SERINE-PROTEASE INHIBITION AND MITOCHONDRIAL DYSFUNCTION ASSOCIATED WITH CISPLATIN RESISTANCE IN HUMAN TUMOR-CELL LINES - TARGETS FOR THERAPY

Indicators of mitachondrial function were studied in two different cel l culture models of cis-diamminedichloroplatinum-II (CDDP) resistance: the intrinsically resistant human ovarian cancer cell line CI-80-13S, and resistant clones (HeLa-S1a and HeLa S1b) generated by stable expr ession of the serine protease inhibitor-plasminogen activator inhibito r type-2 (PAI-2), in the human cervical cancer cell line HeLa. In both models, CDDP resistance was associated with sensitivity to killing by adriamycin, etoposide, auranofin, bis[1,2-bis(diphenylphosphino)ethan e]gold(I) chloride {[Au(DPPE)(2)]Cl}, CdCl2 and the mitochondrial inhi bitors rhodamine-123 (Rh123), dequalinium chloride (DeCH), tetraphenyl phosphonium (TPP), and ethidium bromide (ErBr) and with lower constitu tive levels of ATP. Unlike the HeLa clones, CI-80-13S cells were addit ionally sensitive to chloramphenicol, 1-methyl-4-phenylpyridinium ion (MPP+), rotenone, thenoyltrifluoroacetone (TTFA), and antimycin A, and showed poor reduction of 1-[4,5-dimethylthiazol-2-yl]-2,5- diphenylte trazolium bromide (MTT), suggesting a deficiency in NADH dehydrogenase and/or succinate dehydrogenase activities. Total platinum uptake and DNA-bound platinum were slightly lower in CI-80-13S than in sensitive cells. The HeLa-S1a and HeLa-S1b clones, on the other hand, showed poo r reduction of triphenyltetrazolium chloride (TTC), indicative of low cytochrome c oxidase activity. Total platinum uptake by HeLa-S1a was s imilar to HeLa, but DNA-bound platinum was much lower than for the par ent cell line. The mitochondria of CI-80-13S and HeLa Sla showed alter ed morphology and were fewer in number than those of JAM and HeLa. Tn both models, CDDP resistance was associated with less platinum accumul ation and with mitochondrial and membrane defects, brought about one c ase with expression of a protease inhibitor which is implicated in tum or progression. Such markers may identify tumors suitable for treatmen t with gold phosphine complexes or other mitochondrial inhibitors. BIO CHEM PHARMACOL 53;11:1673-1682, 1997. (C) 1997 Elsevier Science Inc.