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Bcl-2 and Bcl-X_L Antagonize the Mitochondrial Dysfunction Preceding Nuclear Apoptosis Induced by Chemotherapeutic Agents¹

Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, 19 rue Guy Môquet, B.P. 8, F-94801 Villejuif, France [D. D., T. H., M. C., P. M., A. M., G. K.], and Institute for General and Experimental Pathology of the University of Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria [S. G., R. K.]

A number of apoptosis-inducing agents used in cancer therapy (etoposide, doxorubicin, 1-ß-D-arabinofuranosylcytosine), as well as the proapoptotic second messenger ceramide, induce a disruption of the mitochondrial transmembrane potential (_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 _m disruption after in vitro culture that precedes nuclear apoptosis. Transfection-enforced hyperexpression of the proto-oncogenes bcl-2 and bcl-X_L 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 _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-X_L, hyperexpression of the protease inhibitor cytokine response modifier A fails to protect tumor cells against chemotherapy-induced _m disruption and apoptosis, although cytokine response modifier A does prevent the _m collapse and posterior nuclear apoptosis triggered by cross-linking of Fas/Apo-1/CD95. In conclusion, _m disruption seems to be an obligatory step of early (pre-nuclear) apoptosis, and _m is stabilized by two members of the bcl-2 gene family conferring resistance to chemotherapy.

¹ This work has been partially supported by the Agence Nationale pour la Recherche sur le Sida, Association pour la Recherche sur le Cancer, Centre National de La Recherche Scientifique, Fondation de France, Fondation pour la Recherche Médicale, Institut National pour la Santé et la Recherche Médicale, Leo Foundation, NATO, Picasso Program. Sidaction (to G. K.), and the Austrian Science Fund (F204 to R. K.). D. D. and S. G. contributed equally to this paper.

² To whom requests for reprints should be addressed. Phone: 33-1-49-58-35-13; Fax: 33-1-49-58-35-09.

Received 6/10/96. Accepted 11/ 1/96.

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