title: Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs.
abstract: Vitamin C is an antioxidant vitamin that has been hypothesized to antagonize the effects of reactive oxygen species-generating antineoplastic drugs. The therapeutic efficacy of the widely used antineoplastic drugs doxorubicin, cisplatin, vincristine, methotrexate, and imatinib were compared in leukemia (K562) and lymphoma (RL) cell lines with and without pretreatment with dehydroascorbic acid, the commonly transported form of vitamin C. The effect of vitamin C on viability, clonogenicity, apoptosis, P-glycoprotein, reactive oxygen species (ROS), and mitochondrial membrane potential was determined. Pretreatment with vitamin C caused a dose-dependent attenuation of cytotoxicity, as measured by trypan blue exclusion and colony formation after treatment with all antineoplastic agents tested. Vitamin C given before doxorubicin treatment led to a substantial reduction of therapeutic efficacy in mice with RL cell-derived xenogeneic tumors. Vitamin C treatment led to a dose-dependent decrease in apoptosis in cells treated with the antineoplastic agents that was not due to up-regulation of P-glycoprotein or vitamin C retention modulated by antineoplastics. Vitamin C had only modest effects on intracellular ROS and a more general cytoprotective profile than N-acetylcysteine, suggesting a mechanism of action that is not mediated by ROS. All antineoplastic agents tested caused mitochondrial membrane depolarization that was inhibited by vitamin C. These findings indicate that vitamin C given before mechanistically dissimilar antineoplastic agents antagonizes therapeutic efficacy in a model of human hematopoietic cancers by preserving mitochondrial membrane potential. These results support the hypothesis that vitamin C supplementation during cancer treatment may detrimentally affect therapeutic response.
authors.affiliation: Departments of Medicine and Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. heaneym@mskcc.org
authors.forename: Mark L
authors.initials: ML
authors.lastname: Heaney
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gardner
authors.forename: Nicos
authors.initials: N
authors.lastname: Karasavvas
authors.forename: David W
authors.initials: DW
authors.lastname: Golde
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
authors.forename: Emily A
authors.initials: EA
authors.lastname: Smith
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D001205:Ascorbic Acid / Q000378:metabolism / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects; D003683:Dehydroascorbic Acid / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid