curcumin and Adenocarcinoma-of-Lung

As the main component of turmeric (. LUAD mRNA expression data were obtained from TCGA database and differentially expressed genes (DEGs) were identified using R software. Functional enrichment analysis was conducted to further clarify its biological properties and hub genes were identified by a protein-protein interaction (PPI) network analysis. Survival analysis and molecular docking were used to analyze the effectiveness of the hub genes. By an in vitro study, we evaluated whether curcumin could influence the proliferation, migration, and invasion activities of LUAD cells.. In this study, 1783 DEGs from LUAD tissue samples compared to normal samples were evaluated. Functional enrichment analysis and the PPI network revealed the characteristics of the DEGs. We performed a topological analysis and identified 10 hub genes. Of these, six genes (. The results of this study suggest that the therapeutic effects of curcumin on LUAD may be achieved through the intervention of

Topics: Adenocarcinoma of Lung; Biomarkers, Tumor; Computational Biology; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Molecular Docking Simulation

The synthesized 1,5 diarylpenta-1,4-dien-3-one derivatives (compounds 1-6) as synthetic curcumin analogues were tested for their potential anticancer activity against human ovarian and lung adenocarcinoma cells. The absorption, distribution, metabolism, excretion, and toxicity (ADMET/pharmacokinetic) parameters of all the compounds were predicted by admetSAR software. The pharmacokinetics, pharmacodynamics and bioactivity scores properties based on Lipinski rule and Ghose filter, calculated with the help of Molinspiration and ChemDraw. Molecular docking evaluation of all the compounds was also performed by using AutoDock Vina and iGEMDOCK against three most common human anticancer targets; epidermal growth factor receptor (EGFR), heat shock protein (Hsp 90-α), and vascular endothelial growth factor receptor-2 (VEGFR2). The obtained results were compared with the reference compound 7 and drugs 8-10 (7: GO-035; 8: Quinazolin; 9: Naquotinib and 10: Ribofuranuronamide). Finding indicates, all the compounds were potentially interacting with VEGFR2 through the average -9.1 binding energy (BE) with closer contact <5.0 Å deep in the active site of the ligand-receptor complex. All the compounds showed excellent oral bioavailability, bioactivity score, and none of the compounds are virtually found to be toxic. Compounds 1-6 were also successfully characterized by the physical properties as well as spectroscopic techniques (FT-IR and

Topics: Adenocarcinoma of Lung; Alkadienes; Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Screening Assays, Antitumor; ErbB Receptors; Female; Heat-Shock Proteins; Humans; Ligands; Lung Neoplasms; Molecular Docking Simulation; Molecular Structure; Ovarian Neoplasms; Reactive Oxygen Species; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

This study was designed to explore the effects of curcumin on proliferation, migration and invasion of human lung adenocarcinoma LTEP-A2 cells and determine its mechanism. Human lung adenocarcinoma LTEP-A2 cell was cultured in vitro. After incubation with different concentrations of curcumin (5, 10, 15 μmol/L), the effects of curcumin on proliferation, migration and invasion of human lung adenocarcinoma LTEP-A2 cells were observed by MTT assay, wound healing and transwell assay. The expression levels of COX-2 and MMP-9 were detected by western blot. Compared with the blank control group, curcumin decreased the survival rate of LTEP-A2 cells, shorten the cell migration distance and decrease the number of LTEP-A2 cells penetrating membrane. The expression levels of COX-2 and MMP-9 were both down-regulated by curcumin. Curcumin can inhibit the proliferation, migration and invasion of human lung adenocarcinoma LTEP-A2 cells. The mechanism may be related to the down-regulation of COX-2 and MMP-9 expression.

Topics: Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Cyclooxygenase 2; Humans; Lung Neoplasms; Matrix Metalloproteinase 9

Nanoscale drug delivery systems have emerged as promising alternatives to overcome the problems associated with by conventional chemotherapy for cancer treatment such as poor drug stability and bio-distribution. Herein, we report a single walled carbon nanotubes (SWCNTs) based drug delivery system functionalized with polysaccharides such as alginate (ALG) and chitosan (CHI), which can be loaded with an anticancer drug curcumin (CUR). Modification of SWCNTs renders high drug loading efficiency and sustained drug release, imperative for drug activity. These were characterized through various tools viz, microscopic (transmission electron microscopy, scanning electron microscopy and atomic force microscopy) and zeta potential analysis. Incorporation of CUR inside the modified SWCNTs was studied through Fourier transform infrared spectroscopy, fluorescence and UV-visible spectroscopy. In vitro release studies were conducted to gain an insight into the pH-dependent release behavior of the entrapped CUR from modified SWCNTs. The anti-cancer potential was further demonstrated using human lung adenocarcinoma (A549) cells as a model system. Various cell culture based assays were performed to study the ability of released CUR from modified SWCNTs for inhibiting the cancer cell proliferation by inducing apoptosis.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Lung Neoplasms; Nanotubes, Carbon; Tumor Cells, Cultured

Curcumin, a natural polyphenolic compound isolated from the plant

Topics: A549 Cells; Adenocarcinoma; Adenocarcinoma of Lung; Autophagy; Curcumin; Enzyme Induction; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Neoplasm Proteins; Sialyltransferases

Curcumin, a dietary supplement or herbal medicine from Curcuma longa, has shown antitumor activity in different cancer cell lines and clinical trials. CA916798, a novel protein, is overexpressed in multidrug-resistant tumor cells. This study aimed to assess the effects of curcumin on regulating chemosensitivity in cisplatin-resistant non-small cell lung cancer (NSCLC) cells in vitro and to explore the underlying molecular mechanisms. Human cisplatin-sensitive A549 and cisplatin-resistant A549/CDDP lung adenocarcinoma cells were treated with curcumin to assess cell viability and gene modulations using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. CA916798 shRNA and point mutations were used to assess the CA916798 functions and phosphorylation sites. Bisdemethoxycurcumin sensitized cisplatin-resistant lung cancer cells to various chemotherapeutic agents, including cisplatin. Bisdemethoxycurcumin reduced the levels of CA916798 mRNA and protein in A549 and A549/CDDP cells, while it also suppressed phosphatidylinositol-3-kinase (PI3K)/AKT signaling. CA916798, as a downstream gene, interacted with AKT after bisdemethoxycurcumin treatment in A549 and A549/CDDP cells. Moreover, A549/CDDP cells expressing the point-mutated CA916798-S20D protein were more resistant to cisplatin and bisdemethoxycurcumin, whereas tumor cells expressing CA916798-S20A, CA916798-S31A, CA916798-S60A, CA916798-S93A, or CA916798-T97A (different sites of amino acid phosphorylation) showed similar sensitivity or resistance to cisplatin and bisdemethoxycurcumin, compared with the control cells. Bisdemethoxycurcumin is able to sensitize cisplatin-resistant NSCLC cells to chemotherapeutic agents by inhibition of CA916798 and PI3K/AKT activities. Moreover, phosphorylation of CA916798 at the S20 residue plays a critical role in mediating bisdemethoxycurcumin antitumor activity.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Cisplatin; Curcumin; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Curcumin (1) down-regulates the expression as well as phosphorylation of epidermal growth factor receptor (EGFR) in lung adenocarcinoma cells expressing gefitinib-resistant EGFR. Thirty-seven newly synthesized curcumin analogues including dimethoxycurcumin (2, DMC) were evaluated for their effects on EGFR expression as well as phosphorylation in two gefitinib-resistant lung adenocarcinoma cell lines, CL1-5 (EGFR(wt)) and H1975 (EGFR(L858R+T790M)). Based on the identified structure-activity relationships, methoxy substitution at C-3', C-4', or both positions favored inhibitory activity (compounds 1, 2, 5, 8-15, 17, 36), while compounds with more polar substituents were generally less active in both cell lines. Compound 36 with a fluorine substituent at C-6' and its protonated counterpart 2 did not lose activity, suggesting halogen tolerance. In addition, a conjugated linker was essential for activity. Among all evaluated curcumin derivatives, compound 2 showed the best inhibitory effects on both wild-type and mutant EGFR by efficiently inducing gefitinib-insensitive EGFR degradation. Compound 23 also reduced gefitinib-induced gastrointestinal damage in the non-transformed intestinal epithelial cell line IEC-18.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Cell Line, Tumor; Curcumin; Drug Resistance, Neoplasm; ErbB Receptors; Gastrointestinal Diseases; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Xenograft Model Antitumor Assays

β-elemene, the active component of elemene (1-methyl-1-vinyl-2,4-diisopropenyl-cyclohexane), is a naturally occurring compound isolated from the traditional Chinese medicinal herb Curcuma wenyujin. Studies have confirmed that β-elemene enhances the radiosensitivity of lung cancer cell lines such as A549, by multiple pathways; however, their underlying mechanisms and pathways are yet to be elucidated. In the present study, two-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry were used to profile the different proteins in A549 cell xenograft models of both treatment groups. The protein/mRNA expression was assessed by reverse transcription-polymerase chain reaction and western blotting techniques in tumor samples from all treatment groups. As a critical player in redox regulation of cancer cells, inhibition of peroxiredoxin-1 (Prx-1) may be an effective option for enhancing the tumor response to radiation. We further verified Prx-1 expression at the transcription and translation levels. β-elemene at a dose of 45 mg/kg had little effect on the Prx-1 protein expression, which was correlated with a moderate antitumor effect. However, a 45 mg/kg dose of β-elemene significantly inhibited the Prx-1 mRNA expression, thereby suggesting a possible influence on the transcriptional process, and radiation significantly increased the Prx-1 mRNA/protein expression compared to the control group (p<0.01). Notably, Prx-1 mRNA/protein expression was significantly lower in the β-elemene/radiation co-treatment group compared to the baseline levels in the control group (p<0.01). These results suggest that radiation-induced Prx-1 expression is directly or indirectly suppressed by β-elemene, thus suggesting a new pathway by which to reverse radioresistance.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Cell Line, Tumor; Curcuma; Down-Regulation; Female; Humans; Lung Neoplasms; Medicine, Chinese Traditional; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Peroxiredoxins; Plant Extracts; Radiation Tolerance; Radiation-Sensitizing Agents; Radiography; RNA, Messenger; Sesquiterpenes; Tandem Mass Spectrometry; Transcription, Genetic; Transplantation, Heterologous

The supermolecular curcumin (SMCCM) exhibiting remarkably improved solubility and release characteristics was fabricated to increase the oral bioavailability in rat as well as the antiproliferative and proapoptotic activities of curcumin (CCM) against human lung adenocarcinoma cell A549. SMCCM was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, morphology and structure, aqueous solubility, and release behavior in vitro. Computer modeling of the supermolecular structure was performed. The pharmacokinetics, antiproliferative and proapoptotic activities of SMCCM were evaluated. The mechanisms by which SMCCM inhibited proliferation and induced apoptosis were identified. The formation of SMCCM was testified and the supermolecular structure was studied by a computer modeling technique. Compared to free CCM, SMCCM with much higher aqueous solubility exhibited obviously enhanced release and more favorable pharmacokinetic profiles, and, furthermore, SMCCM showed higher anticancer efficacy, enhanced induction of G2/M-phase arrest and apoptosis in A549 cells, which might be involved with the increases in reactive oxygen species production and intracellular Ca(2+) accumulation, and a decrease in mitochondrial membrane potential. SMCCM remarkably enhanced not only the oral bioavailability but also the antiproliferative and proapoptotic activities of CCM along with improved solubility and release characteristics of CCM.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Calcium; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Lung; Lung Neoplasms; Male; Models, Molecular; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Solubility

The purpose of this manuscript was to study the regulation effects of β-elemene combined with radiotherapy on three different gene expressions in lung adenocarcinoma A549 cell. mTOR gene, HIF-1α gene, Survivin gene were included in the gene group. Cell culture and RT-PCR were applied to finish this research. Hypoxia Control group, Hypoxia β-elemene group, Hypoxia β-elemene combined with irradiation group were set to compare the differences of three different gene expressions. The most active effects were found in the group of Hypoxia irradiation combined with β-elemene. In this group, the mTOR gene, HIF-1α gene, Survivin gene expressions were all down-regulated when compared with the single treatment groups, and there were significantly statistical differences.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Chemotherapy, Adjuvant; Curcuma; Down-Regulation; Gene Expression; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Phytotherapy; Plant Extracts; Reverse Transcriptase Polymerase Chain Reaction; Sesquiterpenes; Survivin; TOR Serine-Threonine Kinases

CLEFMA or 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] is a curcuminoid being developed as an anticancer drug. We recently reported that it potently inhibits proliferation of various cancer cells. In this project, we investigated the effect of CLEFMA on gene expression profile in H441 lung adenocarcinoma cells, and studied its mechanism of action. In microarray data, we observed a deregulation of genes involved in redox and glutamate metabolism. Based on the affected ontologies, we hypothesized that antiproliferative activity of CLEFMA could be a result of the induction of reactive oxygen species (ROS). We tested this hypothesis by determining the levels of glutathione (GSH) and ROS in H441 cells treated with CLEFMA. We observed a rapid depletion of intracellular GSH/GSSG ratio. Using a cell-permeable fluorogenic substrate, we found that CLEFMA significantly induced ROS in a time- and dose-dependent manner (p < 0.05). Flow-cytometry with a mitochondria-selective fluorescent reporter of ROS indicated that the CLEFMA-induced ROS was of mitochondrial origin. In contrast to the cancer cells, the normal lung fibroblasts (CCL-151) did not show any increase in ROS and were resistant to CLEFMA-induced cell death. Furthermore, the addition of antioxidants, such as catalase, superoxide dismutase and N-acetylcysteine, rescued cancer cells from CLEFMA-induced cell death. Gene expression pathway analysis suggested that a transcription factor regulator Nrf2 is a pivotal molecule in the CLEFMA-induced deregulation of redox pathways. The immunoblotting of Nrf2 showed that CLEFMA treatment resulted in phosphorylation and nuclear translocation of Nrf2 in a time-dependent fashion. Based on these results, we conclude that induction of ROS is critical for the antiproliferative activity of CLEFMA and the Nrf2-mediated oxidative stress response fails to salvage H441 cells.

Topics: Active Transport, Cell Nucleus; Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Antioxidants; Benzylidene Compounds; Blotting, Western; Cell Death; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glutathione; Humans; Lung Neoplasms; NF-E2-Related Factor 2; Oligonucleotide Array Sequence Analysis; Oxidation-Reduction; Oxidative Stress; Phosphorylation; Piperidones; Reactive Oxygen Species; Time Factors

Curcumin, a yellow pigment derived from Curcuma longa Linn, has been favored by the Eastern as dietary ingredients for centuries. During the past decade, extensive investigations have revealed curcumin sensitized various chemotherapeutic agents in human breast, colon, pancreas, gastric, liver, brain and hematological malignant disorders in vivo and in vitro. Several pathways and specific targets including NF-κB, STAT3, COX-2, Akt and multidrug resistant protein have been identified to facilitate curcumin as a chemosensitizer. Recent studies suggest HIF-1α participated in the development of drug resistance in cancer cells and targeting HIF-1α either by RNAi or siRNA successfully overcame chemotherapeutic resistance. To investigate the mechanism basis of curcumin as a chemosensitizer in lung cancer, we examined curcumin's effects on HIF-1α in cis-platin (DDP) sensitive A549 and resistant A549/DDP cell lines by RT-PCR and Western blot. HIF-1α in A549/DDP cells was found to be overexpressed at both mRNA and protein levels together with a poor response to DDP. Results from transient transfection and flow cytometry showed the HIF-1α abnormality contributed to DDP resistance in A549/DDP lung cancer cells. Combined curcumin and DDP treatment markedly inhibited A549/DDP cells proliferation, reversed DDP resistance and triggered apoptotic death by promoting HIF-1α degradation and activating caspase-3, respectively. Expression of HIF-1α-dependent P-gp also seemed to decrease as response to curcumin in a dose-dependent manner. Our findings shed light on drug resistant reversing effect of curcumin in lung cancer cells by inhibiting HIF-1α expression and activating caspase-3.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cisplatin; Curcumin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms

Radiation pneumonitis (RP) is an important dose-limiting toxicity during thoracic radiotherapy. Previous investigations have shown that curcumin is used for the treatment of inflammatory conditions and cancer, suggesting that curcumin may prevent RP and sensitize cancer cells to irradiation. However, the clinical advancement of curcumin is limited by its poor water solubility and low bioavailability after oral administration. Here, a water-soluble liposomal curcumin system was developed to investigate its prevention and sensitizing effects by an intravenous administration manner in mice models. The results showed that liposomal curcumin inhibited nuclear factor-κB pathway and downregulated inflammatory factors including tumor necrosis factor-α, interleukin (IL)-6, IL-8, and transforming growth factor-β induced by thoracic irradiation. Furthermore, the combined treatment with liposomal curcumin and radiotherapy increased intratumoral apoptosis and microvessel responses to irradiation in vivo. The significantly enhanced inhibition of tumor growth also was observed in a murine lung carcinoma (LL/2) model. There were no obvious toxicities observed in mice. The current results indicate that liposomal curcumin can effectively mitigate RP, reduce the fibrosis of lung, and sensitize LL/2 cells to irradiation. This study also suggests that the systemic administration of liposomal curcumin is safe and deserves to be investigated for further clinical application.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Analysis of Variance; Animals; Carcinoma, Lewis Lung; Cell Line, Tumor; Combined Modality Therapy; Curcumin; Cytokines; Histocytochemistry; Liposomes; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Radiation Pneumonitis; Radiation-Sensitizing Agents; Radiography, Thoracic

Endoplasmic reticulum (ER) stress-induced cancer cell apoptosis has become a novel signaling target for development of cancer therapeutic drugs. Curcumin exhibits growth-suppressive activity against a variety of cancer cells. We previously synthesized a series of monocarbonyl analogues of curcumin with strong cytotoxicity against tumor cells. In this study, we found that only compound 19 [(1E,4E)-1,5-bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one] can induce C/EBP-homologous protein (CHOP) expression in human lung cancer H460 cells. Treatment with 19 induced H460 cell apoptosis in a dose-responsive manner, and this effect was associated with corresponding increases in a series of key components in ER stress-mediated apoptosis pathway, followed by caspase cleavage and activation. However, curcumin at the same concentrations does not display such properties. CHOP knockdown by specific siRNA attenuated 19-induced cell apoptosis, further indicating that the apoptotic pathway is ER stress-dependent. In vivo, 19 showed a dramatic 53.5% reduction in H460 xenograft tumor size after 22 days of treatment. Taken together, these mechanistic insights on the novel compound 19, with nontoxicity, may provide us with a novel anticancer candidate.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Cell Proliferation; Curcumin; Endoplasmic Reticulum; Female; Humans; Lentivirus; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Molecular Targeted Therapy; Oxidative Stress; RNA, Small Interfering; Signal Transduction; Transcription Factor CHOP; Xenograft Model Antitumor Assays