Bcl-2 and Bcl-XL antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents.
A number of apoptosis-inducing agents used in cancer therapy (etoposide, doxorubicin, 1-beta-D-arabinofuranosylcytosine), as well as the proapoptotic second messenger ceramide, induce a disruption of the mitochondrial transmembrane potential (delta psi m) that precedes nuclear DNA fragmentation. This effect has been observed in tumor cell lines of T-lymphoid, B-lymphoid, and myelomonocytic origin in vitro. Circulating tumor cells from patients receiving chemotherapy in vivo also demonstrate a delta psi m disruption after in vitro culture that precedes nuclear apoptosis. Transfection-enforced hyperexpression of the proto-oncogenes bcl-2 and bcl-XL protects against chemotherapy-induced apoptosis, at both the level of the mitochondrial dysfunction preceding nuclear apoptosis and the level of late nuclear apoptotic events. Bcl-2-mediated inhibition of ceramide-induced delta psi m disruption is observed in normal as well as anucleate cells, indicating that bcl-2 acts on an extranuclear pathway of apoptosis. In contrast to Bcl-2 and Bcl-XL, hyperexpression of the protease inhibitor cytokine response modifier A fails to protect tumor cells against chemotherapy-induced delta psi m disruption and apoptosis, although cytokine response modifier A does prevent the delta psi m collapse and posterior nuclear apoptosis triggered by cross-linking of Fas/Apo-1/CD95. In conclusion, delta psi m disruption seems to be an obligatory step of early (pre-nuclear) apoptosis, and delta psi m is stabilized by two members of the bcl-2 gene family conferring resistance to chemotherapy.
Decaudin
D
D
Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, Villejuif, France.
Geley
S
S
Hirsch
T
T
Castedo
M
M
Marchetti
P
P
Macho
A
A
Kofler
R
R
Kroemer
G
G
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015605:Cowpox; D003561:Cytarabine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014764:Viral Proteins / Q000378:metabolism / Q000502:physiology*; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D051020:bcl-X Protein; D003561:Cytarabine; D005047:Etoposide; D004317:Doxorubicin