A chemical inhibitor of Apaf-1 exerts mitochondrioprotective functions and interferes with the intra-S-phase DNA damage checkpoint.
QM31 represents a new class of cytoprotective agents that inhibit the formation of the apoptosome, the caspase activation complex composed by Apaf-1, cytochrome c, dATP and caspase-9. Here, we analyzed the cellular effects of QM31, as compared to the prototypic caspase inhibitor Z-VAD-fmk. QM31 was as efficient as Z-VAD-fmk in suppressing caspase-3 activation, and conferred a similar cytoprotective effect. In contrast to Z-VAD-fmk, QM31 inhibited the release of cytochrome c from mitochondria, an unforeseen property that may contribute to its pronounced cytoprotective activity. Moreover, QM31 suppressed the Apaf-1-dependent intra-S-phase DNA damage checkpoint. These results suggest that QM31 can interfere with the two known functions of Apaf-1, namely apoptosome assembly/activation and intra-S-phase cell cycle arrest. Moreover, QM31 can inhibit mitochondrial outer membrane permeabilization, an effect that is independent from its action on Apaf-1.
Mondragón
Laura
L
U848, INSERM, 94805 Villejuif, France.
Galluzzi
Lorenzo
L
Mouhamad
Shahul
S
Orzáez
Mar
M
Vicencio
José-Miguel
JM
Vitale
Ilio
I
Moure
Alejandra
A
Messeguer
Angel
A
Perez-Paya
Enrique
E
Kroemer
Guido
G
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D053477:Apoptotic Protease-Activating Factor 1 / Q000037:antagonists & inhibitors* / Q000172:deficiency; D001381:Azepines / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D004249:DNA Damage; D005455:Fluorescent Antibody Technique; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects*; D034444:Peptoids / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D016196:S Phase / Q000187:drug effects*; D014162:Transfection
C539692:1-(3',3'-diphenylpropyl)-4-(2'-(2'',4''-dichlorophenyl)ethyl)-7-(N-aminocarbonylmethyl-N-(2-(2'',4''-dichlorophenyl)ethyl)aminocarbonyl)perhydro-1,4-diazepine-2,5-dione; C506592:APAF1 protein, human; D000590:Amino Acid Chloromethyl Ketones; D053477:Apoptotic Protease-Activating Factor 1; D001381:Azepines; D034444:Peptoids; D034741:RNA, Small Interfering; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone