BCL-2 AND BCL-X(L) ANTAGONIZE THE MITOCHONDRIAL DYSFUNCTION PRECEDINGNUCLEAR APOPTOSIS INDUCED BY CHEMOTHERAPEUTIC-AGENTS

A number of apoptosis-inducing agents used in cancer therapy (etoposid e, doxorubicin, 1-beta-D-arabinofuranosylcytosine), as well as the pro apoptotic second messenger ceramide, induce a disruption of the mitoch ondrial transmembrane potential (Delta Psi(m)) that precedes nuclear D NA fragmentation. This effect has been observed in tumor cell lines of T-lymphoid, B-lymphoid, and myelomonocytic origin irt vitro. Circulat ing tumor cells from patients receiving chemotherapy in vivo also demo nstrate a Delta Psi(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 ap optosis, 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 o bserved in normal as well, as anucleate cells, indicating that bcl-2 a cts on an estranuclear 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 D elta Psi(m) disruption and apoptosis, although cytokine response modif ier A does prevent the Delta Psi(m) collapse and posterior nuclear apo ptosis triggered by cross-linking of Fas/Apo-1/CD95. In conclusion, De lta Psi(m) disruption seems to be an obligatory step of early (pre-nuc lear) apoptosis, and Delta Psi(m) is stabilized by two members of the bcl-2 gene family conferring resistance to chemotherapy.