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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.

SUBMITTER: Heaney ML

PROVIDER: S-EPMC3695824 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs.

Heaney Mark L ML Gardner Jeffrey R JR Karasavvas Nicos N Golde David W DW Scheinberg David A DA Smith Emily A EA O'Connor Owen A OA

Cancer research 20081001 19

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, apopto ...[more]

PMID: 18829561

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Project description:ObjectiveThe role of Quercetin in ovarian cancer treatment remains controversial, and the mechanism is unknown. The aim of this study was to investigate the therapeutic effects of Quercetin in combination with Cisplatin and other anti-neoplastic drugs in ovarian cancer cells both in vitro and in vivo, along with the molecular mechanism of action.MethodsQuercetin treatment at various concentrations was examined in combination with Cisplatin, taxol, Pirarubicin and 5-Fu in human epithelial ovarian cancer C13* and SKOV3 cells. CCK8 assay and Annexin V assay were for cell viability and apoptosis analysis, immunofluorescence assay, DCFDA staining and realtime PCR were used for reactive oxygen species (ROS)-induced injury detection and endogenous antioxidant enzymes expression. Athymic BALB/c-nu nude mice were injected with C13*cells to obtain a xenograft model for in vivo studies. Immunohistochemical analysis was carried out to evaluate the ROS-induced injury and SOD1 activity of xenograft tumors.ResultsContrary to the pro-apoptotic effect of high concentration (40 µM-100 µM) of Quercetin, low concentrations (5 µM-30 µM) of Quercetin resulted in varying degrees of attenuation of cytotoxicity of Cisplatin treatment when combined with Cisplatin. Similar anti-apoptotic effects were observed when Quercetin was combined with other anti-neoplastic agents: Taxol, Pirarubicin and 5-Fluorouracil (5-Fu). Low concentrations of Quercetin were observed to suppress ROS-induced injury, reduce intracellular ROS level and increase the expression of endogenous antioxidant enzymes, suggesting a ROS-mediated mechanism of attenuating anti-neoplastic drugs. In xenogeneic model, Quercetin led to a substantial reduction of therapeutic efficacy of Cisplatin along with enhancing the endogenous antioxidant enzyme expression and reducing ROS-induced damage in xenograft tumor tissue.ConclusionTaken together, these data suggest that Quercetin at low concentrations attenuate the therapeutic effects of Cisplatin and other anti-neoplastic drugs in ovarian cancer cells by reducing ROS damage. Quercetin supplementation during ovarian cancer treatment may detrimentally affect therapeutic response.

Project description:BACKGROUND:We examined the association between the administration of antineoplastic drugs (AD) and fecundity among female nurses. METHODS:AD administration and use of exposure controls (EC) such as gloves, gowns, and needleless systems were self-reported at baseline among 2649 participants of the Nurses' Health Study 3, who were actively attempting pregnancy. Every 6 months thereafter, the nurses reported the current duration of their pregnancy attempt. Multivariable accelerated failure time models were used to estimate time ratios (TR) and 95% confidence intervals (CI) adjusted for age, race, body mass index, smoking, marital status, hours of work, and other occupational risk factors. RESULTS:Mean (standard deviation) age and BMI at baseline were 30.7 years (4.7) and 26.0?kg/m2 (6.4). Forty-one percent of nurses reported ever administering AD; 30% only in the past and 11% currently. The former administration of AD (TR?=?1.02, 95% CI, 0.93-1.12) was unrelated to the ongoing duration of pregnancy attempt. Among nurses currently administering AD, those who had administered AD for 6 years and above had a 27% (95% CI, 6%-53%) longer duration of pregnancy attempt than nurses who never handled ADs in unadjusted analyses. This difference disappeared in multivariable analyses (TR?=?1.01, 95% CI, 0.85-1.21). 93% (n?=?270) of the nurses currently administering ADs reported consistent use of EC. These nurses had a similar median duration of pregnancy attempt to those who never handled AD (TR?=?1.00, 95% CI, 0.87-1.15). CONCLUSIONS:Administration of ADs did not appear to have an impact on fecundity in a cohort of nurses planning for pregnancy with a high prevalence of consistent ECs. Our results may not be generalizable to women who are less compliant with PPE use or with less availability to ECs. Therefore, it is possible that we did not observe an association between occupational exposure to AD and reduced fecundity because of lower exposure due to the more prevalent use of effective ECs.

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Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs.

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Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs.

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