Apoptosis induction by the photosensitizer verteporfin: identification of mitochondrial adenine nucleotide translocator as a critical target.
We report that the photosensitizer verteporfin kills lymphoma cells by an apoptotic process involving a dissipation of the mitochondrial inner transmembrane potential (deltapsim). Light-activated verteporfin-induced apoptosis was abolished by transfection with Bcl-2, a procedure reported to inhibit the mitochondrial permeability transition pore complex (PTPC). Verteporfin triggered the deltapsim loss in isolated mitochondria in vitro, and this effect was suppressed by bongrekic acid and cyclosporin A. Verteporfin plus light also permeabilized proteoliposomes containing the semipurified PTPC or the purified PTPC component adenine nucleotide translocator (ANT), yet had no effect on protein-free control liposomes. Verteporfin phototoxicity on ANT proteoliposomes was mediated by reactive oxygen species and was prevented by recombinant Bcl-2 or the adenine nucleotides ATP and ADP. In conclusion, verteporfin belongs to a class of clinically used chemotherapeutic agents acting on PTPC and ANT.
Centre National de la Recherche Scientifique, UMR 6022, Université de Technologie de Compiègne, France.
A S
AS
Belzacq
E
E
Jacotot
H L
HL
Vieira
D
D
Mistro
D J
DJ
Granville
Z
Z
Xie
J C
JC
Reed
G
G
Kroemer
C
C
Brenner
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007473:Ion Channels; D019169:Jurkat Cells / Q000166:cytology / Q000187:drug effects; D008081:Liposomes; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D000226:Mitochondrial ADP, ATP Translocases / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011166:Porphyrins / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D000077362:Verteporfin
D000970:Antineoplastic Agents; D007473:Ion Channels; D008081:Liposomes; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017319:Photosensitizing Agents; D011166:Porphyrins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077362:Verteporfin; D000226:Mitochondrial ADP, ATP Translocases