Induction of mitochondrial dysfunction and apoptosis in HeLa cells by bis-pyridinium oximes, a newly synthesized family of lipophilic biscations.
When tested on HeLa cells, bis-pyridinium oximes (BPO), a family of newly 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 mitochondrial oxygen consumption and ATP stores and were blocked in the G1 phase of the cell cycle. Mitochondrial membrane potential, as assayed with the dye 3,3'-diexyloxacarbocyanine iodide [DiOC6(3)], increased in BPO-treated cells with time of exposure. Cell growth inhibition as well mitochondrial dysfunction were observed only with derivatives having a long polymethylene linking chain (N > or = 6). Furthermore, the concentration of the compound eliciting such effects was inversely related to the number of methylene groups in the linking chain. 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 cleavage occurred massively, indicating that the death mode induced by these compounds is apoptosis. The possible pathway of action and the potential pharmacological interest of these compounds are discussed.
Nocentini
S
S
CNRS UMR 218 et LRC n 1 du CEA, Institut Curie, Section de Recherche, Paris, France.
Moreno
G
G
Petit
P X
PX
Guggiari
M
M
Salet
C
C
Demerseman
P
P
Dodin
G
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D001562:Benzimidazoles / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008564:Membrane Potentials; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D010101:Oxygen Consumption; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000378:metabolism
D001562:Benzimidazoles; D002232:Carbocyanines; D004272:DNA, Mitochondrial; D005456:Fluorescent Dyes; D010091:Oximes; D011726:Pyridinium Compounds; D011838:Radiation-Sensitizing Agents; C007392:3,3'-dihexyl-2,2'-oxacarbocyanine; D000255:Adenosine Triphosphate; C017807:bisbenzimide ethoxide trihydrochloride