The role of p66shc in taxol- and dichloroacetic acid-dependent renal toxicity

István Arany, Jeb S. Clark, Dustin Reed, Istvan Szabo, Istvan Ember, Luis A. Juncos

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6 Citations (Scopus)

Abstract

Background/Aim: Taxol and dichloroacetic acid (DCA) are anticancer agents with potential renal toxicity. Previously, we have shown that the Ser36-phosphorylated p66shc adaptor protein mediates renal toxicity of selected anticancer modalities through increasing production of intracellular reactive oxygen species and consequent mitochondrial depolarization. Here, we analyzed whether p66shc plays a role in potential renal toxicity of Taxol and DCA. Materials and Methods: Cultured renal proximal tubule cells (TKPTS) were used. ROS production, mitochondrial depolarization (JC-1), cell injury [lactate dehydrogenase (LDH) release] and Ser36 phosphorylation of p66shc were determined after treatment with Taxol and DCA. Involvement of p66shc in adverse effects of these drugs was determined in p66shc knockdown, Ser36 phosphorylation (S36A) and cytochrome c-binding (W134F)- deficient cells. Results: Both Taxol and DCA increased ROS production, mitochondrial depolarization, injury and Ser36 phosphorylation of p66shc in TKPTS cells. We showed that ROS production is responsible for mitochondrial depolarization and consequent injury. Knockdown of p66shc, mutation of its Ser36 (S36A) or cytochrome c binding site (W134F) attenuated adverse effects of the two drugs. Conclusion: Taxol and DCA are potentially nephrotoxic owing their adverse effects on activation of p66shc. Manipulation of expression or activity of p66shc may provide a means of ameliorating nephrotoxicity of these agents.

Original languageEnglish
Pages (from-to)3119-3122
Number of pages4
JournalAnticancer research
Volume33
Issue number8
Publication statusPublished - Aug 1 2013

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Keywords

  • Dichloroacetic acid
  • Renal
  • Taxol
  • Toxicity
  • p66shc

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Arany, I., Clark, J. S., Reed, D., Szabo, I., Ember, I., & Juncos, L. A. (2013). The role of p66shc in taxol- and dichloroacetic acid-dependent renal toxicity. Anticancer research, 33(8), 3119-3122.