INDUCTION OF MITOCHONDRIAL DYSFUNCTION AND APOPTOSIS IN HELA-CELLS BYBIS-PYRIDINIUM OXIMES, A NEWLY SYNTHESIZED FAMILY OF LIPOPHILIC BISCATIONS

When tested on HeLa cells, bis-pyridinium oximes (BPO), a family of ne wly synthesized molecules whose charged pyridinium moieties are linked by a linear polymethylene chain of variable length (N = 3 to 12) have been shown to possess an inhibitory effect on cell growth and finally to provoke cell death. BPO-affected cells displayed reduced mitochond rial oxygen consumption and ATP stores and were blocked in the G1 phas e of the cell cycle. Mitochondrial membrane potential, as assayed with the dye 3,3'-diexyloxacarbocyanine iodide [DiOC(6)(3)], increased in BPO-treated cells with time of exposure. Cell growth inhibition as wel l mitochondrial dysfunction were observed only with derivatives having a long polymethylene linking chain (N greater than or equal to 6). Fu rthermore, the concentration of the compound eliciting such effects wa s inversely related to the number of methylene groups in the linking c hain. None of the BPO with N = 6 to 12 modified the mitochondrial DNA content, relative to the nuclear DNA content. In BPO (N = 8 and N = 12 )-treated cells, chromatin fragmentation and internucleosomal DNA clea vage occurred massively, indicating that the death mode induced by the se compounds is apoptosis. The possible pathway of action and the pote ntial pharmacological interest of these compounds are discussed. (C) 1 997 Elsevier Science Inc.