Vitamin C suppresses cell death in MCF-7 human breast cancer cells induced by tamoxifen

J Cell Mol Med. 2014 Feb;18(2):305-13. doi: 10.1111/jcmm.12188. Epub 2013 Nov 25.

Abstract

Vitamin C is generally thought to enhance immunity and is widely taken as a supplement especially during cancer treatment. Tamoxifen (TAM) has both cytostatic and cytotoxic properties for breast cancer. TAM engaged mitochondrial oestrogen receptor beta in MCF-7 cells and induces apoptosis by activation of pro-caspase-8 followed by downstream events, including an increase in reactive oxygen species and the release of pro-apoptotic factors from the mitochondria. In addition to that, TAM binds with high affinity to the microsomal anti-oestrogen-binding site and inhibits cholesterol esterification at therapeutic doses. This study aimed to investigate the role of vitamin C in TAM-mediated apoptosis. Cells were loaded with vitamin C by exposure to dehydroascorbic acid, thereby circumventing in vitro artefacts associated with the poor transport and pro-oxidant effects of ascorbic acid. Pre-treatment with vitamin C caused a dose-dependent attenuation of cytotoxicity, as measured by acridine-orange/propidium iodide (AO/PI) and Annexin V assay after treatment with TAM. Vitamin C dose-dependently protected cancer cells against lipid peroxidation caused by TAM treatment. By real-time PCR analysis, an impressive increase in FasL and tumour necrosis factor-α (TNF-α) mRNA was detected after TAM treatment. In addition, a decrease in mitochondrial transmembrane potential was observed. These results support the hypothesis that vitamin C supplementation during cancer treatment may detrimentally affect therapeutic response.

Keywords: ROS; apoptosis; breast cancer; free radical; lipid peroxidation; tamoxifen; vitamin C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annexin A5
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Dehydroascorbic Acid / metabolism
  • Dehydroascorbic Acid / pharmacology*
  • Dose-Response Relationship, Drug
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / metabolism
  • Female
  • Humans
  • Lipid Peroxidation / drug effects
  • Membrane Potential, Mitochondrial / drug effects
  • Propidium
  • Reactive Oxygen Species / metabolism
  • Tamoxifen / antagonists & inhibitors
  • Tamoxifen / pharmacology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Annexin A5
  • Antineoplastic Agents, Hormonal
  • FASLG protein, human
  • Fas Ligand Protein
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Tamoxifen
  • Propidium
  • Caspase 8
  • Dehydroascorbic Acid