcumin; Hep G2 Cells; Humans; Lipid Metabolism; Liver; Liver Neoplasms; Oleic Acid; Phosphorylation; Sterol Regulatory Element Binding Protein 1; Triglycerides

To explore effects and possible mechanisms of curcumin on hypoxia induced epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma cell line HepG2.. HepG2 cells were divided to 3 groups, i.e., the normal control group, the CoCl2 group, and the CoCl2 plus 10 micromol/L curcumin group. The proliferation of HepG2 was determined using MTT assay. The migration of HepG2 was detected by wound healing assay.The mRNA expression of hypoxia-inducible factor-1 (HIF-1alpha) was evaluated with real-time RT-PCR. The protein expressions of HIF-1alpha, epithelial-cadherin (E-cadherin), and vimentin were determined using Western blot.. Compared with the normal control group, the proliferation and migration of HepG2 cells under CoCl2-induced hypoxia significantly increased, the expression of HIF-1alpha was up-regulated, and the expression of E-cadherin protein was obviously down-regulated, and the expression of vimentin significantly increased (all P < 0.05). Intervention by curcumin significantly inhibited the proliferation and migration of hypoxic HepG2 cells, and expressions of HIF-1alpha and vimentin decreased, and the expression of E-cadherin was up-regulated, showing statistical difference when compared with those of the CoCl2 group (P < 0.05). There was no statistical difference in HIF-1alpha mRNA expression among the 3 groups (P > 0.05).. Curcumin could reverse the proliferation and migration of HepG2 cells under CoCl2-induced hypoxia condition, which might be associated with inhibiting up-regulated expressions of HIF-1alpha protein and EMT.

Topics: Antigens, CD; Cadherins; Carcinoma, Hepatocellular; Cell Hypoxia; Curcumin; Epithelial-Mesenchymal Transition; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Vimentin

The potential neuroprotective benefits of curcumin against cisplatin neurotoxicity were investigated. Curcumin is a polyphenol derived from the rhizome of Curcuma longa whose pharmacological effects include antioxidant, anti-inflammatory and anti-cancer properties. Cisplatin is a potent chemotherapeutic drug with activity against a wide variety of tumors, although it has notorious side effects. Cisplatin neurotoxicity is clinically evident in patients that have undergone a full course of chemotherapy and develop a peripheral neuropathy that may affect the treatment regimen and the patient's qualify of life. In this study, we examined whether curcumin can protect against cisplatin neurite outgrowth inhibition in PC12 cells, which is an indicator of the protective potential against neuropathy. We also investigated whether curcumin affects cisplatin effectiveness by analyzing the modulation of p53 gene expression and its effect on cisplatin cytotoxicity in HepG2 tumor cells. Non-cytotoxic concentrations of curcumin reduced in vitro neurotoxicity of cisplatin in PC12 cells. The treatment of PC12 cells with cisplatin (10μg/mL) significantly reduced neurite outgrowth. The tested concentration of curcumin (1.0 and 10μg/mL) did not result in neurite toxicity but nevertheless diminished cisplatin-induced inhibition of neurite outgrowth by up to 50% (p<0.05). Our results indicate that curcumin does not compromise cisplatin's anticancer activity. Curcumin neither suppressed p53 mRNA transcription nor protected tumor cells against cisplatin cytotoxicity. These results indicate that curcumin may reduce cisplatin-induced neurotoxicity, and clinical studies should potentially be considered.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Differentiation; Cell Survival; Cisplatin; Curcumin; Cytoprotection; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Nerve Growth Factor; Neurites; Neurons; Neuroprotective Agents; PC12 Cells; Rats; RNA, Messenger; Transcription, Genetic; Tumor Suppressor Protein p53

Rhizoma paridis saponins (RPS) played a good antitumor role in many clinical applications. However, low oral bioavailability limited its application. In this research, water extract of Curcuma (CW) significantly increased antitumor effect of Rhizoma paridis saponins (RPS). GC-MS was used to identify its polar composition. HPLC was applied for determination of the content of curcuminoids in CW. As a result, 47 analytes with 0.65% of curcuminoids were identified in CW. According to the in vivo anti-tumor data, the best proportion of curcuminoids in CW with RPS was 16:500 (w/w). Using this ratio, curcuminoids significantly increased absorption of RPS in the everted rat duodenum sac system. In addition, curcuminoids decreased the promotion of RPS on rhodamine 123 efflux. The effect of curcuminoids was similar to that of the P-gp inhibitor, cyclosporin A in combination with RPS. In conclusion, drug combination of water extract of Curcuma with RPS was a good method to increase the antitumor effect of RPS. This combination would be a potent anticancer agent used in the prospective application.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcuma; Dose-Response Relationship, Drug; Female; Fluorescent Dyes; Gas Chromatography-Mass Spectrometry; Intestinal Absorption; Liliaceae; Liver Neoplasms; Mice; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Rhizome; Rhodamine 123; Saponins; Solvents; Water

Chemopreventive effects of caffeine and curcumin were evaluated in the diethylnitrosamine (DEN)-induced hepatocarcinogenic rat model. Animals injected with DEN for 10 weeks (G2-10w) and 14 weeks (G2-14w) were hepato-carcinogenic rats. Animals injected with DEN and treated with curcumin and caffeine for 10 weeks (G3-10w, G4-10w) and 14 weeks (G3-14w, G4-14w) were compared with those in G2. Macroscopic and microscopic features suggested that treatment with caffeine, but not curcumin, for 10 and 14 weeks was effective in inhibiting DEN-induced hepatocarcinogenesis. Immunohistochemical and western blot analysis with proliferating cell nuclear antigen and glutathione S-transferase-P antibodies also showed that expression levels of these hepato-carcinogenic markers were more efficiently reduced by treatment with caffeine than curcumin. Our data demonstrate that caffeine could be a more potent compound than curcumin for prevention of hepatocarcinogenesis in DEN-induced rats.

Topics: Animals; Anticarcinogenic Agents; Caffeine; Carcinoma, Hepatocellular; Curcumin; Diethylnitrosamine; Glutathione S-Transferase pi; Liver; Liver Neoplasms; Male; Organ Size; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Transaminases

Recent understanding on cancer therapy indicated that targeting metastatic signature or angiogenic switch could be a promising and rational approach to combat cancer. Advancement in cancer research has demonstrated the potential role of various tumor suppressor proteins in inhibition of cancer progression. Current studies have shown that axonal sprouting inhibitor, semaphorin 3A (Sema 3A) acts as a potent suppressor of tumor angiogenesis in various cancer models. However, the function of Sema 3A in regulation of melanoma progression is not well studied, and yet to be the subject of intense investigation.. In this study, using multiple in vitro and in vivo approaches we have demonstrated that Sema 3A acts as a potent tumor suppressor in vitro and in vivo mice (C57BL/6) models. Mouse melanoma (B16F10) cells overexpressed with Sema 3A resulted in significant inhibition of cell motility, invasiveness and proliferation as well as suppression of in vivo tumor growth, angiogenesis and metastasis in mice models. Moreover, we have observed that Sema 3A overexpressed melanoma clone showed increased sensitivity towards curcumin and Dacarbazine, anti-cancer agents.. Our results demonstrate, at least in part, the functional approach underlying Sema 3A mediated inhibition of tumorigenesis and angiogenesis and a clear understanding of such a process may facilitate the development of novel therapeutic strategy for the treatment of cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Apoptosis; Blotting, Western; Case-Control Studies; Cell Adhesion; Cell Movement; Cell Proliferation; Cells, Cultured; Curcumin; Dacarbazine; Human Umbilical Vein Endothelial Cells; Humans; Immunoenzyme Techniques; Liver Neoplasms; Lung Neoplasms; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Phosphorylation; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Semaphorin-3A; Wound Healing

Survivin is a potential therapeutic target for cancer. Increased survivin expression promotes cell survival and therapeutic resistance. However, there is little information regarding whether the expression level of survivin affects curcumin treatment in hepatocellular carcinoma (HCC).. Survivin expression was suppressed in HCC cells using a short interfering RNA (siRNA) technique. The anticancer effects of curcumin were examined using a biosensor system, MTT assay, TUNEL assay, and cell cycle analysis.. Curcumin resistance developed in cells with suppressed survivin, in contrast to the parental cells, as determined by survival assays. Cell cycle analysis and TUNEL assays revealed that the apoptotic cell population was increased in the scrambled-siRNA cells treated with curcumin compared with the survivin-siRNA cells. Suppression of survivin expression resulted in curcumin resistance via the modulation of Bcl-2 and Bax expression.. We conclude that the expression levels of survivin may mediate the therapeutic efficacy of curcumin in HCC cells.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Survival; Curcumin; Drug Resistance, Neoplasm; Hep G2 Cells; Humans; Inhibitor of Apoptosis Proteins; Liver Neoplasms; Proto-Oncogene Proteins c-bcl-2; RNA Interference; RNA, Small Interfering; Survivin

This study aimed at exploring the role of curcumin and taurine alone or in combination against cultured human hepatoma cells (Huh-7 cells).. Huh-7 cells were plated and treated with various concentrations of curcumin and/or taurine. Hemocytometer cell count, cell viability, quantification of γ-IFN concentrations, and flow cytometric analyses for CD4, CD8, and CD25 were carried out.. There were significant increases in the levels of cell density, γ-IFN, and CD8, accompanied with significant decrease in the level of CD4, when comparing cultured cells treated with curcumin and taurine with control cultured cells.. Curcumin/taurine in combination formula is better treatment than single therapy, with respect to cell density and γ-IFN. Moreover, curcumin/taurine combined therapy enhances immunity by stimulating the CD4(+) T-helper cells with consequent induction of CD8 T-cell responses to lyse tumor cells.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; CD4 Antigens; CD8 Antigens; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Interferon-gamma; Interleukin-2 Receptor alpha Subunit; Liver Neoplasms; Taurine

Tumor hypoxia, a common pathophysiological feature of solid tumors, contributes to drug resistance and treatment failure. Here, we demonstrate that hypoxia in HepG2 cells induces resistance towards cytotoxicity of curcumin, a promising anticancer agent.. The number of surviving cells after exposure to chemotherapeutic drugs under normoxia (ambient O(2)) and hypoxia (1% O(2)) was determined by crystal violet staining. The expression levels of drug transporter genes were analyzed by quantitative real-time reverse transcription-polymerase chain reaction.. Increased resistance to curcumin, as well as to etoposide and doxorubicin, was observed in HepG2 cells under hypoxia. Gene expression analysis revealed that hypoxia increased the expression of ATP-binding cassette (ABC) drug transporter genes, sub-family C including ABCC1, ABCC2, and ABCC3, by more than two-fold. While expression of ABC drug transporter genes sub-family B member 1 and sub-family G member 2 (ABCB2/P-gp and ABCG2, respectively) did not change significantly. Both inhibitors of ABCC1/ABCC2 and depletion of intracellular glutathione levels were able to reverse hypoxia-induced curcumin resistance.. ABCC1 and ABCC2 play an important role in hypoxia-induced curcumin resistance in human hepatocellular carcinoma.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Hypoxia; Curcumin; Drug Resistance, Neoplasm; Glutathione; Hep G2 Cells; Humans; Liver Neoplasms; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins

The aim of the present study was to assess the potential chemopreventive effects of myrrh (Commiphora molmol) vs. turmeric (Curcuma longa) in hepatocarcinogenic rats induced by a single intraperitoneal injection of diethylnitrosamine (DENA) (200 mg/kg body weight). Ninety male Wistar rats used in this study were randomly divided into six equal groups (n=15). Group 1 rats served as negative controls; group 2 received a single i.p. injection of DENA and served as positive controls. Rats in both groups were fed on basal diet. Group 3 rats were fed a diet containing 5% turmeric, whereas group 4 rats were fed a diet containing 2% myrrh. Rats in groups 5 and 6 received a single i.p. injection of DENA and were fed diets containing 5% turmeric and 2% myrrh, respectively. The study demonstrated that DENA caused a significant increase in serum indices of liver enzymes and also severe histological and immunohistochemical changes in hepatic tissues. These included disorganized hepatic parenchyma, appearance of pseudoacinar and trabecular arrays of hepatocytes and alterations in CD10-immunoreactivity. Dietary supplementation of turmeric relatively improved the biochemical parameters to values approximating those of the negative controls and delayed the initiation of carcinogenesis. In contrast, myrrh did not improve the biochemical parameters or delay the hepatocarcinogenesis. Both turmeric and myrrh induced significant biochemical and histological changes in non-treated rats. In conclusion, DENA significantly changes the biological enzymatic activities in serum and the integrity of hepatic tissues. Phytochemicals with potential hepatoprotective effects must be applied cautiously owing to their potential hepatotoxicity.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carcinoma, Hepatocellular; Curcuma; Dietary Supplements; Diethylnitrosamine; Liver Neoplasms; Male; Nitric Oxide; Rats; Rats, Wistar; Terpenes; Vascular Endothelial Growth Factor A

The mechanisms underlying the antiproliferative and antitumor activities of aromatic turmerone (ar-turmerone), a volatile turmeric oil isolated from Curcuma longa Linn., have been largely unknown. In this study, 86% pure ar-turmerone was extracted by supercritical carbon dioxide and liquid-solid chromatography and its potential effects and molecular mechanisms on cell proliferation studied in human hepatocellular carcinoma cell lines. Ar-turmerone exhibited significant antiproliferative activity, with 50% inhibitory concentrations of 64.8 ± 7.1, 102.5 ± 11.5, and 122.2 ± 7.6 μg/mL against HepG2, Huh-7, and Hep3B cells, respectively. Ar-turmerone-induced apoptosis, confirmed by increased annexin V binding and DNA fragmentation, was accompanied by reactive oxygen species (ROS) production, mitochondrial membrane potential dissipation, increased Bax and p53 up-regulated modulator of apoptosis (PUMA) levels, Bax mitochondrial translocation, cytochrome c release, Fas and death receptor 4 (DR4) augmentation, and caspase-3, -8, and -9 activation. Exposure to caspase inhibitors, Fas-antagonistic antibody, DR4 antagonist, and furosemide (a blocker of Bax translocation) effectively abolished ar-turmerone-triggered apoptosis. Moreover, ar-turmerone stimulated c-Jun N-terminal kinase (JNK) and extracellular signal-related kinase (ERK) phosphorylation and activation; treatment with JNK and ERK inhibitors markedly reduced PUMA, Bax, Fas, and DR4 levels and reduced apoptosis but not ROS generation. Furthermore, antioxidants attenuated ar-turmerone-mediated ROS production; mitochondrial dysfunction; JNK and ERK activation; PUMA, Bax, Fas, and DR4 expression; and apoptosis. Taken together, these results suggest that ar-turmerone-induced apoptosis in HepG2 cells is through ROS-mediated activation of ERK and JNK kinases and triggers both intrinsic and extrinsic caspase activation, leading to apoptosis. On the basis of these observations, ar-turmerone deserves further investigation as a natural anticancer and cancer-preventive agent.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Carbon Dioxide; Carcinoma, Hepatocellular; Caspases; Cell Line, Tumor; Chromatography, Supercritical Fluid; Curcuma; Cytochromes c; Drug Screening Assays, Antitumor; Extracellular Signal-Regulated MAP Kinases; Fas Ligand Protein; Hep G2 Cells; Humans; Ketones; Liver Neoplasms; MAP Kinase Kinase 4; Membrane Potential, Mitochondrial; Proto-Oncogene Proteins; Reactive Oxygen Species; Sesquiterpenes; Signal Transduction

Glucose-regulated protein 78 (GRP78) plays an important role in the therapeutic treatment and progression of cancer. However, little is known about the effect of GRP78 expression to curcumin in hepatocellular carcinoma (HCC).. In this study, we generated GRP78 knockdown cells (GRP78KD) by a short interfering RNA (siRNA) technique. The antiproliferation effects of curcumin were determined by MTT assay, TUNEL assay, and cell cycle determination.. We found that GRP78KD cells were more resistant to curcumin treatment compared with the parental cells in MTT assay. The apoptosis cell population was increased in scrambled-siRNA cells treated with curcumin compared with GRP78KD cells in cell cycle distribution and TUNEL assays. Finally, we found that knocking down GRP78 causes resistance to curcumin treatment through the suppression of caspase-3 and caspase-8 expression levels.. We conclude that the expression level of GRP78 may contribute to the therapeutic effect of curcumin on HCC cells.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Cycle; Cell Proliferation; Curcumin; Endoplasmic Reticulum Chaperone BiP; Flow Cytometry; Heat-Shock Proteins; Humans; In Situ Nick-End Labeling; Liver Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Tumor Cells, Cultured

Curcumin, a yellow component of turmeric or curry powder, has been demonstrated to exhibit anti-carcinogenic effects in vitro, in vivo, and in human clinical trials. One of its molecular targets is protein kinase C (PKC) which has been reported to play essential roles in apoptosis, cell proliferation, and carcinogenesis. In this study, PKC mRNA expression was significantly inhibited in curcumin-treated human hepatocellular carcinoma (HCC) Hep 3B cells identified using a kinase cDNA microarray. Furthermore, curcumin decreased total protein expression of all PKCs in a time-related manner by immunoblotting of whole cell lysates, nuclear, membrane, and cytosolic fractions. In cytosolic fraction, the expression of PKC-α was totally inhibited by curcumin. In contrast, the expression levels of PKC-ζ and -μ were dramatically increased. Increases in expression of PKC-δ and PKC-ζ in the membrane and nucleus, and PKC-ι in the membrane were detected. In summary, the changes in expression and distribution of subcellular PKC isoforms in curcumin-treated Hep 3B cells suggest possible PKC-associated anti-tumor mechanisms of curcumin and provide alternative therapies for human HCC.

Topics: Anticarcinogenic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Membrane; Cell Nucleus; Curcumin; Cytosol; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Liver Neoplasms; Oligonucleotide Array Sequence Analysis; Protein Kinase C

Curcumin is a major active component of Curcuma aromatica salisb, which has been shown to inhibit proliferation of a wide variety of tumor cells. In this study, the molecular mechanisms of curcumin inducing apoptosis in human hepatoma SMMC-7721 cells were examined. We find that curcumin inhibits the growth of SMMC-7721 cells significantly in a concentration-depenent manner, with typical apoptotic morphological changes of cellular nuclei. Annexin-V/PI double staining detected by flow cytometry and expression of the relative apoptotic proteins (Bax, Bcl-2 and caspase-3) revealed a strong apoptosis-inducing competent of curcumin in SMMC-7721 cells. Curcumin increased the expression of bax protein while decreasing that of bc1-2 protein significantly. The results suggest that curcumin induction of apoptosis involves modulation of bax/bcl-2 in SMMC-7721 cells and provide a molecular basis for the development of naturally compounds as novel anticancer agents for human hepatomas.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Hepatocellular; Caspase 3; Cell Growth Processes; Cell Line, Tumor; Cell Nucleus; Curcumin; Humans; Liver Neoplasms

Curcuma zedoaria (Berg.) Rosc., a traditional Chinese herb, was used widely but absolutely prohibited for the pregnant in clinic. Based on that there is abundant angiogenesis in endometrium and placenta during gestation period, we hypothesized that some components from it could inhibit angiogenesis and then damaged the supply of oxygen and nutrition to the embryo, which finally led to gestation failure.. This study was set to demonstrate whether essential oil, major components of Curcuma zedoaria had anti-angiogenic effect.. Essential oil of Curcuma zedoaria (EO-CZ) was abstracted by steam distillation extraction. Cell proliferation assay and two angiogenic models, rat aortic ring assay and chick embryo chorioallantoic membrane assay were presented. Furthermore, melanoma growth and experimental lung metastasis assay in mice were performed to evaluate its anti-angiogenesis effect in vivo. Immunohistochemical analysis and enzyme-linked immunosorbent assay (ELISA) were used to respectively detect the expression of CD34 and matrix metalloproteinases (MMPs).. EO-CZ exhibited anti-proliferative effect on B16BL6 and SMMC-7721 cells, the IC(50), respectively was 41.8 μg/ml and 30.7 μg/ml, and on HUVEC (Human Umbilical Vein Endothelial Cells) cells with IC(50) of far more than 120 μg/ml. Both 20 μg/ml and 40 μg/ml EO-CZ indicated significant suppression on sprouting vessels of aortic ring and formation of microvessels in chick embryo chorioallantoic membrane in vitro. Moreover, solid melanoma grown in left oxter of mice was obviously inhibited after oral intake of 100 and 200 mg/kg of EO-CZ a day for 28 days, and CD34 expression indicating angiogenesis in melanoma reduced significantly compared with control; melanoma metastatic nodules in lung were detected to be inhibited, as well as MMP-2 and MMP-9 expression in serum.. Essential oil, a fat-soluble fraction of Curcuma zedoaria, presented anti-angiogenic activity in vitro and in vivo, resulting in suppressing melanoma growth and lung metastasis. And this was associated with down-regulating MMPs.

Topics: Angiogenesis Inhibitors; Animals; Aorta, Thoracic; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Chick Embryo; Chorioallantoic Membrane; Curcuma; Endothelial Cells; Humans; In Vitro Techniques; Liver Neoplasms; Lung Neoplasms; Male; Melanoma, Experimental; Mice; Neovascularization, Pathologic; Neovascularization, Physiologic; Oils, Volatile; Phytotherapy; Plant Extracts; Rats; Rhizome

Two-year toxicity studies were conducted on the widely used herbal products, goldenseal and milk thistle, in male and female F344/N rats and B6C3F1 mice. With goldenseal root powder, the primary finding was an increase in liver tumors in rats and mice, and with milk thistle extract, a decrease in spontaneous background tumors including mammary gland tumors in female rats and liver tumors in male mice. Increased tumorigenicity in rodents exposed to goldenseal root powder may be due in part to the topoisomerase inhibition properties of berberine, a major alkaloid constituent in goldenseal, or its metabolite, berberrubine. In the clinic, use of topoisomerase-inhibiting agents has been associated with secondary tumor formation and inhibition in DNA repair processes. In contrast, the radical-scavenging and antioxidant properties of silibinin and other flavonolignans in milk thistle extract may have contributed to the decrease in background tumors in rodents in the present studies. The fate of the active constituents of goldenseal and milk thistle is similar in humans and rodents; therefore, the modes of action may translate across species. Further studies are needed to extrapolate the findings to humans.

Topics: Animals; Berberine; Body Weight; Carcinogens; Female; Flavonolignans; Hydrastis; Liver Neoplasms; Male; Mice; Mice, Inbred Strains; Plant Preparations; Plant Roots; Rats; Rats, Inbred F344; Silybin; Silybum marianum; Silymarin; Topoisomerase Inhibitors; Toxicity Tests, Chronic

The aim of the present study was to investigate the apoptosis of human hepatocellular carcinoma cell line HepG 2 induced by a new curcumin analogue, GL63. HepG 2 cells were treated with increasing doses of GL63 and curcumin for 48 h. The proliferation of cells was detected with MTT. The apoptosis were examined by flow cytometry. The caspase-3 activity was detected by western blotting. ER calcium stores were assessed by the fluorescent calcium indicator fura-2/AM. The protein expression of ER stress pathway, GRP78, XBP-1, ATF-4 and CHOP were examined with western blotting. Growth inhibitory effect was observed for treatment with GL63 in a dose-dependent manner and with more potential than curcumin. GL63 at 20 microM induced significant apoptosis in HepG 2 cells. Furthermore, GL63 induced the ER stress response, up-regulation of CHOP, XBP-1, ATF-4 and GRP78 expression in a dose-dependent, while curcumin had no effect on ER stress. These results suggest that GL63 has more potent anti-tumor activity than curcumin, which is associated with activation of ER stress and induction of apoptosis in HepG 2 cells.

Topics: Activating Transcription Factor 4; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Blotting, Western; Bromobenzenes; Calcium; Carcinoma, Hepatocellular; Caspase 3; Cell Survival; Curcumin; DNA-Binding Proteins; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Flow Cytometry; Heat-Shock Proteins; Hep G2 Cells; Humans; Liver Neoplasms; Pentanones; Rats; Regulatory Factor X Transcription Factors; Stress, Physiological; Time Factors; Transcription Factor CHOP; Transcription Factors; X-Box Binding Protein 1

Hepatitis B virus (HBV)-induced hepatitis and carcinogen-induced hepatocellular carcinoma (HCC) are associated with serum androgen concentration. However, how androgen or the androgen receptor (AR) contributes to HBV-induced hepatocarcinogenesis remains unclear. We found that hepatic AR promotes HBV-induced hepatocarcinogenesis in HBV transgenic mice that lack AR only in the liver hepatocytes (HBV-L-AR(-/y)). HBV-L-AR(-/y) mice that received a low dose of the carcinogen N'-N'-diethylnitrosamine (DEN) have a lower incidence of HCC and present with smaller tumor sizes, fewer foci formations, and less alpha-fetoprotein HCC marker than do their wild-type HBV-AR(+/y) littermates. We found that hepatic AR increases the HBV viral titer by enhancing HBV RNA transcription through direct binding to the androgen response element near the viral core promoter. This activity forms a positive feedback mechanism with cooperation with its downstream target gene HBx protein to promote hepatocarcinogenesis. Administration of a chemical compound that selectively degrades AR, ASC-J9, was able to suppress HCC tumor size in DEN-HBV-AR(+/y) mice. These results demonstrate that targeting the AR, rather than the androgen, could be developed as a new therapy to battle HBV-induced HCC.

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Base Sequence; Carcinoma, Hepatocellular; Cell Transformation, Viral; Curcumin; Diethylnitrosamine; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Humans; Liver; Liver Neoplasms; Male; Mice; Mice, Knockout; Mice, Transgenic; Molecular Sequence Data; Promoter Regions, Genetic; Receptors, Androgen; RNA, Viral; Time Factors; Transcription, Genetic; Transfection; Tumor Burden; Viral Load

A case of life-threatening infantile hemangioendothelioma of the liver in a 6-month-old infant treated successfully with the dietary supplement curcumin is reported, with 6-year follow-up. Implications for pathogenesis based on sites of action of curcumin are considered.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Curcumin; Diagnostic Imaging; Dietary Supplements; Hemangioendothelioma; Humans; Infant; Liver Neoplasms; Remission Induction; Treatment Outcome

We have synthesized novel cationic poly(butyl) cyanoacrylate (PBCA) nanoparticles coated with chitosan, formulation of curcumin nanoparticles. The size and zeta potential of prepared curcumin nanoparticles were about 200 nm and +29.11 mV, respectively with 90.04% encapsulation efficiency. The transmission electron microscopy (TEM) study revealed the spherical nature of the prepared nanoparticles along with confirmation of particle size. Curcumin nanoparticles demonstrate comparable in vitro therapeutic efficacy to free curcumin against a panel of human hepatocellular cancer cell lines, as assessed by cell viability (3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide assay [MTT assay]) and proapoptotic effects (annexin V/propidium iodide staining). In vivo, curcumin nanoparticles suppressed hepatocellular carcinoma growth in murine xenograft models and inhibited tumor angiogenesis. The curcumin nanoparticles' mechanism of action on hepatocellular carcinoma cells is a mirror that of free curcumin.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Biological Availability; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Chitosan; Curcumin; Drug Carriers; Enbucrilate; Humans; Liver Neoplasms; Male; Mice; Mice, Nude; Microscopy, Electron, Transmission; Nanoparticles; Neoplasm Transplantation; Rats; Rats, Sprague-Dawley; Transplantation, Heterologous

Hepatocellular carcinoma (HCC) is one of the most common human cancers and the patients' five-year survival rate is very low. Growing evidence indicates that interleukin-6 (IL-6) is a risk factor for HCC. High serum IL-6 may promote HCC development in hepatitis B patients. Therefore, IL-6 could be considered a HCC biomarker and blockade of IL-6 pathway may be a promising therapeutic alternative for HCC. STAT3 is major pathway to mediate signal from IL-6 to the nucleus, where different genes associated with proliferation and apoptosis are regulated. We previous reported that IL-6 induces cell survival upon drug treatment in HCC cells and inhibition of IL-6/STAT3 pathway using anti-IL-6 antibody or STAT3 small-molecule inhibitor LLL12 reduces this effect. Here we summarized the recent studies of IL-6 in HCC and showed another STAT3 small-molecule inhibitor FLLL32 also blocked IL-6-induced STAT3 activation in HCC cells. FLLL32 is a novel curcumin analogue, which has been described to suppress the constitutive activation of STAT3 in pancreatic and breast cancer cells in vitro and vivo. We demonstrated that FLLL32 blocked IL-6-induced STAT3 phosphorylation and nuclear translocation.

Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Nucleus; Curcumin; Humans; Interleukin-6; Liver Neoplasms; Phosphorylation; Risk Factors; STAT3 Transcription Factor

To assess the interaction of the hydroxy-3-methylglutaryl-coezyme A reductase inhibitor lovastatin individually and in combination with 3 natural plant compounds on hepatocarcinoma cell growth.. The cytotoxic effects of lovastatin in combination with epigallocatechin gallate (EGCG), capsaicin, and curcumin were investigated in cultured hepatocarcinoma cells (Hep-G2), and the interactions were depicted using an isobolographical analysis.. All compounds tested reduced Hep-G2 cell growth to various degrees. In terms of individual cytotoxicity LC50 values, curcumin (55.5 ± 7.6 µmol/L) was found to be the most cytotoxic and had the lowest LC50, followed by lovastatin (62.3 ± 5.34 µmol/L), EGCG (82.1 ± 15.1 µmol/L), and capsaicin (199.5 ± 11.72 µmol/L). The individual LC50 values were used in a fix-fraction isobolographical analysis to predict the effect of combining lovastatin and the individual compounds. Experimentally derived LC50 values of 5 fractions containing fixed proportions of lovastatin to each of the 3 natural compounds allowed comparison of the experimentally derived LC50 to the predicted values depicted on the isobologram.. Lovastatin in combination with capsaicin was found to be synergistic at all concentrations tested, and EGCG combinations produced both synergistic and additive results. Unexpectedly, lovastatin in combination with curcumin produced an antagonistic effect on cell growth, resulting in a greater concentration required than if the compounds were used individually.

Topics: Antineoplastic Agents; Capsaicin; Carcinoma, Hepatocellular; Catechin; Cell Line, Tumor; Cells, Cultured; Curcumin; Drug Synergism; Hep G2 Cells; Herb-Drug Interactions; Humans; Liver Neoplasms; Lovastatin; Plant Extracts

Curcumin (diferuloylmethane), which is obtained from turmeric, the rhizome of Curcuma longa (L.), inhibits many human cancer cells. However, the molecular mechanisms responsible for curcumin-induced endoplasmic reticulum stress in human hepatic cellular carcinoma J5 cells, are not yet clearly understood. J5 cells were treated with various concentrations of curcumin for different durations. The cell viability was detected by MTT assay. The protein expressions of caspase-12, ATF6, GADD153, Calnexin, Calreticulin, PDI and Ero1-Lα, which are associated with endoplasmic reticulum stress and the unfolding protein response pathway, were examined by Western blot analysis. The cell cycle was analyzed by flow cytometry. The protein expressions of TCTP, Mcl-1, Bcl-2 and Bax, which are related to mitochondrial dysfunction, were detected by Western blot analysis. We also detected the ATF6 protein location by immunocytochemistry. The results showed that curcumin inhibits the proliferation of J5 cells in a time- and dose-dependent manner. Curcumin induced the unfolding protein response by down-regulating the protein expressions of Calnexin, PDI and Ero1-Lα and up-regulating the Calreticulin expression. Curcumin induces the GADD153 expression by cleaving caspase-12 and ATF6, and then by translocating ATF6 to the nucleus. Curcumin also down-regulates the protein expressions of TCTP, Mcl-1 and Bcl-2, in order to induce mitochondrial dysfunction. Curcumin induced cell cycle arrest at the G2/M phase by decreasing the Cdc2 expression. In conclusion, the present study showed that curcumin inhibits the proliferation of J5 cells by inducing endoplasmic reticulum stress and mitochondrial dysfunction.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Hepatocellular; Caspase 12; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Humans; Liver Neoplasms; Mice; Mitochondria; Tumor Protein, Translationally-Controlled 1

Topics: Aged; Antineoplastic Agents; Colonic Neoplasms; Curcumin; Female; Humans; Liver Neoplasms; Palliative Care

In the present study, shRNA plasmid of pSi-p21 targeting p21 mRNA was constructed and the effect of p21 shRNA on curcumin-induced apoptosis of human hepatoma Huh7 cells was investigated. The effect of curcumin on the expression of p21 mRNA and protein and the silence efficiency of pSi-p21 were detected with RT-PCR and Western blotting. The effect of pSi-p21 on curcumin-induced apoptosis of Huh7 cells was evaluated with DAPI staining. The results showed that curcumin significantly upregulated p21 mRNA and protein expression, which was knocked down by pSi-p21 of Huh7 cells. DAPI staining results showed that pSi-p21 significantly decreased curcumin-induced apoptosis of Huh7 cells. The data suggested that curcumin induced apoptosis of Huh7 cells via upregulation of p21 expression.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Plasmids; RNA, Messenger; RNA, Small Interfering; Transfection; Up-Regulation

The effect of curcumin on JAK-STAT signaling pathway was investigated in hepatoma cell lines Huh7 and Hep3B. Curcumin inhibited cell proliferation and induced apoptosis of both cell lines, but Huh7 cells were more sensitive to curcumin than Hep3B cells. Curcumin (50 micromol x L(-1)) significantly increased phosphorylations of p38 (T180/Y182) and STAT-1 (S727) in Huh7 and Hep3B cells, and caused relocalization of phosphorylated-STAT-1 (Y701) from cytoplasm to nucleus in Hep3B cells. In addition, curcumin (25 and 50 micromol x L(-1)) dramatically suppressed the phosphorylation level of STAT-1 (Y701) and resulted in a significant reduction of nuclear phosphorylated-STAT-1 (Y701) in Huh7 cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Curcuma; Curcumin; Humans; Janus Kinases; Liver Neoplasms; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Plants, Medicinal; Signal Transduction; STAT1 Transcription Factor

Furanodiene is a sesquiterpene extracted from the essential oil of the rhizome of Curcuma wenyujin Y.H. Chen et C. Ling (Wen Ezhu). Furanodiene is the primary component in Wen Ezhu's essential oil, accounting for more than 20% by weight. In vitro, MTT assay was used to compare the inhibitory effects of furanodiene and Wen Ezhu's essential oil on 11 human cancer cell lines. Compared to the essential oil, furanodiene showed stronger growth inhibitions on Hela, Hep-2, HL-60, PC3, SGC-7901 and HT-1080 cells with IC(50) between 0.6-4.8 microg/ml. In vivo, furanodiene was also found to exhibit inhibitory effects on the growth of uterine cervical (U14) and sarcoma 180 (Sl80) tumors in mice. Our data suggests that furanodiene, an active component from the essential oil of Wen Ezhu, possesses efficacy against uterine cervical cancer.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Division; Curcuma; Drugs, Chinese Herbal; Female; Fibrosarcoma; Furans; HeLa Cells; Heterocyclic Compounds, 2-Ring; HL-60 Cells; Humans; K562 Cells; Leukemia; Liver Neoplasms; Lung Neoplasms; Mice; Mice, Inbred Strains; Organ Size; Sesquiterpenes; Spleen; Thymus Gland; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays

In this study, we showed that curcumin treatment resulted in activation of Chk1-mediated G2 checkpoint, which was associated with the induction of G2/M arrest and the resistance of cancer cells to curcumin-induced apoptosis. Further investigation revealed that inhibition of Chk1 significantly abrogated G2/M arrest and sensitized curcumin-resistant cells to apoptosis via upregulation of Bad and in turn the loss of mitochondrial membrane potential. These results indicate that Chk1-mediated G2/M arrest may serve as a mechanism for curcumin resistance and Chk1 represents a potential target for the reversal of this resistance. Our findings should be helpful for clinical application of curcumin.

Topics: Antineoplastic Agents; Apoptosis; bcl-Associated Death Protein; Carcinoma, Hepatocellular; Cell Division; Cell Line, Tumor; Checkpoint Kinase 1; Curcumin; Drug Resistance, Neoplasm; G2 Phase; Humans; Liver Neoplasms; Membrane Potential, Mitochondrial; Protein Kinases; Up-Regulation

Androgen effects on hepatocellular carcinoma (HCC) remain controversial and androgen ablation therapy to treat HCC also leads to inconsistent results. Here we examine androgen receptor (AR) roles in hepatocarcinogenesis using mice lacking AR in hepatocytes.. By using the Cre-Lox conditional knockout mice model injected with carcinogen, we examined the AR roles in hepatocarcinogenesis. We also tested the possible roles of AR in cellular oxidative stress and DNA damage sensing/repairing systems. By using AR degrading compound, ASC-J9, or AR-small interference RNA, we also examined the therapeutic potentials of targeting AR in HCC.. We found AR expression was increased in human HCC compared with normal livers. We also found mice lacking hepatic AR developed later and less HCC than their wild-type littermates with comparable serum testosterone in both male and female mice. Addition of functional AR in human HCC cells also resulted in the promotion of cell growth in the absence or presence of 5alpha-dihydrotestosterone. Mechanistic dissection suggests that AR may promote hepatocarcinogenesis via increased cellular oxidative stress and DNA damage, as well as suppression of p53-mediated DNA damage sensing/repairing system and cell apoptosis. Targeting AR directly via either AR-small interference RNA or ASC-J9 resulted in suppression of HCC in both ex vivo cell lines and in vivo mice models.. Our data point to AR, but not androgens, as a potential new and better therapeutic target for the battle of HCC.

Topics: Androgen Receptor Antagonists; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; DNA Damage; DNA Repair; Female; Genes, p53; Humans; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Mice; Mice, Knockout; Mice, Nude; Oxidative Stress; Reactive Oxygen Species; Receptors, Androgen; RNA, Small Interfering; Testosterone

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a highly toxic environmental contaminant. When exposed to TCDD, mammalian cells undergo malignant transformation via abnormal intracellular signaling cascades, and the robust inductions of cytochrome P450 (CYP) enzymes are considered to mediate carcinogenesis by producing genotoxic metabolites. We here examined whether curcumin has preventive activity against TCDD-induced CYP production and cell transformation. Initially, the cellular levels of cytochrome P450 (CYP) 1A1 and 1B1 were examined, because these are known to generate estrogen metabolites that mediate genotoxic stress. Curcumin inhibited CYP1A1 and 1B1 induction by TCDD at the mRNA and protein levels. Notably, the nuclear levels of arylhydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) were decreased by curcumin, but those in the cytoplasm were not. It was also found that oxidative stress mediated the curcumin-induced degradations of AhR and ARNT. Furthermore, in vitro transformation assays showed that in normal human embryonic kidney cells and normal prostate cells curcumin prevents the anchorage-independent growth induced by TCDD. In conclusion, curcumin attenuates AhR/ARNT-mediated CYP induction by dioxin and presumably this mode-of-action may be responsible for the curcumin prevention of malignant transformation. The findings of this study should be found helpful in the design stage of pharmacodynamic studies for developing curcumin as a chemopreventive or anticancer agent.

Topics: Antigens, Polyomavirus Transforming; Aryl Hydrocarbon Receptor Nuclear Translocator; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Line; Cell Line, Transformed; Cell Line, Tumor; Cell Transformation, Viral; Curcumin; Cytochrome P-450 Enzyme System; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Liver Neoplasms; Male; Polychlorinated Dibenzodioxins; Prostatic Neoplasms; Reactive Oxygen Species; RNA, Small Interfering

To investigate the effect of curcumin on indoleamine 2, 3 -dioxygenase (IDO) expression induced by IFN-gamma in cancer cells.. A431, HeLa, HepG2, CNE2 cells were treated with curcumin for 24 hours, then the cell proliferation was detected by methyl thiazolyl tetrazolium (MTF) assay. The effects of curcumin on IDO expression induced by IFN-gamma in these cancer cells were demonstrated by Western blot. The transcription of interferon responsive factor-1 (IRF-1), which was a key transcription factor regulating IDO expression, was analyzed by reverse transcription polymerase chain reaction (RT-PCR) under the treatment of curcumin.. Curcumin inhibited the expression of IDO in these cancer cells. However, curcumin did not inhibit the transcription of IRF-1 in cancer cells.. Curcumin could inhibit the expression of IDO in cancer cells.

Topics: Breast Neoplasms; Cell Proliferation; Curcuma; Curcumin; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; HeLa Cells; Humans; Immunoblotting; Indoleamine-Pyrrole 2,3,-Dioxygenase; Interferon Regulatory Factor-1; Interferon-gamma; Liver Neoplasms; Reverse Transcriptase Polymerase Chain Reaction

CD147, also named as extracelluar matrix metalloproteinase inducer (EMMPRIN), has been proved to be involved in several aspects of tumor progression. In addition to its ability to induce vascular endothelial growth factor (VEGF) production, it confers resistance to some chemotherapeutic drugs. To investigate the possible role of CD147 in the mouse hepatocarcinoma cell line Hepa1-6 with no metastatic potential in the lymph nodes, we used RNA interference (RNAi) approach to silence CD147 expression. The results showed that silencing of CD147 in Hepa1-6 cells significantly impeded the expression of VEGF-A at both mRNA and protein levels. The siRNA-treated cells exhibited significantly decreased growth ability when compared with control cells. Colony formation of CD147 deficient cells was dramatically inhibited in soft agar, and tumorigenicity was reduced in nude mice. Furthermore, the downregulation of CD147 expression also sensitized cells to be more sensitive to curcumin. These results suggested that CD147 might be a potential target for therapeutic antitumor drugs.

Topics: Animals; Basigin; Cell Line, Tumor; Cell Proliferation; Curcumin; Down-Regulation; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Mice; Mice, Nude; RNA Interference; Vascular Endothelial Growth Factor A

To determine the effect of tetrahydrocurcumin (THC) on tumor angiogenesis compared with curcumin (CUR) by using both in vitro and in vivo models of human hepatocellular carcinoma cell line (HepG2).. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used for testing the anti-proliferating activities of CUR and THC. In male BALB/c nude mice, 2 multiply 10(6) human HepG2 cells were inoculated onto a dorsal skin-fold chamber. One day after HepG2 inoculation, the experimental groups were fed oral daily with CUR or THC (300 mg/kg or 3000 mg/kg). On d 7, 14 and 21, the tumor microvasculature was observed using fluorescence videomicroscopy and capillary vascularity (CV) was measured.. Pathological angiogenic features including microvascular dilatation, tortuosity, and hyper-permeability were observed. CUR and THC could attenuate these pathologic features. In HepG2-groups, the CV were significantly increased on d 7 (52.43%), 14 (69.17%), and 21 (74.08%), as compared to controls (33.04%, P < 0.001). Treatment with CUR and THC resulted in significant decrease in the CV (P < 0.005 and P < 0.001, respectively). In particular, the anti-angiogenic effects of CUR and THC were dose-dependent manner. However, the beneficial effect of THC treatment than CUR was observed, in particular, from the 21 d CV (44.96% and 52.86%, P < 0.05).. THC expressed its anti-angiogenesis without any cytotoxic activities to HepG2 cells even at the highest doses. It is suggested that anti-angiogenic properties of CUR and THC represent a common potential mechanism for their anti-cancer actions.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Dose-Response Relationship, Drug; Humans; Inhibitory Concentration 50; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation

To investigate the effects of the essential oil of Curcuma wenyujin (CWO) on growth inhibition and on the induction of apoptosis in human HepG2 cancer cells.. The cytotoxic effect of drugs on HepG2 cells was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide (MTT) assay. DNA fragmentation was visualized by agarose gel electrophoresis. Cell cycle and mitochondrial transmembrane potential (Delta psi m) were determined by flow cytometry (FCM). Cytochrome C immunostaining was evaluated by fluorescence microscopy. Caspase-3 enzymatic activity was assayed by the cleavage of Ac-DEVD-R110. Cleaved PARP and active caspase-3 protein levels were measured by FCM using BD(TM) CBA Human Apoptosis Kit.. Treatment with CWO inhibited the growth of HepG2 cells in a dose-dependent manner, and the IC50 of CWO was approximately 70 mug/mL. CWO was found to inhibit the growth of HepG2 cells by inducing a cell cycle arrest at S/G(2). DNA fragmentation was evidently observed at 70 mug/mL after 72 h of treatment. During the process, cytosolic HepG2 cytochrome C staining showed a markedly stronger green fluorescence than in control cells in a dose-dependent fashion, and CWO also caused mitochondrial transmembrane depolarization. Furthermore, the results clearly demonstrated that both, activity of caspase-3 enzyme and protein levels of cleaved PARP, significantly increased in a dose-dependent manner after treatment with CWO.. CWO exhibits an antiproliferative effect in HepG2 cells by inducing apoptosis. This growth inhibition is associated with cell cycle arrest, cytochrome C translocation, caspase 3 activation, Poly-ADP-ribose polymerase (PARP) degradation, and loss of mitochondrial membrane potential. This process involves a mitochondria-caspase dependent apoptosis pathway. As apoptosis is an important anti-cancer therapeutic target, these results suggest a potential of CWO as a chemotherapeutic agent.

Topics: Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Cell Cycle; Cell Line; Cell Line, Tumor; Curcuma; Cytochromes c; Humans; Liver Neoplasms; Membrane Potentials; Microscopy, Fluorescence; Mitochondrial Membranes; Oils, Volatile; Plant Extracts

Curcuminoids, the yellow pigments of curcuma, exhibit anticarcinogenic, antioxidative and hypocholesterolemic activities. To understand the molecular basis for the hypocholesterolemic effects, we examined the effects of curcumin on hepatic gene expression, using the human hepatoma cell line HepG2 as a model system. Curcumin treatment caused an up to sevenfold, concentration-dependent increase in LDL-receptor mRNA, whereas mRNAs of the genes encoding the sterol biosynthetic enzymes HMG CoA reductase and farnesyl diphosphate synthase were only slightly increased at high curcumin concentrations where cell viability was reduced. Expression of the regulatory SREBP genes was moderately increased, whereas mRNAs of the PPARalpha target genes CD36/fatty acid translocase and fatty acid binding protein 1 were down-regulated. LXRalpha expression and accumulation of mRNA of the LXRalpha target gene ABCg1 were increased at low curcumin concentrations. Although curcumin strongly inhibited alkaline phosphatase activity, an activation of a retinoic acid response element reporter employing secreted alkaline phosphatase was observed. These changes in gene expression are consistent with the proposed hypocholesterolemic effect of curcumin.

Topics: Anticholesteremic Agents; Carcinoma, Hepatocellular; CD36 Antigens; Cell Line, Tumor; Cholesterol; Curcumin; DNA-Binding Proteins; Fatty Acid-Binding Proteins; Gene Expression; Geranyltranstransferase; Homeostasis; Humans; Hydroxymethylglutaryl CoA Reductases; Liver Neoplasms; Liver X Receptors; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Receptors, LDL; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2; Transfection

Curcumin, a major pigment of turmeric, is a natural antioxidant possessing a variety of pharmacological activities and therapeutic properties. But its mechanisms are unknown. In our previous study, we found that a 2-h exposure to curcumin induced DNA damage to both the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA) in HepG2 cells and that mtDNA damage was more extensive than nDNA damage. Therefore, experiments were initiated to evaluate the role of mtDNA damage in curcumin-induced apoptosis. The results demonstrated that HepG2 cells challenged with curcumin for 1 h showed a transient elevation of the mitochondrial membrane potential (DeltaPsim), followed by cytochrome c release into the cytosol and disruption of DeltaPsim after 6 h exposure to curcumin. Apoptosis was detected by Hoechst 33342 and annexin V/PI assay after 10 h treatment. Interestingly, the expression of Bcl-2 remained unchanged. A resistance to apoptosis for the corresponding rho0 counterparts confirmed a critical dependency for mitochondria during the induction of apoptosis in HepG2 cells mediated by curcumin. The effects of PEG-SOD in protecting against curcumin-induced cytotoxicity suggest that curcumin-induced cytotoxicity is directly dependent on superoxide anion O2- production. These data suggest that mitochondrial hyperpolarization is a prerequisite for curcumin-induced apoptosis and that mtDNA damage is the initial event triggering a chain of events leading to apoptosis in HepG2 cells.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Nucleus; Curcumin; Cytochromes c; DNA Damage; DNA, Mitochondrial; Free Radical Scavengers; Humans; Liver Neoplasms; Membrane Potential, Mitochondrial; Proto-Oncogene Proteins c-bcl-2; Superoxides

To investigate the effect of curcumin (Cur) on histone deacetylase (HDAC1) and P21(WAF1/CIP1), a cyclin dependent kinase inhibitor, in HepG2 cells for exploring the mechanism of Cur in anti-cancer.. The HDAC1, P21(WAF1/CIP1) proteins and P21(WAF1/CIP1) mRNA were extracted from human hepatoma cells treated with or without Cur of different concentrations at different time points. Western blot analysis was performed to determine the levels of HDAC1 and P21(WAF1/CIP1) proteins, respectively. RT-PCR was performed to detect the level of P21(WAF1/CIP1) mRNA.. The IC50 of concentration treated by Cur was 25 micromol x L(1) on HepG2 cell. The level of HDAC1 was obviously inhibited by Cur, and decreased at 4 hours at IC, and lasted for 48 h in a time-dependent manner. The inhibition of HDAC1 was significant at the Cur concentration of 12.5 micromol x L(-1) but there was no difference between 50 and 100 micromol x L(-1). The levels of P21(WAF1/CIP1) mRNA and protein were up-regulated by Cur in dose and time-dependent manner, and the change of mRNA and protein was detected at 8 hours and lasted for 48 hours.. Cur can inhibit the level of HDAC1 and enhance the expression of P21(WAF1/CIP1) protein and mRNA, and the results suggest that inhibiting HDAC1 and increasing P21(WAF1/CIP1) may be one of the possible mechanisms of anti-cancer by Cur.

Topics: Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcuma; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Liver Neoplasms; Plants, Medicinal; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

To test the effect on human pregnane X receptor (hPXR)-mediated transcription regulation of CYP3A4 by five selected phytochemicals.. Transient cotransfection reporter gene assays in HepG(2) cells were performed with the hPXR expression plasmid and the reporter gene plasmid which contains XRE in the promoter of CYP3A4 linked to luciferase.. In the dose-effect study, soybean isoflavone, luteolin and curcumin induced the CYP3A4 transcription via PXR in an evident dose-dependent manner, but isorhamnetin and rutin did not. The inducibility of soybean isoflavone, luteolin and curcumin was also increased in concentrations between 1 micromol/L and 50 micromol/L, 24 h after induction, 50 micromol/L soybean isoflavone, luteolin and curcumin exhibited a 5.46-fold, 2.87-fold, and 2.07-fold increase respectively, compared with 0.1% DMSO treated cells. In the time-effect study, 10 micromol/L and 50 micromol/L soybean isoflavone, luteolin and curcumin induced CYP3A4 transcription between 12 h and 48 h, the strongest induction appeared in 48 h. 48 h after induction, 50 micromol/L soybean isoflavone, luteolin and curcumin exhibited a 6.72-fold, 3.24-fold, and 2.13-fold increase respectively, compared with 0.1% DMSO treated cells.. Three phytochemicals, i.e. soybean isoflavone, luteolin and curcumin stimulate the PXR-mediated transcription of CYP3A4. Isorhamnetin and rutin have no effect on the CYP3A4 transcription via PXR.

Topics: Carcinoma, Hepatocellular; Curcumin; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Glycine max; Humans; Isoflavones; Liver Neoplasms; Luteolin; Plant Preparations; Pregnane X Receptor; Receptors, Steroid; Transcription, Genetic; Transfection; Tumor Cells, Cultured

Hypoxia-inducible factor-1 (HIF-1) has a central role in cellular responses to hypoxia, including the transcriptional activation of a number of genes involved in angiogenesis in tumors. We found that curcumin, a natural, biologically active compound isolated from the commonly used spice turmeric, significantly decreases hypoxia-induced HIF-1alpha protein levels in HepG2 hepatocellular carcinoma cells. Moreover, curcumin suppressed the transcriptional activity of HIF-1 under hypoxia, leading to a decrease in the expression of vascular endothelial growth factor (VEGF), a major HIF-1 target angiogenic factor. Curcumin also blocked hypoxia-stimulated angiogenesis in vitro and down-regulated HIF-1alpha and VEGF expression in vascular endothelial cells. These findings suggest that curcumin may play pivotal roles in tumor suppression via the inhibition of HIF-1alpha-mediated angiogenesis.

Topics: Cell Growth Processes; Cell Hypoxia; Curcumin; Down-Regulation; Endothelial Cells; Hepatoblastoma; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Neovascularization, Pathologic; RNA, Messenger; Transcriptional Activation; Transfection; Vascular Endothelial Growth Factor A

Cancer cells may often support their own growth, survival, and drug resistance by autocrine/paracrine loops based on the production of different factors; results from us and others have shown that similar interleukin-6 (IL-6)-related loops are operative in multiple myeloma and prostate or renal cancer. Because this aspect has not been investigated in detail for hepatocellular carcinoma (HCC), we have examined it in HA22T/VGH cells. These differ from other primary liver cancer cell lines (that is, HepG2, HuH-6, and HuH-7) in that enzyme-linked immunosorbent assay (ELISA) showed the HA22T/VGH cells to secrete remarkable amounts of IL-6 (16.8 ng/10(6) cells/24 h); this production, due to constitutive activation of NF-kappaB, is inhibited by agents like curcumin and dehydroxymethylepoxyquinomicin (DHMEQ), which interfere with the transcription factor. Flow cytometry, ELISA, mRNA, and Western blotting analyses were performed to characterize the status of the IL-6 receptor in HA22T/VGH cells. Two transmembrane glycoproteins that form the functional IL-6 receptor have been identified: the ligand-binding gp80 and the signal-transducer gp130. Soluble forms of gp80 also trigger membrane gp130 signaling when complexed with IL-6, while soluble forms of gp130 inhibit the same process. Our results showed that HA22T/VGH cells express gp130 at their surface, but release only traces of its soluble form. For gp80, the cells produced the mRNAs of both its membrane and soluble form. However, in immunoblotting they exhibited a very faint content of the same subunit, which, in addition, was neither expressed at the cell surface nor secreted. In MTT assays, incubation with a neutralizing anti-IL-6 antibody for up to 7 days did not affect the growth of HA22T/VGH cells. Also, other specific anti-IL-6 approaches (siRNA or AODN) failed to produce this result. In conclusion, autostimulatory loops mediated by IL-6 are less likely to occur in HCC than in other kinds of cancer. However, since release of IL-6 is frequent in HCC, especially in its more advanced stages, the use of agents like curcumin or DHMEQ might be beneficial to counteract its adverse systemic effects (e.g., cachexia).

Topics: Antibodies; Benzamides; Carcinoma, Hepatocellular; Cell Membrane; Curcumin; Cyclohexanones; Cytokine Receptor gp130; Humans; Interleukin-6; Liver Neoplasms; Models, Biological; NF-kappa B; Receptors, Interleukin-6; RNA, Small Interfering; Tumor Cells, Cultured

Curcumin (Cur), a well-known dietary pigment derived from Curcuma longa, is a promising anticancer drug, but its in vivo target molecules remain to be clarified. Here we report that exposure of human hepatoma cells to Cur led to a significant decrease of histone acetylation. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are the enzymes controlling the state of histone acetylation in vivo. Cur treatment resulted in a comparable inhibition of histone acetylation in the absence or presence of trichostatin A (the specific HDAC inhibitor), and showed no effect on the in vitro activity of HDAC. In contrast, the domain negative of p300 (a most potent HAT protein) could block the inhibition of Cur on histone acetylation; and the Cur treatment significantly inhibited the HAT activity both in vivo and in vitro. Thus, it is HAT, but not HDAC that is involved in Cur-induced histone hypoacetylation. At the same time, exposure of cells to low or high concentrations of Cur diminished or enhanced the ROS generation, respectively. And the promotion of ROS was obviously involved in Cur-induced histone hypoacetylation, since Cur-caused histone acetylation and HAT activity decrease could be markedly diminished by the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) or their combination, but not by their heat-inactivated forms. The data presented here prove that HAT is one of the in vivo target molecules of Cur; through inhibiting its activity, Cur induces histone hypoacetylation in vivo, where the ROS generation plays an important role. Considering the critical roles of histone acetylation in eukaryotic gene transcription and the involvement of histone hypoacetylation in the lose of cell viability caused by high concentrations of Cur, these results open a new door for us to further understand the molecular mechanism involved in the in vivo function of Cur.

Topics: Acetylation; Acetyltransferases; Antineoplastic Agents; Blotting, Western; Carcinoma, Hepatocellular; Catalase; Cell Cycle Proteins; Cell Line, Tumor; Curcumin; Dose-Response Relationship, Drug; Flow Cytometry; Histone Acetyltransferases; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Liver Neoplasms; p300-CBP Transcription Factors; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Superoxide Dismutase; Time Factors; Transcription Factors

The hepatic cancer HA22T/VGH cell line, which constitutively expresses activated nuclear factor-kappaB (NF-kB), was chosen as a model to examine the antitumor activity of curcumin, also in relationship to its possible influences on the activation of the transcription factor and on the expression of the inhibitory of apoptosis proteins (IAPs) and of other NF-kB target genes. Curcumin exerted cell growth inhibitory and apoptotic effects, related, at least part, to free radical generation and mainly dependent on caspase-9 and -3 activation. The combination of curcumin with cisplatin resulted in a synergistic antitumor activity and that with doxorubicin in additivity or sub-additivity. Curcumin exerted biphasic changes in the levels of NF-kB, with an increase at 8 h after its administration and a decrease at 16 h. For the combinations of curcumin with the other drugs, the levels of the transcription factor were lower than those predicted from the effects of the single agents, especially with a blunting of the remarkable increases in NF-kB activation induced by doxorubicin. Except for Bcl-2, the HA22T/VGH cells expressed different other genes, including the IAPs, implicated in cell proliferation and survival. Curcumin determined early changes in COX-2 and c-myc mRNAs, which were down-regulated, and in livin mRNA, which was up-regulated. Later it decreased Bcl-X(L) mRNA and increased Bcl-X(S) and c-IAP-2 mRNAs. Cisplatin and doxorubicin exerted distinct effects on gene expression. The cytotoxic interactions between curcumin and these agents were accompanied by synergistic (in particular with cisplatin) or additive effects of decrease in the expression of different genes, including c-myc, Bcl-X(L), c-IAP-2, NAIP and XIAP. However, the combinations attenuated also certain other influences on mRNA expression of the single agents, like, for example, the increases in Bcl-X(s) given by curcumin and doxorubicin. Overall, the effects of the drugs, alone or in combination, on tumor cell growth, cell death and gene expression did not show a simple relationship to the relative influences on NF-kB activation, inferring that they can be due also to other mechanisms.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Cell Proliferation; Cisplatin; Curcumin; Doxorubicin; Drug Interactions; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Liver Neoplasms; NF-kappa B; Proteins; Tumor Cells, Cultured

Curcumin exhibits anti-inflammatory and antitumor activities. Although its functional mechanism has not been elucidated so far, numerous studies have shown that curcumin induces apoptosis in cancer cells. In the present study, we show that subtoxic concentrations of curcumin sensitize human renal cancer cells to the tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. This apoptosis induced by the combination of curcumin and TRAIL is not interrupted by Bcl-2 overexpression. We found that treatment with curcumin significantly induces death receptor 5 (DR5) expression both at its mRNA and protein levels, accompanying the generation of the reactive oxygen species (ROS). Not only the pretreatment with N-acetylcystine but also the ectopic expression of peroxiredoxin II, an antioxidative protein, dramatically inhibited the apoptosis induced by curcumin and TRAIL in combination, blocking the curcumin-mediated DR5 upregulation. Taken together, the present study demonstrates that curcumin enhances TRAIL-induced apoptosis by ROS-mediated DR5 upregulation.

Topics: Antineoplastic Agents; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Carcinoma, Hepatocellular; Caspase Inhibitors; Caspases; Colonic Neoplasms; Curcumin; Cystine; Cytochromes c; Drug Combinations; Drug Resistance, Neoplasm; Enzyme Activation; Flow Cytometry; Humans; Liver Neoplasms; Luciferases; Membrane Glycoproteins; Peroxidases; Peroxiredoxins; Promoter Regions, Genetic; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Up-Regulation

Studies in vitro and in animal models of colorectal and hepatocellular cancers suggest that curcumin is an effective chemopreventive agent. In this pilot trial, we investigated whether oral administration of curcumin results in concentrations of the agent in normal and malignant human liver tissue, which are sufficient to elicit pharmacological activity. In total, 12 patients with hepatic metastases from colorectal cancer received 450-3600 mg of curcumin daily, for 1 week prior to surgery. Levels of curcumin and its metabolites were measured by HPLC in portal and peripheral blood, bile and liver tissue. Curcumin was poorly available, following oral administration, with low nanomolar levels of the parent compound and its glucuronide and sulphate conjugates found in the peripheral or portal circulation. While curcumin was not found in liver tissue, trace levels of products of its metabolic reduction were detected. In patients who had received curcumin, levels of malondialdehyde-DNA (M(1)G) adduct, which reflect oxidative DNA changes, were not decreased in post-treatment normal and malignant liver tissue when compared to pretreatment samples. The results suggest that doses of curcumin required to furnish hepatic levels sufficient to exert pharmacological activity are probably not feasible in humans.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Anticarcinogenic Agents; Biological Availability; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Curcumin; DNA Adducts; Feasibility Studies; Female; Humans; Liver Neoplasms; Male; Malondialdehyde; Mass Spectrometry; Middle Aged; Pilot Projects; Portal Vein

To evaluate the safety of Curcuma aromatica oil gelatin microspheres (CAO-GMS) infused via hepatic artery against primary liver cancer.. The safety of CAO-GMS was evaluated in view of its acute toxicity in rats, long-term toxicity in Beagle dogs and general pharmacology in rats and mongrel dogs.. The 50% lethal dose (LD50) of CAO-GMS infused via the hepatic artery was 17.19 mg/kg, and the serum biochemical indices of dying rats after the administration changed markedly while those of survived rats did not. Subsequent pathological examination of the tissues from the dead rats indicated improper embolism. Similar edema and small necrotic foci in the hepatic lobule were found in the hepatic tissue of rats receiving 10 and 5 mg/kg CAO-GMS and GMS 60 d after the last administration, while not in the rats of the blank control group, indicating that microspheres infused via the hepatic artery may induce irreversible liver damage dose-dependently. General pharmacological study showed that the activities (posture and gait), respiration frequency, blood pressure or heart rate of the dogs were not affected by CAO-GMS, nor were salivation, tremor or pupil changes of the rats observed or their balancing ability compromised, suggesting CAO-GMS infused via the hepatic artery did not significantly affect the nervous, respiratory and cardiovascular systems.. CAO-GMS embolization administered via the hepatic artery is safe but undesired embolization induced by vascular variation should be given due attention in its clinical application. Individualized embolization dosage and super-selective catheterization technique are recommended to avoid undesired embolism and reduce complications.

Topics: Acute Disease; Animals; Blood Pressure; Chemoembolization, Therapeutic; Curcuma; Dogs; Drugs, Chinese Herbal; Female; Gelatin; Heart Rate; Hepatic Artery; Injections, Intra-Arterial; Liver; Liver Neoplasms; Male; Microspheres; Nervous System; Plant Oils; Rats; Rats, Sprague-Dawley; Respiration

Curcumin has been shown to have potent anti-metastatic activity, however, its mechanism of action is still unclear. Here, we analyzed the anti-metastatic mechanism using hepatocellular carcinoma, CBO140C12 cells. Daily oral administration of curcumin suppressed intrahepatic metastasis in a dose-dependent manner, whereas the growth of implanted tumors was not affected. We next examined the effect of curcumin on several metastatic properties in vitro. Curcumin inhibited the invasion of tumor cells through Matrigel-coated filters and the production of MMP-9. In addition, curcumin significantly inhibited adhesion and haptotactic migration to fibronectin and laminin without affecting the expression of integrins on the cell surface. Furthermore, the formation of actin stress fibers was affected by treatment with curcumin. These results suggested that curcumin suppressed the intrahepatic metastasis mediated by the inhibiton of several metastatic properties, in which the functional alteration of cytoskeletal organization, at least in part, could play an important role.

Topics: Actin Cytoskeleton; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Adhesion; Cell Movement; Curcumin; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Liver Neoplasms; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Specific Pathogen-Free Organisms; Tumor Cells, Cultured

To investigate the effect of curcumin on the proliferation, cell cycle distribution and apoptosis of hepatocarcinoma cell line QGY.. The MTT method was used to assay the biologic activities of curcumin in different times and different doses. The cell cycle distribution was detected by flow cytometic analysis. The cell ultrastructure was observed by electronic microscopy.. Curcumin could inhibit effectively QGY in a dose- and time- dependent manner. IC(50) of curcumin to QGY was 49.50 micromol/L in 72 hours. The cell growth was arrested at S stage. Curcumin could lead to the degeneration, necrosis, and apoptosis.. Curcumin can interrupt the cell cycle and has a role in cytotoxicity, antiproliferation and inducing apoptosis of QGY.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Division; Curcumin; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Liver Neoplasms; Microscopy, Electron; Time Factors; Tumor Cells, Cultured

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; B-Lymphocytes; Carcinoma, Hepatocellular; Curcumin; Dietary Supplements; Herpesvirus 4, Human; Humans; Liver Neoplasms; Mice; Mice, Inbred C3H; Nasopharyngeal Neoplasms

Curcumin, a well-known dietary pigment derived from Curcuma longa, has been shown to be a potent antiinflammatory, antioxidant, and anticarcinogenic compound. The present study was designed to investigate the cytotoxic potential of curcumin against a range of human tumor cell lines in an attempt to understand its mechanism of action, which may lead to its possible therapeutic applications. We have shown that different cancer cell lines differ in their sensitivity to curcumin. Cell lines established from malignancies like leukemia, breast, colon, hepatocellular, and ovarian carcinomas underwent apoptosis in the presence of curcumin, whereas cell lines from lung, kidney, prostate, cervix, CNS malignancies, and melanomas showed resistance to the cytotoxic effects of curcumin. Sensitivity of the cancer cell lines to curcumin correlated with the generation of superoxide radicals as determined by the reduction of ferricytochrome C. Curcumin-resistant tumor cell lines showed significantly higher production of Hsp70, thus mounting a stress response and protecting the cells from the apoptotic cell death. These observations yield clues toward understanding the regulation of the cell death machinery by the stress proteins. Interestingly, curcumin had no effect on nontransformed cell lines, which showed neither superoxide generation nor the induction of a stress response. These observations demonstrate that curcumin is an interesting molecule with varied actions, depending on the cell type.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line; Colonic Neoplasms; Curcumin; Cytoprotection; Drug Resistance, Neoplasm; fas Receptor; Female; Fibroblasts; HSP70 Heat-Shock Proteins; Humans; Leukemia; Liver Neoplasms; Neoplasms; Ovarian Neoplasms; Rats; Reactive Oxygen Species; Tumor Cells, Cultured

To evaluate the effectiveness, toxicity and prospective application of hepatic arterial infusion (HAI) with Embolized Curcuma Aromatic oil (CAO) in treating primary liver cancer (PLC).. In the treated group, 32 patients with PLC were treated by HAI with 1-3 ml of embolized CAO and oral administration of Chinese herbal medicine. In the control group, 32 patients with PLC were treated with transcatheter artery chemoembolization (TACE).. In the treated group, one patient attained complete remission (CR) and 13 partial remission (PR), the total effective rate being 43.75%. The level of alpha fetal protein (AFP) turned to normal range in 7 cases and decreased in other 7. In the control group, 10 obtained PR and the total effective rate being 31.25%, AFP level turned to normal in 5 and decreased in 2. There was no statistical significance between the two groups. The incidences of post-embolism syndrome, such as fever, abdominal pain and vomiting were similar between the two groups but no myelosuppression occurred in the treated group with significant difference (P < 0.01) as comparing with that in the control group. The mean survival time, median survival time, 1-, 2- and 3-year survival rate in the treated group was 11.5 months, 10 months, 37.5%, 13.3% and 6.9% respectively, while in the control group was 7.25 months, 6 months, 15.6%, 3.2% and 0 respectively. The treated group was better in mean survival time, median survival time and 1-year survival rate than that of the control group (P < 0.05).. HAI with embolized CAO showed a similar favorite effect in treating PLC as that of TACE, but superior than TACE with longer survival time and milder myelosuppression.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Case-Control Studies; Chemoembolization, Therapeutic; Curcuma; Drugs, Chinese Herbal; Female; Hepatic Artery; Humans; Liver Neoplasms; Male; Middle Aged; Oils, Volatile; Phytotherapy

Curcumin (CCM), a major yellow pigment of turmeric obtained from powdered rhizomes of the plant Curcuma longa Linn, is commonly used as coloring agent in foods, drugs and cosmetics. In this study we report that gavage administration of 200 mg/kg or 600 mg/kg CCM effectively suppressed diethylnitrosamine (DEN)-induced liver inflammation and hyperplasia in rats, as evidenced by histopathological examination. Immunoblotting analysis showed that CCM strongly inhibited DEN-mediated the increased expression of oncogenic p21(ras) and p53 proteins in liver tissues of rats. In cell-cycle-related proteins, CCM selectively reduced the expression of proliferating cell nuclear antigen (PCNA), cyclin E and p34(cdc2), but not Cdk2 or cyclin D1. Moreover, CCM also inhibited the DEN-induced increase of transcriptional factor NF-kappa B. However, CCM failed to affect DEN-induced c-Jun and c-Fos expression. It has become widely recognized that the development of human hepatocellular carcinoma (HCC) is predominantly due to the chronic inflammation by virus, bacteria or chemical. Our results suggest a potential role for CCM in the prevention of HCC.

Topics: Animals; Blotting, Western; Carcinoma, Hepatocellular; CDC2 Protein Kinase; Cell Cycle Proteins; Chemical and Drug Induced Liver Injury; Curcumin; Diethylnitrosamine; Hyperplasia; Liver; Liver Neoplasms; Male; NF-kappa B; Oncogene Protein p21(ras); Organ Size; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Tumor Suppressor Protein p53

The modifying effects of the naturally occurring antioxidants n-tritriacontane-16,18-dione (TTAD), curcumin, dihydroguaiaretic acid (DHGA), chlorophyllin, tannic acid and phytic acid on the initiation stage in a rat multi-organ carcinogenesis model were examined in male F344 rats. Animals were initiated with two i.p. injections of 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN), followed by two i.g. administrations of N-ethyl-N-hydroxyethylnitrosamine (EHEN), and then three s.c. injections of 3,2'-methyl-4-aminobiphenyl (DMAB) during the first 3 weeks. Starting 1 day before the first carcinogen application, groups of rats received diet containing one of the antioxidants (0.2% TTAD, the others at 1% each) until 1 week after the last carcinogen exposure. Surviving animals were killed and complete autopsies were performed at the end of week 36. Histological examination revealed no inhibitory effects in terms of the multiplicities and/or incidences of neoplastic lesions in any of the organs examined, other than a significant increase in seminal vesicle atypical hyperplasia observed in rats treated with tannic acid. Thus, the antioxidants, with the exception of tannic acid, did not show any modifying effects on the initiation stage in the present multi-organ carcinogenesis model and at the present dose levels applied.

Topics: Aminobiphenyl Compounds; Animals; Antimutagenic Agents; Antineoplastic Agents; Antioxidants; Carcinogens; Chlorophyllides; Curcumin; Diethylnitrosamine; Guaiacol; Hydrolyzable Tannins; Lignans; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms, Experimental; Nitrosamines; Paraffin; Phytic Acid; Precancerous Conditions; Rats; Rats, Inbred F344

Apoptosis of HepG2 cells triggered by various agents is characterized in an attempt to delineate the common apoptosis signaling pathway in human hepatoma cells. Several hallmarks of apoptosis, including DNA laddering, chromatin condensation and fragmentation, and an apoptosis specific cleavage of 28S and 18S ribosomal RNA were observed after treatment with curcumin. Curcumin treatment however did not alter the expression levels of Bcl-2 and Bax proteins. p53 protein accumulated slowly and decreased abruptly after reaching the maximum. Conversely, c-Myc protein decreased initially and subsequently increased preceding the onset of apoptosis. The accumulation of p53 protein is not due to increased levels of p53 mRNA and does not result in growth arrest. Staurosporine, quinacrine, ultraviolet irradiation, hydrogen peroxide, and cyclohexamide are all capable of triggering apoptosis in HepG2 cells. While most of these agents affect the expression levels of p53 and c-Myc similarly, none of them altered the expression levels of the Bcl-2 and Bax proteins. In conclusion, these data suggest that p53 and c-Myc may play a more important role in the apoptosis signaling pathway in HepG2 cells, than the bcl-2 gene family.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Cell Cycle; Curcumin; Gene Expression Regulation, Neoplastic; Hepatoblastoma; Humans; Liver Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; RNA, Messenger; Signal Transduction; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Curcumin, which is a widely used dietary pigment and spice, has been demonstrated to be an effective inhibitor of tumor promotion in mouse skin carcinogenesis. We report that curcumin induces cell shrinkage, chromatin condensation, and DNA fragmentation, characteristics of apoptosis, in immortalized mouse embryo fibroblast NIH 3T3 erb B2 oncogene-transformed NIH 3T3, mouse sarcoma S180, human colon cancer cell HT-29, human kidney cancer cell 293, and human hepatocellular carcinoma Hep G2 cells, but not in primary culture of mouse embryonic fibroblast C3H 10T1/2, rat embryonic fibroblast, and human foreskin fibroblast cells in a concentration- and time-dependent manner. Many cellular and biochemical effects of curcumin in mouse fibroblast cells have been reported, such as inhibition of protein kinase C (PKC) activity induced by phorbol 12-myristate 13-acetate treatment, inhibition of tyrosine protein kinase activity, and inhibition of arachidonic acid (AA) metabolism. Treatment of NIH 3T3 cells with the PKC inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin A, and the AA metabolism inhibitor quinacrine induces apoptotic cell death. These results suggest that, in some immortalized and transformed cells, blocking the cellular signal transduction might trigger the induction of apoptosis.

Topics: 3T3 Cells; Animals; Apoptosis; Carcinoma, Hepatocellular; Chromatin; Colonic Neoplasms; Curcumin; DNA Fragmentation; Humans; Kidney Neoplasms; Liver Neoplasms; Mice; Rats; Sarcoma, Experimental; Signal Transduction; Tumor Cells, Cultured