title: Trolox enhances curcumin's cytotoxicity through induction of oxidative stress.
abstract: Curcumin, a natural polyphenol in the spice turmeric, has been found to exhibit anticancer activity. Although curcumin is generally considered an antioxidant, it is also able to elicit apoptosis through the generation of ROS, thereby functioning as a pro-oxidant in cancer cells. The present study investigated the effects of antioxidant pretreatment on curcumin-induced cytotoxicity in the human cancer cell lines A2780, MCF-7, and MDA-MB-231. Cytotoxicity was enhanced by trolox, vitamin C or vitamin E; trolox, a water soluble vitamin E derivative, was the most potent. The combination of curcumin (10 μM) and trolox (10-50 μM) induced apoptosis of cancer cells as evidenced by PARP cleavage and caspase-3 activation. Furthermore, expression of the pro-apoptotic protein Bad was up-regulated and expression of the anti-apoptotic proteins Bcl-2 and Bcl-xl was down-regulated in cells that had been treated with trolox plus curcumin. ROS generation was detected in curcumin-treated cells and was significantly enhanced when cells were treated with trolox plus curcumin. Exogenous catalase or SOD1 did not alter cytotoxicity, while over-expression of either catalase or SOD1 did, pointing to the importance of intracellular hydrogen peroxide generation in cell killing. In conclusion, we demonstrated for the first time that antioxidants such as trolox can potentiate cancer cell killing by curcumin, a finding which may help in the development of novel drug combination therapies.
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.forename: Kelsey
authors.initials: K
authors.lastname: Payne
authors.forename: Jori E
authors.initials: JE
authors.lastname: Taggart
authors.forename: Hongchao
authors.initials: H
authors.lastname: Jiang
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Lind
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Ding
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001205:Ascorbic Acid / Q000494:pharmacology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002839:Chromans / Q000494:pharmacology*; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059748:Proteolysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000072105:Superoxide Dismutase-1; D014810:Vitamin E / Q000031:analogs & derivatives / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; C494819:BAD protein, human; D002839:Chromans; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D051025:bcl-Associated Death Protein; D014810:Vitamin E; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D003474:Curcumin; D001205:Ascorbic Acid; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid