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Effect of Antitumor Diarylsulfonylureas on in Vivo and in Vitro Mitochondrial Structure and Functions¹

Laboratories for Developmental Therapeutics, Department of Biochemical and Clinical Pharmacology [J. H. T., P. J. H.], and Department of Hematology-Oncology [R. A. A.], St. Jude Children's Research Hospital, Memphis, Tennessee 38101, and Department of Biology [C. C., R. H. B.], Memphis State University, Memphis, Tennessee 38152

Diarylsulfonylureas are novel oncolytic agents shown to have therapeutic 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 diarylsulfonylureas, namely, N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea (ISCU) and the N-4-methyl analogue (MPCU), by studying their effect on mitochondrial 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 µM) doubled the mitochondrial size after 24-h exposure in culture. Also, ISCU (100 µM), like 40 µM carbonylcyanide p-trifluoromethoxyphenylhydrazone, significantly reduced the rhodamine 123 uptake by GC₃/c₁ cells studied by flow cytometry. In isolated mitochondria both ISCU and MPCU uncoupled oxidative phosphorylation at 50 µM, with pyruvate-malate as substrate, as was indicated by a significant 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 mitochondrial functions in the presence of pyruvate-malate as substrates. These data confirm, through morphometric analysis, our previous qualitative observations of abnormal mitochondrial morphology observed in GC₃/c₁ cells grown in the presence of high concentrations of ISCU and MPCU and further suggest that diarylsulfonylureas, by uncoupling mitochondrial 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 concentrations of ISCU for relatively brief periods (2 to 4 h) and possibly contributes to cytotoxicity at drug concentrations that can be achieved in rodents.

¹ Supported in part by NIH Award CA 51949, Cancer Center Support Grant CA 21765, and the American Lebanese Syrian Associated Charities.

² To whom requests for reprints should be addressed.

Received 5/23/91. Accepted 9/23/91.