S. Nocentini et al., INDUCTION OF MITOCHONDRIAL DYSFUNCTION AND APOPTOSIS IN HELA-CELLS BYBIS-PYRIDINIUM OXIMES, A NEWLY SYNTHESIZED FAMILY OF LIPOPHILIC BISCATIONS, Biochemical pharmacology, 53(10), 1997, pp. 1543-1552
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.