title: Curcumin differentially sensitizes malignant glioma cells to TRAIL/Apo2L-mediated apoptosis through activation of procaspases and release of cytochrome c from mitochondria.
abstract: 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.
authors.affiliation: Surgical Research, Department of Surgery, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Gao
authors.forename: Dorrah
authors.initials: D
authors.lastname: Deeb
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.forename: Yong B
authors.initials: YB
authors.lastname: Liu
authors.forename: Scott A
authors.initials: SA
authors.lastname: Dulchavsky
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Gautam
mesh_terms: D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin; D045304:Cytochromes c / Q000378:metabolism*; D004789:Enzyme Activation; D005910:Glioma / Q000473:pathology*; D006801:Humans; D007202:Indicators and Reagents; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D007202:Indicators and Reagents; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003474:Curcumin