SR-4233 (Tirapazamine) acts as an uncoupler of oxidative phosphorylation in human MCF-7 breast carcinoma cells

Gulshan Ara, C. Norman Coleman, Beverly A. Teicher

Research output: Contribution to journalArticle

Abstract

SR-4233 (Tirapazamine) is a hypoxic cell selective cytotoxic agent currently in Phase I clinical trial. Although SR-4233 is selectively cytotoxic toward hypoxic cells some cytotoxicity toward normally oxygenated cells also occurs. SR-4233 (500 μM, 1 h) killed about 70% of normally oxygenated and 99% of hypoxic human MCF-7 breast carcinoma cells. Using a polarographic chamber and a Clark O2 electrode the O2 consumption of MCF-7 cells was measured in the presence or absence of SR-4233 (500 μM) or other inhibitors or uncouplers of oxidative phosphorylation. MCF-7 cells exhibited increased O2 consumption in the presence of SR-4233 alone and after treatment with oligomycin but not after treatment with retenone. The pattern of O2 consumption observed after treatment with SR-4233 was very similar to that seen when the cells were treated with the classical uncoupler FCCP. After 1 h of exposure to SR-4233 (500 μM) the cells were not responsive to treatment with oligomycin or FCCP for at least 3 h, but by 24 h post exposure to SR-4233 the cells had regained responsiveness to both FCCP and oligomycin. These results indicate that in normally oxygenated cells SR-4233 acts as an uncoupler of oxidative phosphorylation so that the cells continue to consume O2 but no ATP is produced. This condition can lead to ATP depletion especially in respiration intensive tissues and may provide an explanation for the muscle cramping observed in some patients treated with SR-4233.

Original languageEnglish (US)
Pages (from-to)195-203
Number of pages9
JournalCancer Letters
Volume85
Issue number2
DOIs
StatePublished - Oct 14 1994

Keywords

  • Breast cancer
  • Hypoxic cell selective cytoxins
  • Mitochondrial cytotoxins
  • SR-4233
  • Tirapazamine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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