curcumin and Glioma

Glioma is the most common primary central nervous tumor and its malignant and high recurrence rate are seriously threatening patient's life. The prognosis of glioma patients is still poor with a variety of modern treatments. Traditional Chinese medicine (TCM) is widely used in the adjuvant treatment or alternative medicine of glioma. Curcumae Rhizoma is one of the most commonly used in traditional Chinese medicine prescriptions for its anti-tumor characteristics. There are also many studies that reveals the anti-tumor effect of its active ingredients and some of which have been made into drugs and have been used in clinical practice. This review summarizes the new research progress on Curcumae Rhizoma for the treatment of glioma in recent years.

Topics: Curcuma; Drugs, Chinese Herbal; Glioma; Humans; Medicine, Chinese Traditional; Rhizome

Gliomas are common and aggressive brain tumors that carry a poor prognosis. The current multimodal therapeutic option for glioma includes surgery subsequently temozolomide chemotherapy and/or radiation; but gliomas are often associated with multidrug resistance, intensive adverse events, and tumor relapse. Thus, novel interventions that can enhance successful chemo-prevention and overcome therapeutic resistance are urgently needed. Phytochemicals have several biological properties with multi-target sites and relatively limited degrees of toxicity. Curcumin is a natural polyphenolic compound with several anti-tumor effects which potentially inhibit tumor growth, development, proliferation, invasion, dissemination, and angiogenesis in different human malignancies. Experimental model studies have demonstrated that curcumin attenuates glioma cell viability by G2/M cell cycle arrest, apoptosis, induction of autophagy, gene expression alteration, and disruption of multi-molecular pathways. Moreover, curcumin has been reported to re-sensitize cancer to chemotherapeutics as well as augment the effect of radiotherapy on glioma cells. In this review, we have provided an update on the in vitro and in vivo effects of curcumin-based therapy on gliomas. We have also discussed the use of curcumin in combination therapies, its effectiveness on drug-resistant cells, and new formulations of curcumin in the treatment of gliomas.

Topics: Apoptosis; Biology; Brain Neoplasms; Cell Line, Tumor; Curcumin; Glioma; Humans; Neoplasm Recurrence, Local

Curcumin is widely consumed in Asia either as turmeric directly or as one of the culinary ingredients in food recipes. The benefits of curcumin in different organ systems have been reported extensively in several neurological diseases and cancer. Curcumin has got its global recognition because of its strong antioxidant, anti-inflammatory, anti-cancer, and antimicrobial activities. Additionally, it is used in diabetes and arthritis as well as in hepatic, renal, and cardiovascular diseases. Recently, there is growing attention on usage of curcumin to prevent or delay the onset of neurodegenerative diseases. This review summarizes available data from several recent studies on curcumin in various neurological diseases such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Huntington's disease, Prions disease, stroke, Down's syndrome, autism, Amyotrophic lateral sclerosis, anxiety, depression, and aging. Recent advancements toward increasing the therapeutic efficacy of curcuma/curcumin formulation and the novel delivery strategies employed to overcome its minimal bioavailability and toxicity studies have also been discussed. This review also summarizes the ongoing clinical trials on curcumin for different neurodegenerative diseases and patent details of curcuma/curcumin in India.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Anxiety; Autistic Disorder; Biological Availability; Curcuma; Curcumin; Dementia; Depression; Drug Delivery Systems; Glioma; Humans; Huntington Disease; Multiple Sclerosis; Muscular Atrophy, Spinal; Neuroprotective Agents; Parkinson Disease; Patents as Topic; Prion Diseases; Stroke

Glioblastoma (GBM) remains the most lethal brain tumor without any curative treatment. Exosomes can mediate cell-to-cell communication, and may function as a new type of targeted therapy. In this study, the therapeutic benefits of exosomes generated by U87 cells treated with curcumin and/or temozolomide were investigated. The cells were cultured and treated with temozolomide (TMZ), curcumin (Cur), or their combination (TMZ+Cur). Exosomes were isolated with a centrifugation kit and characterized using DLS, SEM, TEM, and Western blotting. The levels of exosomal BDNF and TNF-α were measured. Naïve U87 cells were treated with the isolated exosomes, and the effects on apoptosis-related proteins HSP27, HSP70, HSP90, and P53 were assessed. All exosomes, Cur-Exo, TMZ-Exo, and TMZ+Cur-Exo increased cleaved caspase 3, Bax, and P53 proteins, while reducing HSP27, HSP70, HSP90, and Bcl2 proteins. Moreover all treatment groups increased apoptosis in naïve U87 recipient cells. Exosomes released from treated U87 cells had less BDNF and more TNF-α compared to exosomes released from naive U87 cells. In conclusion, we showed for the first time that exosomes released from drug-treated U87 cells could be a new therapeutic approach in glioblastoma, and could reduce the side effects produced by drugs alone. This concept needs to be further examined in animal models before clinical trials could be considered.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Cell Line, Tumor; Curcumin; Drug Resistance, Neoplasm; Exosomes; Glioblastoma; Glioma; HSP27 Heat-Shock Proteins; Temozolomide; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53

A microfluidic method has been developed for real-time measurement of the effects of curcumin on the intracellular calcium concentration in a single glioma cell (U87-MG). This method is based on quantitative fluorescence measurement of intracellular calcium in a cell selected in a single-cell biochip. This biochip consists of three reservoirs, three channels, and a V-shaped cell retention structure. Because of the adherent nature of glioma cells, a single cell can adhere within the aforementioned V-shaped structure. The single-cell calcium measurement will minimize cell damage caused by conventional cell calcium assay methods. Previous studies have shown that curcumin increased cytosolic calcium in glioma cells using the fluorescent dye: Fluo-4. So in this study, the effects of 5 μM and 10 μM solutions of curcumin on the increases of cytosolic calcium in a single glioma cell have been measured. Moreover, the effects of 100 μM and 200 μM of resveratrol are measured. At the final stage of the experiments, ionomycin was used to increase the intracellular calcium to the highest possible level due to dye saturation. It has been demonstrated that microfluidic cell calcium measurement is a real-time cytosolic assay that requires small quantities of reagent, which will have potential uses for drug discovery.

Topics: Calcium; Curcumin; Cytosol; Glioma; Humans; Resveratrol

Camptothecin (CPT) is a potent broad-spectrum antitumor agent with efficient therapeutic effect for various cancers. However, its application in glioma therapy has been impeded by the tumor immunosuppressive environment and blood-brain barrier (BBB)-associated drug delivery challenges. Herein, neurotransmitter analogs-modified liposomes (NTs-LIP) were prepared by doping lipidized tryptamine (Tryp) to co-deliver CPT and curcumin (CUR) for improved chemo-immunotherapy in glioma. The introduction of Tryp promotes the delivery efficiency of CPT and CUR across the BBB. CPT inhibits cell proliferation after cellular uptake of NTs-LIP, the combination of which with CUR downregulates the elevated expression of the programmed cell death 1 ligand 1 (PD-L1) caused by CPT to prevent the inactivation of T-cells and synergistically enhance chemo-immunotherapy efficacy. Furthermore, both Tryp and CUR interfere with the indoleamine 2,3-dioxygenase (IDO) pathway to reduce regulatory T cell (Treg)-mediated immunosuppression, exhibiting the potential to combine with PD-L1 inhibition for synergistic antitumor immunity. Taken together, this platform contributes towards targeted delivery and alleviation of the immunosuppressive environment in glioma therapy.

Topics: Camptothecin; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Glioma; Humans; Immunotherapy; Multifunctional Nanoparticles; Nanoparticles

The brain, protected by the cranium externally and the blood-brain barrier (BBB) internally, poses challenges in chemotherapy of aggressive brain tumors. Maximal tumor resection followed by radiation and chemotherapy is the standard treatment protocol; however, a substantial number of patients suffer from recurrence. Systemic circulation of drugs causes myelodysplasia and other side effects. To address these caveats, we report facile synthesis of a polyester-based supramolecular hydrogel as a brain biocompatible implant for in situ delivery of hydrophobic drugs.. Polycaprolactone-diol (PCL) was linked to polyethyleneglycol-diacid (PEG) via an ester bond. In silico modeling indicated micelle-based aggregation of PCL-PEG co-polymer to form a supramolecular hydrogel. Brain biocompatibility was checked in Sprague Dawley rat brain cortex with MRI, motor function test, and histology. Model hydrophobic drugs carmustine and curcumin entrapment propelled glioma cells into apoptosis-based death evaluated by in vitro cytotoxicity assays and Western blot. In vivo post-surgical xenograft glioma model was developed in NOD-SCID mice and evaluated for efficacy to restrict aggressive regrowth of tumors.. 20% (w/v) PCL-PEG forms a soft hydrogel that can cover the uneven and large surface area of a tumor resection cavity and maintain brain density. The PCL-PEG hydrogel was biocompatible, and well-tolerated upon implantation in rat brain cortex, for a study period of 12 weeks. We report for the first time the combination of carmustine and curcumin entrapped as model hydrophobic drugs, increasing their bioavailability and yielding synergistic apoptotic effect on glioma cells. Further in vivo study indicated PCL-PEG hydrogel with a dual cargo of carmustine and curcumin restricted aggressive regrowth post-resection significantly compared with control and animals with intravenous drug treatment.. PCL-PEG soft gel-based implant is malleable compared with rigid wafers used as implants, thus providing larger surface area contact. This stable, biocompatible, supramolecular gel without external crosslinking can find wide applications by interchanging formulation of various hydrophobic drugs to ensure and increase site-specific delivery, avoiding systemic circulation.

Topics: Animals; Biocompatible Materials; Carmustine; Curcumin; Drug Delivery Systems; Glioma; Humans; Hydrogels; Mice; Mice, Inbred NOD; Mice, SCID; Polyethylene Glycols; Rats; Rats, Sprague-Dawley

Local radiotherapy may cause distant tumor regression via inducing immunogenic cell death (ICD). Here, we investigated the effect of curcumin on ionizing radiation-induced immunogenic cell death in normoxic or hypoxic glioma cells and its mechanism in vitro and vivo.. Hypoxic or normoxic glioma cell apoptosis and the cell surface exposure of calreticulin (CRT) were detected by flow cytometry. Extracellular ATP and HSP70 were measured by chemiluminescence assay and ELISA, respectively. Endoplasmic reticulum (ER) stress protein levels were detected by western blot. Moreover, the induction of bona fide ICD was detected by vaccination assays in mice bearing glioma model. Spleen lymphocytes and tumor-infiltrating lymphocyte subsets were analyzed by flow cytometry and immunohistochemistry.. Curcumin incubation before X-ray irradiation significantly increased radiation-induced apoptosis rate in normoxic or hypoxic glioma cells. Curcumin enhanced radiation-induced CRT exposure, release of HSP70 and ATP, and ER stress signaling activity. After treatment with ER stress pathway inhibitors, cell apoptosis and CRT exposure induced by the combination treatment of curcumin and X-ray were reduced. In vaccination experiments, glioma cells irradiated by X-ray produced a strong immunogenic response rejecting tumor formation in 70% mice. In comparison, cells treated by curcumin and X-ray produced a stronger immune response rejecting tumor formation in 90% mice. The combination treatment increased the percentage of tumor-infiltrating CD4+, CD8+ T lymphocytes, and CD11c+ dendritic cells compared to X-ray irradiation alone.. Ionizing radiation-induced normoxic or hypoxic glioma immunogenic cell death could be further enhanced by curcumin through activating the ER stress PERK-eIF2

Topics: Adenosine Triphosphate; Animals; Apoptosis; Calreticulin; Cell Line, Tumor; Curcumin; Endoplasmic Reticulum Stress; Endoribonucleases; Glioma; Heat-Shock Proteins; Immunogenic Cell Death; Mice; Protein Serine-Threonine Kinases; Radiation, Ionizing; Signal Transduction

Glioblastoma (GBM) recurrences are inevitable, and mainly originate from residual tumor cells and the presence of glioma stem cells (GSC) around the resection cavity borders. We previously showed that the local treatment of GBM with nanomedicine-based Lauroyl-gemcitabine lipid nanocapsules (GemC

Topics: Brain Neoplasms; Cell Line, Tumor; Curcumin; Glioblastoma; Glioma; Humans; Hydrogels; Lipids; Nanomedicine; Neoplastic Stem Cells

Curcuma longa L. has been associated with different antioxidant, antiinflammatory, bactericidal and anticancer effects, but the mechanisms of the effects are not yet clearly understood. This study aimed to investigate the key targets and the effect of potential molecular mechanisms of Curcuma longa L. extracts on glioma using different network pharmacology analysis approaches.. The components of Curcuma longa were extracted by gas chromatography-mass spectrometry (GC-MS), and the active components related to the occurrence and development of glioma were determined by traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) database, and the same targets of the active components and glioma were screened by network pharmacology approach. Then, the protein's function and regulatory pathway of the common targets were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The protein's action and regulatory pathway of the common targets were analyzed with the Cytoscape package using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database to construct the target interaction network through which the key targets were identified.. GC-MS combined with TCMSP database was used to identify the active components related to the occurrence and development of glioma in Curcuma longa. Finally, we identified the active components 1-(1,5-Dimethyl-4-hexenyl)-4-methyl benzene and Zingiberene. At the same time, 190 target genes of Curcuma longa extracts on glioma were obtained using the Venn diagram. The results of GO analysis showed that the biological processes involved included a response to stimulation, metabolic process, inflammatory process, cell differentiation, and regulation of biological processes. KEGG analysis showed that the PI3K-Akt signaling pathway, MAPK signaling pathway, Th17 cell differentiation, and proteoglycan pathway might be involved in cancer. Further analyses showed that the IL-17 signaling pathway and Interleukin-4 and interleukin-13 signaling were involved in the inflammatory pathway. The analysis of key nodes showed that GSK3B, MAPK14, HSP90AA1, MAPK3 and MAPK8 were IL-17 signaling pathways, while HIF1A and JAK3 were Interleukin-4 and interleukin-13 signaling pathways.. Curcuma longa extracts can regulate the occurrence and development of glioma by regulating the immune-inflammatory responses.

Topics: Curcuma; Drugs, Chinese Herbal; Glioma; Humans; Medicine, Chinese Traditional; Molecular Docking Simulation; Network Pharmacology; Phosphatidylinositol 3-Kinases; Plant Extracts

Naturally occurring polyphenol curcumin (4) or demethoxycurcumin (5) and their synthetic derivatives display promising anticancer activities. However, their further development is limited by low bioavailability and poor selectivity. Thus, a mitochondria-targeted compound 14 (DMC-TPP) was prepared in the present study by conjugating a triphenylphosphine moiety to the phenolic hydroxyl group of demethoxycurcumin to enhance its bioavailability and treatment efficacy. The in vitro biological experiments of DMC-TPP showed that it not only displayed higher cytotoxicity as compared with its parent compound 5, but also exhibited superior mitochondria accumulation ability. Glioma cells were more sensitive to DMC-TPP, which inhibited the proliferation of U251 cells with an IC

Topics: Animals; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Glioma; Humans; Mitochondria; Molecular Structure; Rats; Structure-Activity Relationship; Tumor Cells, Cultured

Malignant glioma is the most lethal form of brain cancer, and effective therapeutic modalities remain unavailable to date. We aim to investigate whether low-dose curcumin combined with low-intensity ultrasound (LIUS) effectively suppresses the growth of glioma cells and elucidate the underlying mechanisms. Glioma cells were treated with LIUS and curcumin. Subsequently, the effects of LIUS and curcumin on glioma cells were determined by CCK-8 assay, EdU assay, and flow cytometry analysis, respectively. Western blot analysis was performed to examine the levels of apoptosis-associated proteins and the proteins related to the AKT pathway. The proliferation assay showed that combined treatment with LIUS and curcumin synergistically decreased proliferation in glioma cells. And cell apoptosis was promoted after LIUS-curcumin combination treatment, characterized by the occurrence of more apoptotic cells and a significant increase in Bax level and attenuated Bcl-2 expression. Moreover, the role of LIUS-curcumin combination in downregulation of the AKT pathway was observed. The AKT pathway activator SC79 reversed apoptosis and anti-proliferation induced by combined treatment with LIUS and curcumin. Our findings show that LIUS in combination with low-dose curcumin synergistically suppresses the growth of glioma cells via inhibition of the AKT pathway. LIUS plus curcumin may be a promising therapeutic strategy for preventing glioma growth.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Glioma; Humans; Proto-Oncogene Proteins c-akt; Signal Transduction

Curcumin is a natural polyphenol extracted from the rhizome of Curcuma that has an important antitumour effect, but its effect on adverse psychological stress-induced tumour proliferation and invasion has not been reported to date. Here, we found that curcumin not only inhibited the growth of xenografts in chronically stressed nude mice, but also decreased the expression of matrix metalloproteinase (MMP)-2/9 and CD147 in tumour tissues. Exogenous norepinephrine (NE) was used to stimulate glioma cells to simulate the stress environment in vitro, and it was found that curcumin inhibited the NE-induced proliferation and invasion of glioma cells in a dose-dependent manner. Further research found that the effects of NE on glioma cells could lead to the activation of the mitogen-activated protein kinase (MAPK) signalling pathway through β-adrenergic receptor, while curcumin suppressed the level of extracellular signal-regulated kinase (ERK)1/2 phosphorylation. In addition, blocking ERK1/2 expression with U0126 resulted in the down-regulated expression of CD147, which further led to the decreased expression of MMP-2 and MMP-9. Curcumin could also inhibit the expression of cyclin D1/CDK4/6 and anti-apoptotic protein Bcl-2/Bcl-XL induced by NE, and induced cell cycle changes and increased apoptosis. Therefore, curcumin may be a potential candidate drug for preventing and treating the progression of glioma induced by adverse psychological stress.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Cyclin D1; Down-Regulation; Female; Glioma; Humans; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Norepinephrine; Stress, Psychological

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Curcumin; Down-Regulation; Feedback; Female; Glioma; Humans; MicroRNAs; Rats; Rats, Wistar; Receptors, Calcitriol; RNA, Long Noncoding; RNA, Messenger

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Drug Carriers; Folic Acid; Glioma; Mice; Micelles; Polyethylene Glycols

Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein that selectively induces apoptosis in cancer cells. Although the mechanism of Par-4-mediated induction of apoptosis has been well studied, the involvement of Par-4 in other mechanisms of cell death such as autophagy is unclear. We investigated the mechanism involved in Par-4-mediated autophagic cell death in human malignant glioma. We demonstrate for the first time that the tumor suppressor lipid, ceramide (Cer), causes Par-4 induction, leading to autophagic cell death in human malignant glioma. Furthermore, we identified the tumor suppressor protein p53 and BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) as downstream targets of Par-4 during Cer-mediated autophagic cell death. RNAi-mediated down-regulation of Par-4 blocks Cer-induced p53-BNIP3 activation and autophagic cell death, while upregulation of Par-4 augmented p53-BNIP3 activation and autophagic cell death. Remarkably, in many instances, Par-4 overexpression alone was sufficient to induce cell death which is associated with features of autophagy. Interestingly, similar results were seen when glioma cells were exposed to classical autophagy inducers such as serum starvation, arsenic trioxide, and curcumin. Collectively, the novel Par-4-p53-BNIP3 axis plays a crucial role in autophagy-mediated cell death in human malignant glioma.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Arsenic Trioxide; Autophagic Cell Death; Cell Line, Tumor; Curcumin; Gene Expression Regulation, Neoplastic; Glioma; Humans; Membrane Proteins; Proto-Oncogene Proteins; Transcriptional Activation; Tumor Suppressor Protein p53

To investigate the effect of curcumin on the invasion and migration of human glioma cells. MTT assay was used for screening the optimal curcumin concentrations. The effects of curcumin on the invasion and metastasis of human glioma cell lines U251 and LN229 were tested using Transwell assay, Boyden assay and wound-healing assays. The expression of the related proteins and their interactions were determined using Western blotting and coimmunoprecipitation assay.. Curcumin at the concentration of 20 μmol/L for 48 h was used as the optimal condition for subsequent cell treatment. In the two glioma cell lines, curcumin significantly suppressed the invasion and migration of the cells (. Curcumin suppresses EMT signal by reducing HDGF/β-catenin complex and thereby lowers the migration and invasion abilities of human glioma cells

Topics: beta Catenin; Cell Line, Tumor; Cell Movement; Curcumin; Epithelial-Mesenchymal Transition; Glioma; Humans; Intercellular Signaling Peptides and Proteins; Neoplasm Invasiveness

BACKGROUND This study aimed to prepare doxorubicin- and tetrahydrocurcumin-loaded and transferrin-modified PEG-PLGA nanoparticles (Tf-NPs-DOX-THC) for enhanced and synergistic chemoradiotherapy. MATERIAL AND METHODS Tf-NPs-DOX-THC were prepared via the double-emulsion method. The morphologies and particle sizes of the prepared nanoparticles were examined by TEM and DLS, respectively. The in vitro MTT, apoptosis, and clone formation assays were performed to detect the proliferation and radiosensitivity of cells with various treatments. Cellular uptake assay was also conducted. The tissue distribution of Tf-NPs was investigated by ex vivo DOX fluorescence imaging. The in vivo tumor growth inhibition efficiency of various treatments was evaluated in orthotopic C6 mouse models and C6 subcutaneously grafted mouse models. RESULTS Tf-NPs-DOX-THC exhibited high drug-loading efficiency (6.56±0.32%) and desirable particle size (under 250 nm). MTT, apoptosis, and clone formation assays revealed the enhanced anti-cancer activity and favorable radiosensitizing effect of Tf-NPs-DOX-THC. Strong fluorescence was observed in the brains of mice treated with Tf-NPs-DOX. The in vitro release of drug from nanoparticles was in a pH-sensitive manner. Tf-NPs-DOX-THC in combination with radiation also achieved favorable anti-tumor efficacy in vivo. CONCLUSIONS All results suggest that a combination of Tf-NPs-DOX-THC and radiation is a promising strategy for synergistic and sensitizing chemoradiotherapy of glioma.

Topics: Animals; Cell Line, Tumor; Chemoradiotherapy; Curcumin; Doxorubicin; Drug Carriers; Drug Delivery Systems; Emulsions; Glioma; Humans; Lactates; Mice; Mice, Nude; Nanoparticles; Particle Size; Polyesters; Polyethylene Glycols; Rats; Tissue Distribution; Transferrin; Xenograft Model Antitumor Assays

Glioma is the most common primary cancer in central nervous system, especially in brain. Paclitaxel (PTX) is a microtubule stabilizing agent with anticancer potential, but its clinical application to brain tumours is limited by drug resistance, side effects, and lower brain penetration.. Herein we explored the in vitro effects, in glioma C6 cells, of the combination of PTX with curcumin, a natural compound with chemotherapeutic activity, in order to improve cytotoxic effects and overcome PTX limitations.. Our data confirmed PTX antiproliferative activity that was improved by curcumin. These effects were confirmed by clonogenic assay and G0/G1 cell cycle arrest. PTX significantly promoted generation of intracellular reactive species (RS), while curcumin did not affect RS production; the combination of the two drugs resulted in a slight but significant increase in RS levels. Furthermore, we found a constitutive activation of NF-κB in C6 cell line that was inhibited by PTX and curcumin. Interestingly, combination of the drugs totally inhibited NF-κB nuclear translocation and reduced IκB phosphorylation. Our results also supported the involvement of p53-p21 axis in the anticancer effects of curcumin and PTX. The combination of the two drugs further increased p53 and p21 levels enhancing the antiproliferative effects. Furthermore, PTX plus curcumin most impressively activated caspase-3, effector of apoptosis pathways, and reduced the expression of the anti-apoptotic protein Bcl-2.. In conclusion, our findings demonstrated that combination of PTX and curcumin exerts a potentiated anti-glioma efficacy in vitro that may help in reducing dosage and/or minimizing side effects of cytotoxic therapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Curcumin; Glioma; Humans; NF-kappa B; Paclitaxel; Proto-Oncogene Proteins c-bcl-2; Rats; Signal Transduction

Glioblastoma is a malignant tumor of the brain. The treatment of this tumor is still a challenge. Curcumin has been shown to have therapeutic effects when used to treat malignant diseases. However, the molecular mechanisms of its action are not fully elucidated. We hypothesized that reactive oxygen species (ROS) have a key role in curcumin-induced DNA damage, apoptosis, and cell death. To test our hypothesis, cytotoxic, genotoxic, apoptotic, and ROS-generating effects, as well as mitochondrial membrane potentials of curcumin on rat glioma cells (C-6) and normal fibroblastic cells (L-929) were investigated. We examined concentration-dependent cytotoxic, genotoxic, apoptotic, and ROS generating effects of curcumin at C-6 cells and L-929 cells. The cells were incubated with different doses of curcumin (10-100 µM) for 24 hours. Higher doses of curcumin resulted in greater cellular death of cancer than of normal cells at higher concentrations. Curcumin also induced ROS generation in cancer than normal cells in a concentration-dependent manner. Our results showed that curcumin-induced DNA damage in a dose-dependent manner (p < 0.001). At high curcumin concentration such as 80 µM, the proportions of live cells in cancer and normal cell lines were 11.5 and 44.3, respectively. The higher doses of curcumin resulted in greater apoptosis in cancer than normal cells.This in vitro study provided clear evidence that curcumin induced DNA damage and apoptosis. Cytotoxicity may be due to its pro-oxidant activity in a dose-dependent manner in cancer and normal cells. These activities were higher in cancer cells.

Topics: Animals; Annexin A5; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; DNA Damage; Fluorescein-5-isothiocyanate; Glioma; Humans; Membrane Potential, Mitochondrial; Mice; Mitochondria; Rats; Reactive Oxygen Species

The gliomas treatment is challenging due to the limits imposed by blood-brain barrier to the distribution of the drugs in the brain. Therefore, we designed a brain glioma targeting redox-sensitive hyaluronic acid (HA)-ss-curcumin (CUR) micelles. HA was conjugated to CUR through a disulfide bond, which could form micelles independently in aqueous solution. And we further increased the drug loading by loading free CUR. Brain penetration was achieved with Tween 80, whereas glioma-targeting was inclined by CD44-mediated endocytosis. Compared to the disulfide-free group, the redox-sensitive micelles exhibited rapid in vitro drug release under high glutathione conditions, significantly enhanced cell apoptosis and cellular uptake in G422 glioma cells. Redox-sensitive micelles displayed about 4.70-fold higher area under the curve in rats after intravenous injection in comparison to the free CUR and effectively accumulated in the brain. These findings suggest that redox-sensitive micelles could be a promising candidate to achieve brain targeted CUR delivery.

Topics: Animals; Biological Transport; Brain Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Liberation; Gene Expression Regulation, Neoplastic; Glioma; Hyaluronan Receptors; Hyaluronic Acid; Intracellular Space; Mice; Micelles; Oxidation-Reduction; Tissue Distribution

In this study, a redox-sensitive glioma-targeting micelle system was designed to deliver curcumin (CUR) by conjugating it to hyaluronic acid (HA-s-s-CUR, HSC) via disulfide linkage. The effect of the molecular weight of HA on the physicochemical characteristics of HSC conjugates and their in vitro effects in glioma cells were also explored. These conjugates formed nano-scale micelles (209-926 nm) independently in aqueous solution. The micelles greatly increased the solubility of CUR and improved its stability, which is crucial for harnessing the therapeutic potential of this active molecule. The redox sensitivities of different HSC micelles were measured by using a dynamic light scattering method and in vitro release assay, which showed that the low (50 kDa) and medium molecular weight (200 kDa and 500 kD) HA-based conjugates were sensitive to GSH, whereas higher molecular weights (1000 kDa and 2000 kDa) did not show redox-sensitivity. Increased cytotoxicity and uptake of low and medium molecular weight-modified HSC conjugates by the glioma cells further confirmed that the sensitive micelles are more effective for intracellular drug delivery compared to the high molecular weight-modified HSC conjugates or the plain CUR. In summary, the molecular weight of HA affects the physicochemical attributes of HSC conjugates. Only HSC micelles made with HA molecules less than 500 kDa exhibit redox sensitivity.

Topics: Animals; Brain Neoplasms; Cell Death; Cell Line, Tumor; Curcumin; Drug Liberation; Endocytosis; Glioma; Glutathione; Hyaluronic Acid; Materials Testing; Mice; Micelles; Molecular Weight; Spectrophotometry, Ultraviolet

To evaluate the effects of tetrahydrocurcumin (THC) on the radiosensitivity of glioma cells and the possible molecular mechanism.. MTT assay, colony forming and wound healing assays were performed to detect the proliferation, radiosensitivity and migration of cells with various treatments. Cell apoptosis, cell cycle and GHS level were determined for exploring potent sensitization mechanism of THC. Meanwhile, protein expressions of cyclin D1 and PCNA were also measured. Furthermore, both orthotopic C6 mouse models and C6 subcutaneously grafted mouse models were established to test the tumour inhibitory effects of combined treatment in vivo.. Cells treated with combined THC and radiation demonstrated lower cell viability and higher apoptosis rate as compared to radiation group. Moreover, the intracellular GSH was also decreased in the THC co-treated C6 cells. More importantly, combinatorial treatment group significantly induced G0/G1 cell cycle arrest and a decrease in the S phase cell through the down-regulation of cyclin D1 and PCNA. The in-vivo therapeutic efficacy assay indicated that the growth of tumour was greatly inhibited in combinatorial group.. Tetrahydrocurcumin can synergistically enhance the radiosensitivity of glioma cells by inhibiting the expressions of cyclin D1 and PCNA.

Topics: Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Glioma; Glutathione; Humans; Mice; Radiation Tolerance; Rats; Wound Healing

Previous studies showed Demethoxycurcumin (DMC) has stronger anti-glioma and anti-GSCs effects both in vitro and in vivo. In addition, DMC seems to be lower toxicity than TMZ on nude mice. However, this conclusion was confirmed to be wrong in this study. We have evaluated the antitumor efficacy of DMC or TMZ treatment by an orthotopic glioblastoma xenograft model. Nude mice were injected with U87MG-luc cells in the caudate nucleus of the brain and treated with DMC (30 mg/kg q.d.) or TMZ (10 mg/kg q.d.) by intraperitoneal injection. Bioluminescence imaging (BLI) was used to monitoring tumor growth and response to therapy. Western blot was used to detect the expression of p-Akt, cleaved-caspase-3 and Bax. The average value of BLI showed TMZ determined a significant tumor regression while DMC had a mild regression effect on tumor growth compared with control group. Immunohistochemistry for Ki67, proliferating cell nuclear antigen (PCNA), and TUNEL demonstrated that TMZ more effectively inhibited the expression of Ki67 and PCNA, and increased the ratio of TUNEL-positive cells in in situ tumor tissue. Western blot analysis also indicated that TMZ but not DMC more significantly decreased p-Akt and increased cleaved-caspase-3 and Bax expression.These findings suggested a fact that TMZ appear to be more effective in controlling the growth of glioblastoma than DMC in an orthotopic glioblastoma xenograft model.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Brain Neoplasms; Cell Proliferation; Curcumin; Diarylheptanoids; Glioma; Humans; Male; Mice; Mice, Nude; Temozolomide; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Glioma is the most aggressive and lethal brain tumor in humans, it comprises about 30 per cent of all brain tumors and central nervous system tumors.. The objective of this study was to create novel brain-targeting nanoliposomes to encapsulate curcumin as a promising option for glioma therapy.. Human glioma cells (U251MG) were used to determine cell uptake efficiency and possible internalization mechanism of the curcumin-loaded nanoliposomes modified by a brain-targeting peptide RDP. In addition, intracranial glioma mice model was prepared by transplantation of U251MG cells into the mice striatum, and then the liposomes were intravenously administered into the glioma-bearing mice to evaluate the anti-glioma activity.. RDP-modified liposomes (RCL) could enter the brain and glioma region, and were internalized by the glioma cells perhaps through acetylcholine receptor-mediated endocytosis pathway. Furthermore, the RCL prolonged the survival time of the glioma-bearing mice from 23 to 33 days, and the inhibition mechanism of the RCL on glioma cell was partly due to cell cycle arrest at the S phase and induction of cell apoptosis.. This study would provide a potential approach for targeted delivery of drug-loaded liposomes for glioma treatment.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Drug Liberation; Endocytosis; Glioma; Humans; Liposomes; Male; Mice, Inbred BALB C; Peptides; Xenograft Model Antitumor Assays

Currently, combination drug therapy is one of the most effective approaches to glioma treatment. However, due to the inherent dissimilar pharmacokinetics of individual drugs and blood brain barriers, it was difficult for the concomitant drugs to simultaneously be delivered to glioma in an optimal dose ratio manner. Herein, a cationic micellar core (Cur-M) was first prepared from d-α-tocopherol-grafted-ε-polylysine polymer to encapsulate the hydrophobic curcumin, followed by dopamine-modified-poly-γ-glutamic acid polymer further deposited on its surface as a anion shell through pH-sensitive linkage to encapsulate the hydrophilic doxorubicin (DOX) hydrochloride. By controlling the combinational Cur/DOX molar ratio at 3:1, a pH-sensitive core-shell nanoparticle (PDCP-NP) was constructed to simultaneously target the cancer stem cells (CSCs) and the differentiated tumor cells. PDCP-NP exhibited a dynamic diameter of 160.8 nm and a zeta-potential of -30.5 mV, while its core-shell structure was further confirmed by XPS and TEM. The ratiometric delivery capability of PDCP-NP was confirmed by in vitro and in vivo studies, in comparison with the cocktail Cur/DOX solution. Meanwhile, the percentage of CSCs in tumors was significantly decreased from 4.16% to 0.95% after treatment with PDCP-NP. Overall, PDCP-NP may be a promising carrier for the combination therapy with drug candidates having dissimilar physicochemical properties.

Topics: alpha-Tocopherol; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Carriers; Drug Delivery Systems; Glioma; Glutamic Acid; Humans; Hydrogen-Ion Concentration; Male; Micelles; Nanoparticles; Neoplastic Stem Cells; Polylysine; Polymers; Rats; Rats, Sprague-Dawley

Currently, glioma treatment is limited by two main factors: timely detection at onset or relapse and restriction of drugs by the blood-brain barrier (BBB) from entering the brain and influencing tumor growth. However, a safe BBB-traversing drug delivery system has brought new hope to glioma treatment. Exosomes have strong cargo-loading capacity and have the ability to cross the BBB. They can also be conferred with the ability for targeted delivery. Therefore, exosomes have great promise to be a targeted drug delivery vehicles. In this study, we firstly loaded superparamagnetic iron oxide nanoparticles (SPIONs) and curcumin (Cur) into exosomes and then conjugated the exosome membrane with neuropilin-1-targeted peptide (RGERPPR, RGE) by click chemistry to obtain glioma-targeting exosomes with imaging and therapeutic functions. When administered to glioma cells and orthotopic glioma models, we found that these engineered exosomes could cross the BBB smoothly and provided good results for targeted imaging and therapy of glioma. Furthermore, SPION-mediated magnetic flow hyperthermia (MFH) and Cur-mediated therapy also showed a potent synergistic antitumor effect. Therefore, the diagnostic and therapeutic effects on glioma were significantly improved, while reducing the side effects. We have designed a new type of glioma-targeting exosomes, which can carry nanomaterials and chemical agents for simultaneous diagnosis and treatment of glioma, thus providing a potential approach for improving the diagnosis and treatment effects of intracranial tumors.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Curcumin; Exosomes; Female; Glioma; Humans; Kaplan-Meier Estimate; Magnetite Nanoparticles; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Neuropilin-1; Peptides; RAW 264.7 Cells; Reproducibility of Results

Recently, we have reported that Demethoxycurcumin induced Reactive oxygen species via inhibition of Mitochondrial Superoxide Dismutase is an initial event to trigger apoptosis through caspase-8 and 9 activation and to inhibit Akt/NF-κB survival signaling in human glioma U87 MG cells (Kumar et al., 2018). Although cell-cycle disruption had been suggested to be the possible mechanism for DMC inhibitory effect on human glioma U87 MG cells, comprehensive mechanisms of cell-cycle arrest caused by DMC are not fully understood. The present study was designed to elucidate the DMC induced mechanism of cell cycle arrest in human glioma U87 MG cells. In this study, the results illustrated that DMC induced Reactive oxygen species (ROS) leads to reduced expression of CDC25C, Cyclin B1 and CDK1 (Thr161) triggers G2/M cell cycle arrest in U87 MG glioma cells. Moreover, the DMC induced ROS generation activates ubiquitination and proteasome degradation of CDC25C and Cyclin B1 in U87MG glioma cells. In addition, the immunoprecipitation results showed that significant dissociation of CDK1or CDC2-Cyclin B1 complex leads to G2/M cell cycle arrest. To explore the possibility of direct involvement of DMC in the dissociation of CDK1/Cyclin B1 complex, the molecular docking and MD simulation studies were carried. The results showed that DMC nicely fitted into the binding site of CDK1 and Cyclin B1 with minimum binding energy (ΔG) of -9.46 kcal/mol (Ki = 0.11 μM) and - 9.90 kcal/mol (Ki = 0.05 μM) respectively. Therefore, this is the first study demonstrating CDC25C and Cyclin B1 proteins could be used as potential target for anticancer therapy and DMC may be explored as new therapeutic agent in the cure of Glioblastoma (GBM).

Topics: CDC2 Protein Kinase; cdc25 Phosphatases; Cell Cycle Checkpoints; Cell Division; Cell Line, Tumor; Curcumin; Cyclin B1; Diarylheptanoids; G2 Phase; Glioma; Humans; Molecular Docking Simulation; Proteasome Endopeptidase Complex; Reactive Oxygen Species

Redox-sensitive micelles based onhydrophilic hyaluronic acid-ss-hydrophobic curcumin conjugate were designed as a novel delivery system for gliomas targeting. Furthermore, the obtained micelles were further functionalized with Tween 80 (CUR-THSC) for better brain penetration. Dynamic light scattering experiment and in vitro release study showed that the synthetic disulfide-linked conjugate possessed redox-sensitivity under high glutathione conditions. Spherical micelles with a mean particle size of 74.2 nm, negative zeta potential (-30.25 mV), high entrapment efficiency (94.12%) and drug loading (8.9%) were obtained. XRD analysis of micelles revealed amorphous form of the encapsulated drug. CUR-THSC micelles showed good plasma stability and did not induce any hemolysis in erythrocytes. In addition, highest cytotoxicity in G422 cells was observed compared to the free curcumin group and non-sensitive micelles group. These results indicate that the Tween 80-modified hyaluronic acid-ss-curcumin micelles could emerge as a promising platform for the delivery of curcumin in the treatment of gliomas.

Topics: Brain Neoplasms; Cell Line, Tumor; Chemistry Techniques, Synthetic; Curcumin; Drug Carriers; Glioma; Humans; Hyaluronic Acid; Micelles; Oxidation-Reduction; Polysorbates

BACKGROUND Curcumin has clear anti-tumor activity in various carcinomas. It regulates various signaling pathways like Wnt/β-catenin and JAK2/STAT3, which play vital roles in cell proliferation of several carcinomas, but to the best of our knowledge, there are currently no published reports on human glioma CHME cells. Therefore, the aim of this study was to explore the effect of curcumin on human glioma CHME cells. MATERIAL AND METHODS The CHME cell line was purchased from American Type Culture Collection (ATCC). The expressions of caspases 3, caspases 9, PARP, BAX, and BCL2 were detected by Western blot. Annexin V FITC, mitochondrial membrane potential, and reactive oxygen species were detected by flow cytometry. DAPI staining was detected by fluorescence microscopy. Cell viability was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay. RESULTS We found that curcumin has cytotoxic activity in human glioma CHME cells, as shown by DAPI staining, annexin V/PI, and nuclear morphology. We found that cell growth decreased with increased concentration of curcumin, as well as sowing effects on expression of caspase-3, caspase-9, and cleavage of PARP, which suggests apoptotic cascade activity. The increase in reactive oxygen species and loss of mitochondrial membrane potential (Δψmt) in concentration-dependent manners suggests biochemical induction of apoptosis in CHME cells. CONCLUSIONS Curcumin has effective anticancer activity in human glioma CHME cells by inducing the apoptotic pathway.

Topics: Apoptosis; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Glioma; Humans; Mitochondria; Reactive Oxygen Species; Signal Transduction

It was reported that γ-irradiation had a controversial therapeutic effect on glioma cells. We aimed to investigate the cytotoxic effect on the glioma cells induced by γ-irradiation and explore the treatment to rescue the phenotype alteration of remaining cells. We used transwell assay to detect the glioma cell invasion and migration capacity. Cell proliferation and apoptosis were tested by the CCK-8 assay and flow cytometry respectively. Western Blot was used to detect the activity of Hedgehog signaling pathway and Epithelial-to-Mesenchymal Transition (EMT) status. γ-irradiation showed cytotoxic effect on LN229 cells in vitro, whereas this contribution was limited in U251 cells. However, it could significantly stimulated EMT process in both LN229 and U251. Curcumin (CCM) could rescue EMT process induced by γ-irradiation via the suppression of Gli1 and the upregulation of Sufu. The location and expression of EMT markers were also verified by Immunofluorescence. Immunohistochemistry assay was used on intracranial glioma tissues of nude mice. The capacities of cell migration and invasion were suppressed with combined therapy. This research showed Curcumin could rescue the EMT process induced by γ-irradiation via inhibiting the Hedgehog signaling pathway and potentiate the cell cytotoxic effect in vivo and in vitro.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Epithelial-Mesenchymal Transition; Female; Gamma Rays; Glioma; Hedgehog Proteins; Humans; Mice, Nude; Radiation-Sensitizing Agents; Signal Transduction; Xenograft Model Antitumor Assays

Curcumin, the active ingredient of turmeric, has a remarkable antitumor activity against various cancers, including glioblastoma. However, it has poor absorption and low bioavailability; thus, to cross the blood-brain barrier and reach tumor tissue, it needs to be transferred to tumor site by special drug delivery systems, such as nanoparticles.. We aimed to evaluate the antitumor activity of curcumin on glioblastoma tissue in the rat glioma-2 (RG2) tumor model when it is loaded on poly(lactic-co-glycolic acid)-1,2-distearoyl-glycerol-3-phospho-ethanolamine-N-[methoxy (polyethylene glycol)-2000] ammonium salt (PLGA-DSPE-PEG) hybrid nanoparticles.. Glioblastoma was induced in 42 adult female Wistar rats (250-300g) by RG2 tumor model. The curcumin-loaded nanoparticles were injected by intravenous (n=6) or intratumoral route (n=6). There were five control groups, each containing six rats. First control group was not applied any treatment. The remaining four control groups were given empty nanoparticles or curcumin alone by intravenous or intratumoral route, respectively. The change in tumor volume was assessed by magnetic resonance imaging and histopathology before and 5days after drug injections.. Tumor size decreased significantly after 5days of intratumoral injection of curcumin-loaded nanoparticle (from 66.6±44.6 to 34.9±21.7mm. In this in vivo experimental model, intratumoral administration of curcumin-loaded PLGA-DSPE-PEG hybrid nanoparticles was effective against glioblastoma. Curcumine-loaded nanoparticles may have potential application in chemotherapy of glioblastoma.

Topics: Animals; Curcumin; Female; Glioma; Lactic Acid; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Wistar

Glioblastoma is the most common brain cancer in adults. It represents one of the top ten malignant tumors with an average survival time of nine months despite treatments with surgery, radiotherapy and chemotherapy. Curcumin is a phytochemical turmeric isolated from root of the Curcuma longa plant. Accumulating evidence have proved that curcumin targets numerous cancer signaling pathways. The E3 ubiquitin ligase NEDD4, neural precursor cell expressed developmentally downregulated protein 4, is frequently overexpressed in various cancers. However, whether curcumin regulates NEDD4 expression has not been described in human cancers. Therefore, in this study, we explored the roles of NEDD4 in glioma cell proliferation, apoptosis and mobility. We further investigated whether curcumin exerts its antitumor activities via suppressing NEDD4 expression. We found that curcumin reduced the expression of NEDD4 and Notch1 and pAKT, leading to glioma cell growth inhibition, apoptosis, and suppression of migration and invasion. Moreover, deletion of NEDD4 expression enhanced the sensitivity of glioma cells to curcumin treatment. Thus, inactivation of NEDD4 by curcumin could be a promising approach for therapeutic intervention.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcuma; Curcumin; Gene Expression Regulation, Neoplastic; Glioma; Humans; Nedd4 Ubiquitin Protein Ligases; Oncogene Protein v-akt; Receptor, Notch1; Signal Transduction

Severe toxicity and poor tumour penetration are two intrinsic limited factors to hinder the broad clinical application for most of first-line chemotherapeutics. In this study, a novel vitamin E succinate-grafted ε-polylysine (VES-g-PLL) polymer was synthesized by using ε-polylysine as backbone. By adjusting VES graft ratio, VES-g-PLL (50) with a theoretic VES graft ratio of 50% could self-assemble into a supermolecular micelle with a hydrodynamic diameter (D

Topics: alpha-Tocopherol; Apoptosis; Curcumin; Glioma; Humans; In Situ Nick-End Labeling; Kidney; Liver; Lung; MCF-7 Cells; Micelles; Polylysine; Spleen

Glioma has one of the highest mortality rates among primary brain tumors. The clinical treatment for glioma is very difficult due to its infiltration and specific growth locations. To achieve improved drug delivery to a brain tumor, we report the preparation and in vitro and in vivo evaluation of curcumin nanoparticles (Cur-NPs). The cyclic hexapeptide c(RGDf(N-me) VK)-C (cHP) has increased affinity for cells that overexpress integrins and was designed to target Cur-NPs to tumors. Functional polyethyleneglycol-modified poly(d,l-lactide-co-glycolide) (PEG-PLGA) conjugated to cHP was synthesized, and targeted Cur-NPs were prepared using a self-assembly nanoprecipitation process. The physicochemical properties and the in vitro cytotoxicity, accuracy, and penetration capabilities of Cur-NPs targeting cells with high levels of integrin expression were investigated. The in vivo targeting and penetration capabilities of the NPs were also evaluated against glioma in rats using in vivo imaging equipment. The results showed that the in vitro cytotoxicity of the targeted cHP-modified curcumin nanoparticles (cHP/Cur-NPs) was higher than that of either free curcumin or non-targeted Cur-NPs due to the superior ability of the cHP/Cur-NPs to target tumor cells. The targeted cHP/Cur-NPs, c(RGDf(N-me)VK)-C-modified Cur-NPs, exhibited improved binding, uptake, and penetration abilities than non-targeting NPs for glioma cells, cell spheres, and glioma tissue. In conclusion, c(RGDf(N-me)VK)-C can serve as an effective targeting ligand, and cHP/Cur-NPs can be exploited as a potential drug delivery system for targeting gliomas.

Topics: Animals; Antineoplastic Agents, Phytogenic; Brain Neoplasms; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Glioma; Humans; Male; Nanoparticles; Peptides, Cyclic; Polyesters; Polyethylene Glycols; Rats, Sprague-Dawley

To investigate the effect of curcumin on tumor growth and angiogenesis of human gliomas and identify the underlying molecular mechanisms.. A mouse xenograft glioma model was established by subcutaneously inoculating tumor cell aggregates derived from the U87 cell line. Mice were treated with 0.01ml/g body weight of curcumin or saline. Tumor volume was measured. Microvessel density was assessed by CD34 immunostaining, and angiogenesis by immunohistochemical staining of vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2) and thrombospondin 1 (TSP-1).. At 28 days after treatment, tumor weights in the curcumin-treated group were much smaller than in the control group (0.23±0.11g vs 0.44±0.15g，p＜0.05), resulting in a 45.8% inhibition of tumor growth. Curcumin also markedly inhibited microvessel density. Expression of VEGF and Ang-2 was inhibited by curcumin, whereas TSP-1 expression was up-regulated.. This study shows that curcumin inhibits tumor growth by inhibiting VEGF/Ang-2/TSP-1- mediated angiogenesis in a xenograft glioma mouse model.

Topics: Angiopoietin-2; Animals; Antigens, CD34; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Curcumin; Glioma; Humans; Mice; Neovascularization, Pathologic; Signal Transduction; Thrombospondin 1; Time Factors; Transplantation, Heterologous; Vascular Endothelial Growth Factors

Curcumin is a natural polyphenolic compound isolated from turmeric (

Topics: Cell Line, Tumor; Curcumin; Drug Delivery Systems; Glioma; Humans; Nanoparticles; Neuroglia; Neuroprotective Agents; Polyesters; Polyethylene Glycols

A novel water-soluble derivative of curcumin (Cur-[G-2]-OH) was designed and synthesized from accessible raw materials in only two steps with an overall yield of 80%. The modification of curcumin phenol groups with second-generation polyester dendrons (dendronization) as a strategy to achieve an optimal hydrophilic/hydrophobic balance allows the complete water solubilization of the new curcumin derivative (5mg/ml) at room temperature. The therapeutic potential of Cur-[G-2]-OH was investigated in terms of antioxidant capacity, intracellular uptake and cytotoxicity in both rat glioblastoma cells and normal human dermal fibroblasts. Although the phenolic groups of curcumin were locked by dendronization, Cur-[G-2]-OH exhibited antioxidant capacity in water that was even higher than curcumin in dimethylsulfoxide (DMSO). This compound showed a steady cellular uptake contrasted with curcumin, which has a saturation capture at high concentrations. Combined with improved stability, this property seems to allow the intracellular accumulation of Cur-[G-2]-OH. Furthermore, the new compound exhibited increased cytotoxicity in rat C6 glioma cells in a time- and concentration-dependent manner, whereas in normal human fibroblasts, its IC

Topics: Animals; Antioxidants; Apoptosis; Cell Line, Tumor; Curcumin; Cytotoxins; Glioma; Humans; Rats; Solubility; Water

Gambogic acid (GA), a natural product with a xanthone structure, has a broad range of anti-proliferative effects on cancer cell lines. We evaluated GA for its cytotoxic effects on T98G glioblastoma cells. GA exhibited potent anti-proliferative activity and induced apoptosis in T98G glioblastoma cells in a dose-dependent manner. Incubation of cells with GA revealed apoptotic features including increased Bax and AIF expression, cytochrome c release, and cleavage of caspase-3, -8, -9, and PARP, while Bcl-2 expression was downregulated. Furthermore, GA induced reactive oxygen species (ROS) generation in T98G cells. Our results indicate that GA increases Bax- and AIF-associated apoptotic signaling in glioblastoma cells.

Topics: Antineoplastic Agents; Apoptosis; Brain Neoplasms; Caspase 3; Caspase 8; Caspase 9; Cell Line, Tumor; Cell Proliferation; Cytochromes c; Down-Regulation; Glioma; Humans; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Signal Transduction; Xanthones

Glioblastoma is difficult to cure due to the high risks of invasion and metastasis. Although curcumin has shown beneficial effects against malignant glioma cells, its poor properties have limited its application. The aim of this study was to design a nanocarrier for curcumin to exert sufficient anti-migration and anti-invasion effects on A172 cells. Curcuminloaded layered double hydroxide nanoparticles (Cur/LDH NPs) were synthesized, and the physicochemical properties were characterized using transmission electron microscopy (TEM), zeta potential, Fourier transform infrared spectrometry (FTIR) and X-ray powder diffraction (XRD). Then, Cur/LDH NPs were applied to A172 cells to assess the anti-migration and anti-invasion effects, cellular uptake, autophagy activity, and the related mechanisms. The prepared Cur/LDH NPs were 119±34 nm in size and exhibited a drug-loading efficiency of 21.31±1.83%. Compared with LDH and Cur alone, the Cur/LDH NPs significantly reduced cell migration and invasion when applied at low doses (0.1 and 0.5 μg/ml), and these effects were associated with a down-regulation of PI3K/AKT/mTOR signaling pathway. The Cur/LDH NPs were easily taken up by A172 cells and were mainly located in lysosomes and mitochondria in a time-dependent manner. Importantly, autophagy, which can be triggered by the inhibition of mTOR and by nanomaterials, was detected distinctly in A172 cells exposed to Cur/LDH NPs via the autophagic marker LC3A/B. In addition, the expression levels of Atg5-Atg12 and LAMP-1 were increased in the Cur/LDH NPs groups, and autophagic vacuoles were observed via TEM. Our work suggests that autophagy can promote the anti-migration and anti-invasion effects of Cur/LDH NPs against glioblastoma.

Topics: Antineoplastic Agents; Autophagy; Cell Line, Tumor; Cell Movement; Curcumin; Glioma; Humans; Hydroxides; Nanoparticles

Maintaining a high concentration of therapeutic agents in the brain is difficult due to the restrictions of the blood-brain barrier (BBB) and rapid removal from blood circulation. To enable controlled drug release and enhance the blood-brain barrier (BBB)-crossing efficiency for brain tumor therapy, a new dual-targeting magnetic polydiacetylene nanocarriers (PDNCs) delivery system modified with lactoferrin (Lf) is developed. The PDNCs are synthesized using the ultraviolet (UV) cross-linkable 10,12-pentacosadiynoic acid (PCDA) monomers through spontaneous assembling onto the surface of superparamagnetic iron oxide (SPIO) nanoparticles to form micelles-polymerized structures. The results demonstrate that PDNCs will reduce the drug leakage and further control the drug release, and display self-responsive fluorescence upon intracellular uptake for cell trafficking and imaging-guided tumor treatment. The magnetic Lf-modified PDNCs with magnetic resonance imaging (MRI) and dual-targeting ability can enhance the transportation of the PDNCs across the BBB for tracking and targeting gliomas. An enhanced therapeutic efficiency can be obtained using Lf-Cur (Curcumin)-PDNCs by improving the retention time of the encapsulated Cur and producing fourfold higher Cur amounts in the brain compared to free Cur. Animal studies also confirm that Lf targeting and controlled release act synergistically to significantly suppress tumors in orthotopic brain-bearing rats.

Topics: Animals; Antineoplastic Agents; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Drug Carriers; Ferric Compounds; Glioma; Lactoferrin; Magnetic Resonance Imaging; Magnetite Nanoparticles; Male; Particle Size; Polyacetylene Polymer; Polymers; Polyynes; Rats; Rats, Inbred F344; Survival Rate; Ultraviolet Rays

Transferrin receptor (TfR) has been used as a target for the molecular cancer therapy due to its higher expression in a variety of tumors. Anti-TfR antibodies combined with chemotherapeutic drugs has showed great potential as a possible cancer therapeutic strategy. In our study, we investigated the anti-tumor effects of anti-TfR monoclonal antibody (mAb) alone or in combination with curcumin in vitro.. We detected the apoptosis, proliferation and cell cycle of glioma cells after treated with anti-TfR mAb and curcumin alone or the combinations by flow cytometer.. Anti-TfR mAb or curcumin could inhibit proliferation of tumor cells. Anti-TfR mAb marked S phase arrest and curcumin induced G2/M arrest in tumor cells. When anti-TfR mAb and curcumin were used simultaneously, a synergistic effect was detected in relation to tumor growth inhibition and the induction of cells necrosis.. These results provided a potential role of anti-TfR mAb-containing curcumin in the treatment for gliomas.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Flow Cytometry; Glioma; Humans; In Vitro Techniques; Receptors, Transferrin

It has previously been demonstrated that curcumin possesses an antitumor activity, which is associated with its ability to induce G2/M cell cycle arrest and apoptosis. However the detailed underlying mechanisms remain unclear. The present study aimed to investigate the efficacy and underlying mechanism of curcumin‑induced cell cycle arrest and apoptosis in U87 human glioblastoma cells. By immunofluorescence staining, subcellular fractionation and western blotting, the present study demonstrated that curcumin was able to induce G2/M cell cycle arrest and apoptosis by increasing the expression levels of cyclin G2, cleaved caspase‑3 and Fas ligand (FasL), and decreasing the expression of cyclin‑dependent kinase 1 (CDK1). In addition, increased expression of forkhead box protein O1 (FoxO1) and decreased expression of phosphorylated (p)‑FoxO1 were detected in the curcumin‑treated U87 cells. Curcumin was also able to induce the translocation of FoxO1 from the cytoplasm to the nucleus. Furthermore, following knockdown of FoxO1 expression in curcumin‑treated U87 cells using FoxO1 small interfering RNA, the expression levels of cyclin G2, cleaved caspase‑3 and FasL were inhibited; however, the expression levels of CDK1 were not markedly altered. Notably, following knockdown of CDK1 expression under normal conditions, the total expression of FoxO1 was not affected; however, p‑FoxO1 expression was decreased and FoxO1 nuclear expression was increased. Furthermore, curcumin‑induced G2/M cell cycle arrest and apoptosis could be attenuated by FoxO1 knockdown. These results indicated that curcumin may induce G2/M cell cycle arrest and apoptosis in U87 cells by increasing FoxO1 expression. The present study identified a novel mechanism underlying the antitumor effects of curcumin, and may provide a theoretical basis for the application of curcumin in glioma treatment.

Topics: Apoptosis; Cell Line, Tumor; Curcumin; Forkhead Box Protein O1; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Glioma; Humans; M Phase Cell Cycle Checkpoints; Neoplasm Proteins; Signal Transduction

Curcumin (Cur), a natural polyphenol of Curcuma longa, has been recently reported to possess antitumor activities. However, due to its poor aqueous solubility and low biological availability, the clinical application of Cur is quite limited. The encapsulation of hydrophobic drugs into nanoparticles is an effective way to improve their pharmaceutical activities. In this research, nanomicelles loaded with Cur were formulated by a self-assembly method with biodegradable monomethoxy poly(ethylene glycol)-poly(lactide) copolymers (MPEG-PLAs). After encapsulation, the cellular uptake was increased and Cur could be released from MPEG-PLA micelles in a sustained manner. The Cur-loaded MPEG-PLA micelles (Cur/MPEG-PLA micelles) exhibited an enhanced toxicity on C6 and U251 glioma cells and induced more apoptosis on C6 glioma cells compared with free Cur. Moreover, the therapy efficiency of Cur/MPEG-PLA micelles was evaluated at length on a nude mouse model bearing glioma. The Cur/MPEG-PLA micelles were more effective on suppressing tumor growth compared with free Cur, which indicated that Cur/MPEG-PLA micelles improved the antiglioma activity of Cur in vivo. The results of immunohistochemical and immunofluorescent analysis indicated that the induction of apoptosis, antiangiogenesis, and inhibition of cell proliferation may contribute to the improvement in antiglioma effects. Our data suggested that Cur/MPEG-PLA may have potential clinic applications in glioma therapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biocompatible Materials; Cell Proliferation; Curcumin; Drug Carriers; Drug Screening Assays, Antitumor; Female; Glioma; Humans; Male; Mice, Nude; Micelles; Polyesters; Polyethylene Glycols; Rats, Sprague-Dawley

Curcumin can be used to prevent and treat cancer. However, its exact underlying molecular mechanisms remain poorly understood. Cathepsin L, a lysosomal cysteine protease, is overexpressed in several cancer types. This study aimed to determine the role of cathepsin L in curcumin-mediated inhibition of growth, migration, and invasion of glioma cells. Results revealed that the activity of cathepsin L was enhanced in curcumin-treated glioma cells. Cathepsin L knockdown induced by RNA interference significantly promoted curcumin-induced cytotoxicity, apoptosis, and cell cycle arrest. The knockdown also inhibited the migration and invasion of glioma cells. Our results suggested that the inhibition of cathepsin L can enhance the sensitivity of glioma cells to curcumin. Therefore, cathepsin L may be a new target to enhance the efficacy of curcumin against cancers.

Topics: Apoptosis; Brain Neoplasms; Cathepsin L; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Gene Knockdown Techniques; Glioma; Humans; Neoplasm Invasiveness; Up-Regulation

Chemotherapy is one of the most important strategies for glioma treatment. However, the "impermeability" of the blood-brain barrier (BBB) impedes most chemotherapeutics from entering the brain, thereby rendering very few drugs suitable for glioma therapy, letting alone application of a combination of chemotherapeutics. Thereby, there is a pressing need to overcome the obstacles. A dual-targeting strategy was developed by a combination of magnetic guidance and transferrin receptor-binding peptide T7-mediated active targeting delivery. The T7-modified magnetic PLGA nanoparticle (NP) system was prepared with co-encapsulation of the hydrophobic magnetic nanoparticles and a combination of drugs (i.e., paclitaxel and curcumin) based on a "one-pot" process. The combined drugs yielded synergistic effects on inhibition of tumor growth via the mechanisms of apoptosis induction and cell cycle arrest, displaying significantly increased efficacy relative to the single use of each drug. Dual-targeting effects yielded a >10-fold increase in cellular uptake studies and a >5-fold enhancement in brain delivery compared to the nontargeting NPs. For the in vivo studies with an orthotopic glioma model, efficient brain accumulation was observed by using fluorescence imaging, synchrotron radiation X-ray imaging, and MRI. Furthermore, the antiglioma treatment efficacy of the delivery system was evaluated. With application of a magnetic field, this system exhibited enhanced treatment efficiency and reduced adverse effects. All mice bearing orthotopic glioma survived, compared to a 62.5% survival rate for the combination group receiving free drugs. This dual-targeting, co-delivery strategy provides a potential method for improving brain drug delivery and antiglioma treatment efficacy.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Glioma; Lactic Acid; Mice; Mice, Inbred BALB C; Nanoparticles; Paclitaxel; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer

The aim of this work was to evaluate the potential of polyelectrolyte complex nanoparticles (PENPs) based on hyaluronic acid/chitosan (HA/CS) as carriers for water-insoluble curcuminoid (CUR) and explore in vitro performance against brain glioma cells. PENPs were observed to be affected by the order of addition, mass ratios and initial concentrations of the HA/CS, pH and ionic strength. PENPs remained stable over a temperature range of 5–-55(C. CUR was successfully encapsulated into the PENPs. CUR-PENPs showed spherical shape with a mean diameter of 207 nm and positive charge of 25.37 mV. High encapsulation efficiency (89.9%) and drug loading (6.5%) was achieved. Drug release studies revealed initial burst release of drug from the PENPs up to 4h followed by sustained release pattern. DSC thermograms and XRD patterns showed that CUR was encapsulated inside the PENPs in a molecular or amorphous state. Compared with CUR-solution, CUR-PENPs showed stronger dose dependent cytotoxicity against C6 glioma cells and higher performance in uptake efficiency in C6 cells. Cellular uptake of CUR-PENPs was found to be governed by multi-mechanism in C6 cells, involving active endocytosis, macropinocytosis, clathrin-, caveolae-, and CD44-mediated endocytosis. In conclusion, CUR-PENPs might be a promising carrier for therapy of brain gliomas.

Topics: Animals; Cell Death; Cell Line, Tumor; Chitosan; Curcumin; Drug Delivery Systems; Electrolytes; Endocytosis; Glioma; Hyaluronic Acid; Hydrogen-Ion Concentration; Molecular Weight; Nanoparticles; Nephelometry and Turbidimetry; Osmolar Concentration; Particle Size; Rats; Solutions; Temperature

In recent times, dozens of articles have been rushing to report the excellent performance of curcumin in inhibiting the proliferation of glioma cells and in inducing apoptosis and autophagy. However, in this study, we found that curcumin could not only effectively inhibit the proliferation of glioma cells but also induce glioma cells to be stem-like, which showed that it caused some glioma cells to form spheres with CD133 and Nestin positive markers. Further research on its underlying mechanism showed that curcumin suppressed transition of the cells from G1 to S phase and enhanced the expression of Sox4, Sox2, and Oct4, which were essential to retain the stemness properties of glioma-initiating cells. In conclusion, we believe these findings can complement our knowledge on curcumin and arouse our attention to use curcumin for further research on glioma treatment.

Topics: Antineoplastic Agents; Cell Dedifferentiation; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Glioma; Humans; Interphase; Neoplastic Stem Cells; Octamer Transcription Factor-3; SOXB1 Transcription Factors; SOXC Transcription Factors; Tumor Cells, Cultured

Studies have demonstrated that curcumin exerts its tumor suppressor function in a variety of human cancers including glioma. However, the exact underlying molecular mechanisms remain obscure. Emerging evidence has revealed that Skp2 (S-phase kinase associated protein 2) plays an oncogenic role in tumorigenesis. Therefore, we aim to determine whether curcumin suppresses the Skp2 expression, leading to the inhibition of cell growth, invasion, induction of apoptosis, and cell cycle arrest. To this end, we conducted multiple methods such as MTT assay, Flow cytometry, Wound healing assay, invasion assay, RT-PCR, Western blotting, and transfection to explore the functions and molecular insights of curcumin in glioma cells. We found that curcumin significantly inhibited cell growth, suppressed cell migration and invasion, induced apoptosis and cell cycle arrest in glioma cells. Furthermore, we observed that overexpression of Skp2 promoted cell growth, migration, and invasion, whereas depletion of Skp2 suppressed cell growth, migration, and invasion and triggered apoptosis in glioma cells. Mechanistically, we defined that curcumin markedly down-regulated Skp2 expression and subsequently up-regulated p57 expression. Moreover, our results demonstrated that curcumin exerts its antitumor activity through inhibition of Skp2 pathway. Collectively, our findings suggest that targeting Skp2 by curcumin could be a promising therapeutic approach for glioma prevention and therapy.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Cyclin-Dependent Kinase Inhibitor p57; Dose-Response Relationship, Drug; Down-Regulation; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Glioma; Humans; Neoplasm Invasiveness; RNA Interference; S-Phase Kinase-Associated Proteins; Signal Transduction; Time Factors; Transfection

In study, the expression patterns and functional differences between an original glioma cell population (U251 and U87) and sublines (U251-P10, U87-P10) that were selected to be migration-prone were investigated. The expressions levels of VEGF and intracellular adhesion molecule-1 (ICAM-1) were increased in the migration-prone sublines as well as in samples from patients with high-grade glioma when compared to those with low-grade glioma. In addition, cells of the migration-prone sublines showed increased expression of the oncogenic microRNA. miR-21, which was also associated with more advanced clinical pathological stages in the patient tissue specimens. Treatment of U251 cells with an miR-21 mimic dramatically enhanced the migratory activity and expression of anti-apoptotic proteins. Furthermore, treatment with curcumin decreased the miR-21 level and anti-apoptotic protein expression, and increased the expression of pro-apoptosis proteins and microtubule-associated protein light chain 3-II (LC3-II) in U251 cells. The migration-prone sublines showed decreased induction of cell death markers in response to curcumin treatment. Finally, U251-P10 cells showed resistance against curcumin treatment. These results suggest that miR-21 is associated with regulation of the migratory ability and survival in human glioma cells. These findings suggest novel mechanisms of malignancy and new potential combinatorial strategies for the management of malignant glioma.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Blotting, Western; Brain Neoplasms; Cell Movement; Cell Proliferation; Curcumin; Drug Resistance, Neoplasm; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Glioma; Humans; Immunoenzyme Techniques; MicroRNAs; Neoplasm Invasiveness; Proto-Oncogene Proteins c-bcl-2; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Lactoferrin (Lf)-tethered magnetic double emulsion nanocapsules (Lf-MDCs) are assembled from polyvinyl alcohol (PVA), polyacrylic acid (PAA), and iron oxide (IO) nanoparticles. The core-shell nanostructure of the Lf-MDCs (particle diameters from 100 to 150 nm) can simultaneously accommodate a hydrophilic drug, doxorubicin (Dox), and a hydrophobic drug, curcumin (Cur), in the core and shell, respectively, of the nanocapsules for an efficient drug delivery system. The release patterns of the two drugs can be regulated by manipulating the surface charges and drug-loading ratios, providing the capability for a stepwise adjuvant release to treat cancer cells. The results demonstrate that the dual (Dox+Cur)-drug-loaded nanocapsule can be effectively delivered into RG2 glioma cells to enhance the cytotoxicity against the cells through a synergistic effect. The combined targeting, i.e., magnetic guidance and incorporation of Lf ligands, of these Lf-MDCs results in significantly elevated cellular uptake in the RG2 cells that overexpress the Lf receptor. Interestingly, an intravenous injection of the co-delivered chemotherapeutics follows by magnetic targeting in brain tumor-bearing mice not only achieve high accumulation at the targeted site but also more efficiently suppress cancer growth in vivo than does the delivery of either drug alone.

Topics: Acrylic Resins; Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Doxorubicin; Drug Therapy, Combination; Emulsions; Female; Glioma; Humans; Magnetics; Magnetite Nanoparticles; Mice; Mice, Inbred BALB C; Mice, Nude; Nanocapsules; Particle Size

The pulverization of poorly water-soluble drugs and drug candidates into nanoscale particles is a simple and effective means of increasing their pharmacological effect. Consequently, efficient methods for pulverizing compounds are being developed. Femtosecond lasers, which emit ultrashort laser pulses, can be used to generate nanoscale particles without heating and are finding in various fields, including pharmaceutical science. Laser ablation holds promise as a novel top-down pulverization method for obtaining drug nanoparticles. We used a poorly water-soluble compound, curcumin (diferuloyl methane), to understand the characteristics of femtosecond laser pulverization. Various factors such as laser strength, laser scan speed, and the buffer solution affected the size of the curcumin particles. The minimum curcumin particle size was approximately 500 nm; the particle size was stable after 30 days. In vitro studies suggested that curcumin nanoparticles exhibited a cytotoxic effect on C6 rat glioma cells, and remarkable intracellular uptake of the curcumin nanoparticles was observed. The results suggest that femtosecond laser ablation is a useful approach for preparing curcumin nanoparticles that exhibit remarkable therapeutic effects.

Topics: Animals; Antineoplastic Agents, Phytogenic; Buffers; Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Curcumin; Dose-Response Relationship, Drug; Drug Stability; Glioma; Lasers; Nanoparticles; Nanotechnology; Particle Size; Rats; Technology, Pharmaceutical

Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge, where survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome.

Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Carmustine; Cell Line, Tumor; Curcumin; Dacarbazine; Fanconi Anemia; Fanconi Anemia Complementation Group D2 Protein; Glioma; Humans; Neoplasm Grading; Temozolomide

Germacrone is one of the major bioactive components of the traditional Chinese Medicinal plant Curcuma aromatica Salisb. and has been shown to possess anti‑tumor properties. In the present study, the anti‑proliferative effect of germacrone on human glioma cells and the molecular mechanism underlying its cytotoxicity were investigated. Treatment of the U87 and U251 human glioma cell lines with germacrone inhibited the cell proliferation in a dose‑ and time‑dependent manner as assessed by MTT assay, while significantly lower effects were observed on normal human astrocytes. Flow cytometric analysis and DNA fragmentation revealed that germacrone promoted apoptosis of glioma cells, associated with an increased expression of p53 and bax and decreased expression of bcl‑2. Furthermore, flow cytometric cell cycle analysis revealed that germacrone induced G1 phase arrest, associated with an obvious decrease in the expression of cyclin D1 and CDK2 and an increased expression of p21. In conclusion, the present study suggested that germacrone may be a novel potent chemopreventive drug candidate for gliomas via regulating the expression of proteins associated with apoptosis and G1 cell cycle arrest.

Topics: Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Cell Proliferation; Curcuma; Cyclin D1; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p21; DNA Fragmentation; G1 Phase Cell Cycle Checkpoints; Glioma; Humans; Proto-Oncogene Proteins c-bcl-2; Sesquiterpenes, Germacrane; Tumor Suppressor Protein p53

To study the role of curcumin on glioma cells via the SHH/GLI1 pathway in vitro and vivo.. The effects of curcumin on proliferation, migration, apoptosis, SHH/GLI1 signaling, and GLI1 target genes expression were evaluated in multiple glioma cell lines in vitro. A U87-implanted nude mice model was used to study the role of curcumin on tumor volume and the suppression efficacy of GLI1.. Curcumin showed cytotoxic effects on glioma cell lines in vitro. Both mRNA and protein levels of SHH/GLI1 signaling (Shh, Smo, GLI1) were downregulated in a dose- and time-dependent manner. Several GLI1-dependent target genes (CyclinD1, Bcl-2, Foxm1) were also downregulated. Curcumin treatment prevented GLI1 translocating into the cell nucleus and reduced the concentration of its reporter. Curcumin suppressed cell proliferation, colony formation, migration, and induced apoptosis which was mediated partly through the mitochondrial pathway after an increase in the ratio of Bax to Bcl2. Intraperitoneal injection of curcumin in vivo reduced tumor volume, GLI1 expression, the number of positively stained cells, and prolonged the survival period compared with the control group.. This study shows that curcumin holds a great promise for SHH/GLI1 targeted therapy against gliomas.

Topics: Animals; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Colony-Forming Units Assay; Curcumin; Disease Models, Animal; Glioma; Hedgehog Proteins; Humans; Kaplan-Meier Estimate; Mice; Signal Transduction; Transcription Factors; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1

Curcumin has multiple biological and pharmacological activities, including antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and antitumor activities. However, the clinical use of curcumin is limited because of its poor oral absorption and extremely poor bioavailability. In order to overcome these limitations, we conjugate curcumin chemically into the known biocompatible and biodegradable polymer, poly(glycerol-sebacate), and prepare the unitary poly(glycerol-sebacate-curcumin) polymer. The structure, the in vitro degradation, the drug release, and antitumor activity as well as the in vivo degradation and tissue biocompatibility of poly(glycerol-sebacate-curcumin) polymer are investigated. The in vitro degradation and drug release profile of poly(glycerol-sebacate-curcumin) are in a linear manner. The in vitro antitumor assay shows that poly(glycerol-sebacate-curcumin) polymer significantly inhibits human malignant glioma cells, U87 and T98 cells. In view of the cytotoxicity against brain gliomas, local use of this polymer would be a potential method for brain tumors.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Death; Cell Line, Tumor; Curcumin; Decanoates; Elastic Modulus; Gels; Glioma; Glycerol; Humans; Microscopy, Electron, Scanning; Polymers; Rats; Rats, Wistar; Spectrophotometry, Infrared; Water; X-Ray Diffraction

In this study, we developed curcumin-loaded lipid-core nanocapsules (C-LNCs) in an attempt to improve the antiglioma activity of this polyphenol. C-LNC showed nanotechnological properties such as nanometric mean size (196 nm), 100% encapsulation efficiency, polydispersity index below 0.1, and negative zeta potential. The in vitro release assays demonstrated a controlled release of curcumin from lipid-core nanocapsules. In C6 and U251MG gliomas, C-LNC promoted a biphasic delivery of curcumin: the first peak occurred early in the treatment (1-3h), whereas the onset of the second phase occurred after 48 h. In C6 cells, the cytotoxicity of C-LNC was comparable to non-encapsulated curcumin only after 96 h, whereas C-LNCs were more cytotoxic than non-encapsulated curcumin after 24h of incubation in U251MG. Induction of G2/M arrest and autophagy were observed in C-LNC as well as in free-curcumin treatments. In rats bearing C6 gliomas, C-LNC (1.5mg/kg/day, i.p.) decreased the tumor size and malignance and prolonged animal survival when compared to same dose of non-encapsulated drug. In addition, serum markers of tissue toxicity and histological parameters were not altered. Considered overall, the data suggest that the nanoencapsulation of curcumin in LNC is an important strategy to improve its pharmacological efficacy in the treatment of gliomas.

Topics: Animals; Autophagy; Cell Line, Tumor; Curcumin; G2 Phase Cell Cycle Checkpoints; Glioma; Lipids; Male; Nanocapsules; Particle Size; Rats; Rats, Wistar

Topics: AC133 Antigen; Animals; Antigens, CD; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Glioma; Glycoproteins; Humans; Medulloblastoma; Molecular Targeted Therapy; Nanocapsules; Peptides; Polymers; Receptor, IGF Type 1; Signal Transduction; Solubility; Thioredoxin Reductase 1

As a potential anticancer agent, curcumin (Cum) has been reported for its chemopreventive and chemotherapeutic activity in a series of cancers through influencing cell cycle arrest, differentiation, apoptosis, etc. Therefore, the potential activity against various cancers of Cum raises the possibility of its application as a novel model drug in nanoparticle-based delivery systems. The current study reported a spherical core-shell structure curcumin-loaded nanoparticle (Cum-np) formed by amphilic methoxy polyethylene glycol-poly(caprolactone) (mPEG-PCL) block copolymers. Characterization tests indicated that Cum was incorporated into mPEG-PCL-based nanoparticles with high encapsulation efficiency due to its lipophilicity. The incorporated Cum could be released from Cum-np in a sustained manner. Cum was effectively transported into the cells by nanoparticles through endocytosis and localized around the nuclei in the cytoplasms. In vitro studies proved that the cytotoxicity of Cum-np would be pro-apoptosis effect against rat C6 glioma cell line in a dose-dependent manner. The present results suggest that Cum-np could be a potential useful chemotherapeutic formulation for malignant glioma therapy. Moreover, the development of traditional Chinese medicine with nanoscale drug formation warrants more intensive research for its clinical applications.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line; Cell Line, Tumor; Cell Survival; Curcumin; Cytoplasm; Drug Delivery Systems; Flow Cytometry; Glioma; Inhibitory Concentration 50; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Myocytes, Cardiac; Nanoparticles; Polyesters; Polyethylene Glycols; Rats; Time Factors

The purpose of this work was to develop implantable curcumin-loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) nanofibers, which might have potential application in cancer therapy. Curcumin was incorporated into biodegradable PCEC nanofibers by electrospinning method. The surface morphology of the composite nanofibers was characterized on Scanning Electron Microscope (SEM). The average diameter of the nanofibers was 2.3-4.5μm. In vitro release behavior of curcumin from the fiber mats was also studied in detail. The in vitro cytotoxicity assay showed that the PCEC fibers themselves did not affect the growth of rat Glioma 9L cells. Antitumor activity of the curcumin-loaded fibers against the cells was kept over the whole experiment process, while the antitumor activity of pure curcumin disappeared within 48 h. These results strongly suggested that the curcumin/PCEC composite nanofibers might have potential application for postoperative chemotherapy of brain cancers.

Topics: Animals; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Glioma; Nanofibers; Polyesters; Polyethylene Glycols; Rats

The phytochemical curcumin, from the Indian spice turmeric, has many biological properties, including anti-inflammatory and anti-carcinogenic activities. We have examined the effects of curcumin on the rat C6 glioma cell line. Treated and control cells were analyzed by Hoechst 33342 dye and flow cytometry. We observed a decrease in the side population (SP) of C6 cells after daily curcumin treatment of the C6 cells. Direct incubation of curcumin to C6 cells during the Hoechst assay also decreased SP. Since SP has been associated with stem cell populations, curcumin may be a dietary phytochemical with potential to target cancer stem cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Benzimidazoles; Cell Differentiation; Cell Growth Processes; Cell Line, Tumor; Curcumin; Flow Cytometry; Fluorescent Dyes; Glioma; Neoplastic Stem Cells; Phenotype; Rats; Verapamil

New drugs are constantly sought after to improve the survival of patients with malignant gliomas. The ideal substance would selectively target tumor cells without eliciting toxic side effects. Here, we report on the anti-proliferative, anti-migratory, and anti-invasive properties of the natural, nontoxic compound Curcumin observed in five human glioblastoma (GBM) cell lines in vitro.. We used monolayer wound healing assays, modified Boyden chamber trans-well assays, and cell growth assays to quantify cell migration, invasion, and proliferation in the absence or presence of Curcumin at various concentrations. Levels of the transcription factor phospho-STAT3, a potential target of Curcumin, were determined by sandwich-ELISA. Subsequent effects on transcription of genes regulating the cell cycle were analyzed by quantitative real-time PCR. Effects on apoptosis were determined by caspase assays.. Curcumin potently inhibited GBM cell proliferation as well as migration and invasion in all cell lines contingent on dose. Simultaneously, levels of the biologically active phospho-STAT3 were decreased and correlated with reduced transcription of the cell cycle regulating gene c-Myc and proliferation marking Ki-67, pointing to a potential mechanism by which Curcumin slows tumor growth.. Curcumin is part of the diet of millions of people every day and is without known toxic side effects. Our data show that Curcumin bears anti-proliferative, anti-migratory, and anti-invasive properties against GBM cells in vitro. These results warrant further in vivo analyses and indicate a potential role of Curcumin in the treatment of malignant gliomas.

Topics: Antineoplastic Agents; Blotting, Western; Caspases; Cell Adhesion; Cell Cycle; Cell Movement; Cell Proliferation; Curcumin; Enzyme-Linked Immunosorbent Assay; Glioma; Humans; Neoplasm Invasiveness; Phosphorylation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; STAT3 Transcription Factor; Tumor Cells, Cultured; Wound Healing

Glioblastomas are the most common and most deadly primary brain tumors. Here, we evaluated the chemotherapeutic effect of the natural polyphenol curcumin on glioma cells in vitro and in vivo using an immunocompetent orthotopic mouse model.. Curcumin's effects on proliferation, cell cycle, migration, invasion, JAK/STAT3 signaling, STAT3 target gene expression, and STAT3C rescue experiments were determined in murine glioma cell lines in vitro. Therapeutic effects of curcumin in vivo were evaluated in tumor-bearing mice fed a Western-type diet fortified with curcumin (0.05%, w/w) and in control animals. Tumor growth patterns and survival were evaluated by immunohistochemistry, morphometric analyses, and Kaplan-Meier plots.. In vitro, curcumin inhibited JAK1,2/STAT3 tyrosine-phosphorylation in a dose-dependent fashion in murine glioma cell lines. Real-time RT-PCR revealed that curcumin downregulated transcription of the STAT3 target genes c-Myc, MMP-9, Snail, and Twist, and of the proliferation marker Ki67. Curcumin dose-dependently suppressed cell proliferation by inducing a G2/M phase arrest. In wound healing and Matrigel invasion assays, curcumin treatment resulted in a dose-dependent attenuation of the glioma cells' migratory and invasive behavior, which could be rescued by constitutively active STAT3C. In vivo, curcumin intake reduced the growth and midline crossing of intracranially implanted tumors and proliferation of tumor cells ensuing in significant long-term survival compared with control diet.. This preclinical study shows that curcumin is capable of suppressing malignant glioma growth in vitro and in vivo. Our data suggest that the pharmacologically safe agent curcumin holds promise for clinical application in glioma therapy.

Topics: Animals; Brain Neoplasms; Cell Growth Processes; Cell Line, Tumor; Curcumin; Diet; Disease Models, Animal; Down-Regulation; Drug Evaluation, Preclinical; Female; Glioma; Janus Kinase 1; Janus Kinase 2; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Signal Transduction; STAT3 Transcription Factor; Transplantation, Isogeneic

Turmeric, an essential ingredient of culinary preparations of Southeast Asia, contains a major polyphenolic compound, named curcumin or diferuloylmethane, which eliminates cancer cells derived from a variety of peripheral tissues. Although in vitro experiments have addressed its anti-tumor property, no in vivo studies have explored its anti-cancer activity in the brain. Oral delivery of this food component has been less effective because of its low solubility in water.We show that a soluble formulation of curcumin crosses the blood–brain barrier but does not suppress normal brain cell viability. Furthermore, tail vein injection, or more effectively, intracerebral injection through a cannula, blocks brain tumor formation in mice that had already received an intracerebral bolus of mouse melanoma cells (B16F10).While exploring the mechanism of its action in vitro we observed that the solubilized curcumin causes activation of proapoptotic enzymes caspase 3/7 in human oligodendroglioma (HOG) and lung carcinoma (A549) cells, and mouse tumor cells N18(neuroblastoma), GL261 (glioma), and B16F10. A simultaneous decrease in cell viability is also revealed by MTT [3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide]assays. Further examination of the B16F10 cells showed that curcumin effectively suppresses Cyclin D1, P-NF-kB, BclXL, P-Akt, and VEGF, which explains its efficacy in blocking proliferation, survival, and invasion of the B16F10 cells in the brain. Taken together,solubilized curcumin effectively blocks brain tumor formation and also eliminates brain tumor cells. Therefore, judicious application of such injectable formulations of curcumin could be developed into a safe therapeutic strategy for treating brain tumors.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Survival; Curcumin; Glioma; Humans; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neuroblastoma; Oligodendroglioma

Docking analysis of curcumin (C1), demethoxycurcumin (C2) and bisdemethoxycurcumin (C3) with Bcl-2 illustrated that among the three curcuminoids, C2 binds more efficiently into its putative active site. C1, C2 and C3 were purified from turmeric rhizomes to demonstrate the molecular mechanism of their anticancer activity on human glioma U87 cells. Human glioma U87 cells treated with curcuminoids resulted in activation of Bcl-2 mediated G2 checkpoint, which was associated with the induction of G2/M arrest and apoptosis. The binding of C1, C2 and C3 with Bcl-2 protein was confirmed with circular dichroism (CD) spectroscopy. Present work revealed that C2 induced Bcl-2 mediated G2/M arrest and apoptosis most effectively.

Topics: Apoptosis; Binding Sites; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Diarylheptanoids; Down-Regulation; G2 Phase; Glioma; Humans; Proto-Oncogene Proteins c-bcl-2

Curcumin (diferuloyl), from the Indian spice turmeric, reduces oxidative damage and induces apoptosis. Utilizing DNA microarrays, we have demonstrated that a low (5 microM) dose of curcumin added to a mixture of astrocytes and oligodendrocytes (C6 rat glioma cells) in culture for 24 and 48 h significantly modulates gene expression in four primary pathways: oxidative stress, cell cycle control, and DNA transcription and metabolism. Contribution of the pentose phosphate pathway to the pool of NADH upregulates glutathione and activates aldehyde oxidase. We have identified also several new genes, up- or downregulated by curcumin, namely, aldo-keto reductase, glucose-6-phosphate dehydrogenase, and aldehyde oxidase that protect against oxidative stress. The identification of several new cell cycle control genes, including the apoptosis-related protein (pirin) and insulin-like growth factor (IGF), and of the neurofilament M protein involved in neurogenesis suggests that curcumin may have applicability in the treatment of a spectrum of neurodegenerative diseases.

Topics: Animals; Antioxidants; Cell Line, Tumor; Cell Proliferation; Cluster Analysis; Curcumin; Gene Expression Profiling; Gene Expression Regulation; Glioma; Oligodendroglia; Oligonucleotide Array Sequence Analysis; Rats

Curcumin, a natural compound, is a well-known chemopreventive agent with potent anticarcinogenic activity in a wide variety of tumor cells. Curcumin inhibits cancer cell proliferation in part by suppressing cyclin D1 and inducing expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Both p53-dependent and p53-independent mechanisms regulate p21(Waf1/Cip1) expression, but the mechanism by which curcumin regulates p21(Waf1/Cip1) expression remains unknown. Here, we report that transcription of the p21(Waf1/Cip1) gene is activated by early growth response-1 (Egr-1) independently of p53 in response to curcumin treatment in U-87MG human glioblastoma cells. Egr-1 is a transcription factor that helps regulate differentiation, growth, and apoptosis in many cell types. Egr-1 expression is induced by curcumin through extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK), but not the p38, mitogen-activated protein kinase (MAPK) pathways, which mediate the transactivation of Elk-1. Transient expression of Egr-1 enhanced curcumin-induced p21(Waf1/Cip1) promoter activity, whereas suppression of Egr-1 expression by small interfering RNA abrogated the ability of curcumin to induce p21(Waf1/Cip1) promoter activity. In addition, stable knockdown of Egr-1 expression in U-87MG cells suppressed curcumin-induced p21 expression. Our results indicate that ERK and JNK MAPK/Elk-1/Egr-1 signal cascade is required for p53-independent transcriptional activation of p21(Waf1/Cip1) in response to curcumin in U-87MG human glioblastoma cells.

Topics: Apoptosis; Cell Line, Tumor; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Early Growth Response Protein 1; ets-Domain Protein Elk-1; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioma; Humans; Mitogen-Activated Protein Kinase 8; Promoter Regions, Genetic; RNA, Small Interfering; Transcriptional Activation; Tumor Suppressor Protein p53

DNA alkylating agents including temozolomide (TMZ) and 1,3-bis[2-chloroethyl]-1-nitroso-urea (BCNU) are the most common form of chemotherapy in the treatment of gliomas. Despite their frequent use, the therapeutic efficacy of these agents is limited by the development of resistance. Previous studies suggest that the mechanism of this resistance is complex and involves multiple DNA repair pathways. To better define the pathways contributing to the mechanisms underlying glioma resistance, we tested the contribution of the Fanconi anemia (FA) DNA repair pathway. TMZ and BCNU treatment of FA-proficient cell lines led to a dose- and time-dependent increase in FANCD2 mono-ubiquitination and FANCD2 nuclear foci formation, both hallmarks of FA pathway activation. The FA-deficient cells were more sensitive to TMZ/BCNU relative to their corrected, isogenic counterparts. To test whether these observations were pertinent to glioma biology, we screened a panel of glioma cell lines and identified one (HT16) that was deficient in the FA repair pathway. This cell line exhibited increased sensitivity to TMZ and BCNU relative to the FA-proficient glioma cell lines. Moreover, inhibition of FA pathway activation by a small molecule inhibitor (curcumin) or by small interference RNA suppression caused increased sensitivity to TMZ/BCNU in the U87 glioma cell line. The BCNU sensitizing effect of FA inhibition appeared additive to that of methyl-guanine methyl transferase inhibition. The results presented in this paper underscore the complexity of cellular resistance to DNA alkylating agents and implicate the FA repair pathway as a determinant of this resistance.

Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Carmustine; Cell Line, Tumor; Curcumin; Dacarbazine; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Inhibitors; Fanconi Anemia Complementation Group D2 Protein; Fanconi Anemia Complementation Group F Protein; Fanconi Anemia Complementation Group Proteins; Glioma; Guanine; Humans; Protein Processing, Post-Translational; RNA Interference; RNA, Small Interfering; Temozolomide; Time Factors; Transfection; Tumor Suppressor Proteins; Ubiquitins

Autophagy is a response of cancer cells to various anticancer therapies. It is designated as programmed cell death type II and characterized by the formation of autophagic vacuoles in the cytoplasm. The Akt/mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) and the extracellular signal-regulated kinases 1/2 (ERK1/2) pathways are two major pathways that regulate autophagy induced by nutrient starvation. These pathways are also frequently associated with oncogenesis in a variety of cancer cell types, including malignant gliomas. However, few studies have examined both of these signal pathways in the context of anticancer therapy-induced autophagy in cancer cells, and the effect of autophagy on cell death remains unclear. Here, we examined the anticancer efficacy and mechanisms of curcumin, a natural compound with low toxicity in normal cells, in U87-MG and U373-MG malignant glioma cells. Curcumin induced G(2)/M arrest and nonapoptotic autophagic cell death in both cell types. It inhibited the Akt/mTOR/p70S6K pathway and activated the ERK1/2 pathway, resulting in induction of autophagy. It is interesting that activation of the Akt pathway inhibited curcumin-induced autophagy and cytotoxicity, whereas inhibition of the ERK1/2 pathway inhibited curcumin-induced autophagy and induced apoptosis, thus resulting in enhanced cytotoxicity. These results imply that the effect of autophagy on cell death may be pathway-specific. In the subcutaneous xenograft model of U87-MG cells, curcumin inhibited tumor growth significantly (P < 0.05) and induced autophagy. These results suggest that curcumin has high anticancer efficacy in vitro and in vivo by inducing autophagy and warrant further investigation toward possible clinical application in patients with malignant glioma.

Topics: Animals; Antineoplastic Agents; Autophagy; Cell Division; Cell Line, Tumor; Curcumin; Extracellular Signal-Regulated MAP Kinases; G2 Phase; Glioma; Humans; MAP Kinase Signaling System; Mice; NF-kappa B; Protein Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; TOR Serine-Threonine Kinases

Gliomas are the most common and lethal primary tumors of the central nervous system (CNS). Despite current rigorous treatment protocols, effect of chemotherapy has failed to improve patient outcome significantly. Curcumin is a potent antioxidant that possesses both anti-inflammatory and anti-tumor activities, can suppress the initiation, promotion, and metastasis of different tumors. Its anti-tumor properties in various cancer models and negligible toxicity in normal cells make it a promising chemotherapeutic candidate. But the effect and the molecular mechanism of curcumin on gliomas are still recognized limitedly. The goal of the study is to elucidate the inhibitory effect and possible mechanisms of curcumin on glioma. After the treatment of curcumin, glioma cells U251 growth in vitro were significantly inhibited in a dose-dependent manner, and the low dose of curcumin induced G2/M cell cycle arrest. The high dose of curcumin not only enhanced G2/M cell cycle arrest, but also induced S phase of cell cycle arrest. But no obvious pre-G1 peak was observed at the different doses of curcumin. Genome DNA electrophoresis further confirmed that no DNA ladder was formed after the treatment of curcumin in U251 cells. Results of Western blot analysis demonstrated that ING4 expression was almost undetectable in U251 cells, but significantly up-regulated during cell cycle arrest induced by curcumin, and p53 expression was up-regulated followed by induction of p21 WAF-1/CIP-1 and ING4. The results demonstrate that curcumin exerts inhibitory action on glioma cell growth and proliferation via induction of cell cycle arrest instead of induction of apoptosis in a p53-dependent manner, and ING4 possibly is in part involved in the signal pathways.

Topics: Analysis of Variance; Antineoplastic Agents; Brain Neoplasms; Cell Cycle Proteins; Cell Division; Cell Line, Tumor; Curcumin; Dose-Response Relationship, Drug; G2 Phase; Glioma; Growth Inhibitors; Homeodomain Proteins; Humans; Statistics, Nonparametric; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Up-Regulation

Acetylation of histones and nonhistone proteins is an important post-translational modification involved in the regulation of gene expression in mammalian cells. Dysfunction of histone acetyltransferase (HAT) is often associated with the manifestation of several diseases. In this report, HATs are new targets for the development of therapeutics. Our studies first proved that curcumin induces histone hypoacetylation in brain cancer cells and finally induces apoptotic cell death through a (PARP)- and caspase 3-mediated manner. In addition, curcumin induces recontrolling of neural stem cell fates. It induces effective neurogenesis, synaptogenesis, and migration of neural progenitor cells in vitro in brain-derived adult neural stem cells. We also confirmed the neurogenic effect of curcumin in our in vivo experiments. Curcumin actively suppressed differentiation in astrocytes while promoting differentiation into the neurons associated with decrease of histone H3 and H4 acetylation. We suggest that histone hypoacetylation plays an important role in determine stem cell fate through controlling the simultaneous expression of many genes. Thus, the present finding that curcumin, a nontoxic dietary compound, is a histone acetyltransferase inhibitor would supply a new window to understand further the molecular mechanism of histone acetylase inhibitors (HAI) in cancer and neural stem cells and provide a new target molecule for treating central nervous system disorders.

Topics: Acetylation; Animals; Apoptosis; Astrocytes; bcl-2-Associated X Protein; Brain; Caspase 3; Caspases; Cell Differentiation; Cell Line, Tumor; Cell Movement; Cell Survival; Cells, Cultured; Collagen Type XI; Curcumin; Dentate Gyrus; Glioma; Histone Acetyltransferases; Histones; Humans; Mice; Mice, Inbred ICR; Neurons; Stem Cells

G6P translocase (G6PT) is thought to play a crucial role in transducing intracellular signaling events in brain tumor-derived cancer cells. In this report, we investigated the contribution of G6PT to the control of U-87 brain tumor-derived glioma cell survival using small interfering RNA (siRNA)-mediated suppression of G6PT. Three siRNA constructs were generated and found to suppress up to 91% G6PT gene expression. Flow cytometry analysis of propidium iodide/annexin-V-stained cells indicated that silencing the G6PT gene induced necrosis and late apoptosis. The anticancer agent curcumin, also inhibited G6PT gene expression by more than 90% and triggered U-87 glioma cells death. Overexpression of recombinant G6PT rescued the cells from curcumin-induced cell death. Targeting G6PT expression may provide a new mechanistic rationale for the action of chemopreventive drugs and lead to the development of new anti-cancer strategies.

Topics: Antineoplastic Agents; Antiporters; Cell Death; Cell Line, Tumor; Curcumin; Gene Expression Regulation, Neoplastic; Gene Silencing; Glioma; Humans; Microsomes; Monosaccharide Transport Proteins; Recombinant Proteins

The abnormal expression of matrix metalloproteinases (MMPs) plays an important role in the invasion of malignant gliomas into the surrounding normal brain tissue. This study showed that curcumin has broad-spectrum inhibitory activity against MMP gene expression in human astroglioma cells. RNase protection assay showed that curcumin inhibited the PMA-induced mRNA expression of MMP-1, -3, -9, and -14. Curcumin repressed the DNA binding and transcriptional activities of AP-1, which is a common upstream modulator of MMP-1, -3, and -9 gene expression. In addition, curcumin suppressed the PMA-induced MAP kinase activities, which were differentially involved in modulating the MMPs. This suggests that the inhibition of MMP transcriptions by curcumin is mediated at least in part through the AP-1 and MAP kinase pathways. Curcumin was also found to significantly repress the in vitro invasion of glioma cells. Therefore, the broad-spectrum inhibition of MMP gene expression by curcumin might provide a novel therapeutic strategy for treating gliomas.

Topics: Antineoplastic Agents; Astrocytoma; Base Sequence; Brain Neoplasms; Curcumin; Enzyme Inhibitors; Gene Expression; Glioma; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mitogen-Activated Protein Kinases; Ribonucleases; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-3; Transcription Factor AP-1; Tumor Cells, Cultured

Malignant glioma cells are generally resistant or only weakly sensitive to tumor necrosis factor family of cell death-inducing ligands, including TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L. The chemopreventive activity of polyphenolic compounds present in plant-derived food products has been well recognized in epidemiological studies; however, the mechanism of chemoprevention by these dietary constituents largely remains unknown. Curcumin, the yellow pigment in the spice turmeric, has profound anti-inflammatory activity and exhibits chemopreventive and tumor growth inhibitory activity. In the present study, we investigated whether curcumin sensitizes malignant glioma cell lines U251MG and U87MG to TRAIL-induced apoptosis. Treatment with low concentrations (5-20 microM) of curcumin alone had no effect on the viability of either cell line. At low concentration (5 ng/ml) TRAIL induced cytotoxicity in U251MG cells but not in U87MG cells. Whereas curcumin at subtoxic concentration sensitized U87MG cells to TRAIL-induced cytotoxicity, it had no effect on TRAIL-mediated cytotoxicity in U251MG cells. The combined curcumin and TRAIL treatment enhanced accumulation of hypo-diploid U87MG cells in sub G1 cell cycle phase and induced the cleavage of procaspases-3, -8, -9 and release of cytochrome c from mitochondria. These data indicate that curcumin differentially sensitizes glioma cells to TRAIL-induced apoptosis through the activation of both extrinsic (receptor-mediated) and intrinsic (chemical-induced) pathways of apoptosis. These results define a potential use of curcumin to sensitize glioma cells for TRAIL-mediated immunotherapy.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Blotting, Western; Brain Neoplasms; Caspase 3; Caspase 8; Caspase 9; Caspases; Cell Line, Tumor; Cell Survival; Curcumin; Cytochromes c; Enzyme Activation; Glioma; Humans; Indicators and Reagents; L-Lactate Dehydrogenase; Membrane Glycoproteins; Mitochondria; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

It had been observed that BRM-SJS had antitumor effect in our clinical practice. This study was designed to investigate the antitumor activity of BRM-SJS, and mechanism of its action.. In vitro antitumor experiments with MTT method, meanwhile cell morphology, flow cytometry, and agarose gel electrophoresis were performed for determining apoptosis in several tumor cell lines.. BRM-SJS had antitumor effects on human Suzhou human glioma (SHG-44), breast carcinoma (MCF-7), and human pancreas carcinoma (PANC1) in vitro, the IC50 values of BRM-SJS were 0. 299 mg/ml, 1.853 mg/ml and 9.416 mg/ml respectively. At the 2. 5 mg of BRM-SJS on SHG-44 and MCF-7, marked morphological changes, including cell shrinkage and condensation of chromosomes, were observed with electric microscope. The increase of apoptosis in SHG-44 and MCF-7 cells treated with BRM-SJS extracts 0.625 -2.5 mg for 14 -48 h was observed by Annexin-V/PI flow cytometry analysis. Agarose gel electrophoresis of DNA from SHG-44 and MCF-7 cells treated with BRM-SJS extracts 1.25 -5 mg for 24 h or 48 h showed marked DNA Ladder pattern.. Antitumor activity of BRM-SJS may be related with inducement of apoptosis of tumor cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Capsules; Cell Line, Tumor; Cell Proliferation; Curcuma; Drug Combinations; Drugs, Chinese Herbal; Female; Glioma; Humans; Pancreatic Neoplasms; Plants, Medicinal; Scutellaria

Curcumin (CUR), the active chemical of the Asian spice turmeric, has strong anti-oxidant and anti-inflammatory properties. CUR inhibits proliferation and growth of several cell types, e.g. cancer cells. While CUR inhibitory effects on microglial cells are demonstrated, little is known of its effects on neuroglia, astrocytes (AST) and oligodendrocytes (OLG). Our work focuses on CUR's effects on neuroglial proliferation and growth in vitro, utilizing C-6 rat glioma 2B-clone cells, a mixed colony of both neuroglial cells, in 6 day trials.. The doses studied included 4, 5, 10, 15, and 20 microM - concentrations slightly smaller than those shown to stimulate protein expression in ASTs. Automated particle counter was used to determine proliferation, and marker enzyme assays were used to determine AST and OLG activity.. CUR inhibited neuroglial proliferation, with the degree of inhibition correlated directly with the CUR concentration. Proliferative inhibition was observed after a concentration as low as 5 microM by day 6, while inhibition of 20 microM doses occurred by day 2 of culture. Proliferative inhibition is associated with morphological changes, e.g. cell elongation and neurite prolongation, and increased activity of a marker enzyme corresponding to differentiation of OLG and with a reduced activity of the marker enzyme for AST.. Our data suggests CUR acts continuously over a period of time, with low doses being as effective as higher doses given a longer period of treatment. It has been suggested that CUR's anti-inflammatory and anti-oxidant actions may be useful in the prevention-treatment of neurodegenerative diseases, e.g. Alzheimer's and Parkinson's Diseases. Given neuroglial involvement in these diseases, and CUR's observed actions on neuroglia, the data presented here may provide further explanations of CUR's preventative-therapeutic role in these diseases.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Antineoplastic Agents; Astrocytes; Cell Division; Cell Line, Tumor; Curcumin; Glioma; Glutamate-Ammonia Ligase; Oligodendroglia; Rats

Curcumin, a major component of turmeric, a seasoning commonly used in Indian food, and a known antioxidant, anti-inflammatory and anti-carcinogenic agent, is a potent stimulator of the stress-induced expression of Hsp27, alphaB crystallin and Hsp70. When C6 rat glioma cells were exposed to arsenite (100 microM for 1 h), CdCl2 (100 microM for 1 h) or heat (42 degrees C for 30 min) in the presence of 3-10 microM curcumin, induction of the synthesis of all three proteins was markedly stimulated, as detected by specific immunoassays, Western blot analysis and Northern blot analysis. A gel mobility shift assay revealed that curcumin prolonged the stress-induced activation of the heat shock element-binding (HSE-binding) activity of heat shock transcription factor (Hsf) in the cultured cells. The stimulatory effect of curcumin on the responses to stress was also observed in BRL-3A rat liver cells and Swiss 3T3 mouse fibroblasts. Induction of Hsp27, alphaB crystallin and Hsp70 in the liver and adrenal glands of heat-stressed (42 degrees C for 20 min) rats was also enhanced by prior injection of curcumin (20 mg/kg body weight). As curcumin is a potent inhibitor of arachidonic acid metabolism, it is suggested that the mechanism of the stimulation by curcumin of the stress responses might be similar to that of salicylate, indomethacin and nordihydroguaiaretic acid.

Topics: 3T3 Cells; Adrenal Glands; Animals; Antioxidants; Arsenites; Brain Neoplasms; Cells, Cultured; Crystallins; Curcuma; Curcumin; Gene Expression Regulation; Glioma; Heat-Shock Proteins; Hot Temperature; HSP70 Heat-Shock Proteins; Liver; Male; Mice; Plant Extracts; Rats; Rats, Wistar; RNA, Messenger; Sodium Compounds; Stimulation, Chemical; Stress, Physiological; Tumor Cells, Cultured