Enhancement of doxorubicin cytotoxicity by polyunsaturated fatty acids in the human breast tumor cell line MDA-MB-231: relationship to lipid peroxidation

Int J Cancer. 1998 Feb 9;75(4):578-83. doi: 10.1002/(sici)1097-0215(19980209)75:4<578::aid-ijc14>3.0.co;2-5.


Exogenous polyunsaturated fatty acids modulate the cytotoxic activity of anti-cancer drugs. In this study, we examined whether lipid peroxidation is a potential mechanism through which fatty acids enhance drug cytotoxicity. We measured cell viability in the human breast cancer cell line MDA-MB-231 exposed to doxorubicin in the presence of non-cytotoxic concentrations of various polyunsaturated fatty acids for 6 days. To determine the role of lipid peroxidation, the hydroperoxide level was measured in cell extracts. Among all polyunsaturated fatty acids tested, docosahexaenoic acid (DHA, 22:6n-3) was the most potent in increasing doxorubicin cytotoxicity: cell viability decreased from 54% in the presence of 10(-7) M doxorubicin alone to 21% when cells were incubated with doxorubicin and DHA. After addition of an oxidant system (sodium ascorbate/2-methyl-1,4-naphthoquinone) to cells incubated with doxorubicin and DHA, cell viability further decreased to 12%. Cell hydroperoxides increased commensurately. The effect of DHA on doxorubicin activity and lipid hydroperoxide formation was abolished by a lipid peroxidation inhibitor (dl-alpha-tocopherol) or when oleic acid (a non-peroxidizable fatty acid) was used in place of DHA. No effect was observed with mitoxantrone, a drug with a low peroxidation-generating potential. Thus, DHA may increase the efficacy of oxyradical-producing drugs through a mechanism involving a generation of lipoperoxides. This may lead in vivo to a modulation of tumor cell chemosensitivity by DHA and oxidant agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / pathology
  • Docosahexaenoic Acids / pharmacology
  • Doxorubicin / administration & dosage*
  • Drug Synergism
  • Fatty Acids, Unsaturated / administration & dosage*
  • Female
  • Humans
  • Lipid Peroxides / metabolism*
  • Oxidants / pharmacology
  • Time Factors
  • Tumor Cells, Cultured


  • Fatty Acids, Unsaturated
  • Lipid Peroxides
  • Oxidants
  • Docosahexaenoic Acids
  • Doxorubicin