Cisplatin combined with zidovudine enhances cytotoxicity and oxidative stress in human head and neck cancer cells via a thiol-dependent mechanism

David M. Mattson, Iman M. Ahmad, Disha Dayal, Arlene D. Parsons, Nukhet Aykin-Burns, Ling Li, Kevin P. Orcutt, Douglas R. Spitz, Kenneth J. Dornfeld, Andrean L. Simons

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Oxidative stress and mitochondrial dysfunction in cancer cells represent features that may be exploited therapeutically. We determined whether agents that induce mitochondrial dysfunction, such as zidovudine (AZT) and cisplatin (CIS), could enhance killing of human head and neck cancer cells via oxidative stress. AZT- and/or CIS-induced cytotoxicity was determined using clonogenic survival, mitochondrial membrane potential was analyzed to investigate mitochondrial function, and glutathione was measured to determine thiol metabolism perturbations. AZT + CIS significantly increased toxicity and reduced mitochondrial membrane potential in FaDu, Cal-27, and SQ20B head and neck cancer cells while increasing the percentage of glutathione disulfide (%GSSG). Treatment with the thiol antioxidant N-acetylcysteine (NAC) reversed the loss of mitochondrial membrane potential and the increase in %GSSG and partially protected FaDu and Cal-27 cells from AZT + CIS. Finally, an inhibitor of glutathione synthesis, l-buthionine-[S,R]-sulfoximine, sensitized the cells to AZT + CIS-induced cytotoxicity, which was partially reversed by NAC. These results suggest that exposure of cancer cells to agents that induce mitochondrial dysfunction, such as AZT, causes significant sensitization to CIS-induced toxicity via disruptions in thiol metabolism and oxidative stress. These findings provide a biochemical rationale for evaluating agents that induce mitochondrial dysfunction in combination with chemotherapy and inhibitors of glutathione metabolism in head and neck cancer.

Original languageEnglish (US)
Pages (from-to)232-237
Number of pages6
JournalFree Radical Biology and Medicine
Volume46
Issue number2
DOIs
StatePublished - Jan 15 2009

Keywords

  • Azidothymidine
  • BSO
  • Cancer
  • Cisplatin
  • Free radicals
  • Mitochondrial membrane potential
  • NAC
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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