Effect of Antitumor Diarylsulfonylureas on in Vivo and in Vitro Mitochondrial Structure and Functions

Jay H. Thakar, Christian Chapin, R. Howard Berg, Richard A. Ashmun, Peter J. Houghton

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Abstract

Diarylsulfonylureas are novel oncolytic agents shown to have thera peutic activity against both rodent solid tumors and xenografts of human tumors in mice. Previous studies have shown that diarylsulfonylureas localize in mitochondria and cause morphological changes in these organelles. We have investigated the mechanism of action of diarylsulfonylu reas, namely,/V-(5-indanylsulfonyl)-/V'-(4-chlorophenyl)urea (ISCU) and the/V-4-methyl analogue (MPCU), by studying their effect on mitochondria! morphology and uptake of rhodamine 123 in GC3/C1 cells in culture and the oxidative phosphorylation in isolated mitochondria from mouse liver, using pyruvate-malate and succinate as substrates. Morphometric analysis of mitochondria in GC3/C1 cells exposed to ISCU showed that ISCU (165 MM)doubled the mitochondria! size after 24-h exposure in culture. Also, ISCU (100 JIM), like 40 MMcArbonylcyanide.p-Mrifluoromethoxyphenylhydrazone, significantly reduced the rhodamine 123 uptake by GC3/C| cells studied by flow cytometry. In isolated mito chondria both ISCU and MPCU uncoupled oxidative phosphorylation 50 µM,with pyruvate-malate as substrate, as was indicated by a signifi cant increase in the State 4 oxygen consumption. This resulted in the loss of ADP phosphorylation and, therefore, the ADP/oxygen ratio was reduced to zero and the respiratory control ratio to one. The succinate oxidation was also significantly impaired by ISCU, causing some decrease in ADP phosphorylation. On the other hand, MPCU did not exhibit any significant effect on the oxidation of succinate. At concentrations of lower than 50 µM, both of these compounds exhibited a deleterious effect, causing damage to mitochondria! functions in the presence of pyruvatemalate as substrates. These data confirm, through morphometric analy sis, our previous qualitative observations of abnormal mitochondria! morphology observed in GC3/Ci cells grown in the presence of high concentrations of ISCU and MPCU and further suggest that diarylsul fonylureas, by uncoupling mitochondria! oxidative phosphorylation, may lower cellular ATP. It is probable that this mechanism contributes, at least partially, to cytotoxicity in GC3/C1 cells exposed to high concentra tions of ISCU for relatively brief periods (2 to 4 h) and possibly contributes to cytotoxicity at drug concentrations that can be achieved in rodents.

Original languageEnglish (US)
Pages (from-to)6286-6291
Number of pages6
JournalCancer Research
Volume51
StatePublished - Dec 1991
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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