Bcl-2 and Bcl-X(L) antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents

A number of apoptosis-inducing agents used in cancer therapy (etoposide, doxorubicin, 1-β-D-arabinofuranosylcytosine), as well as the pro-apoptotic second messenger ceramide, induce a disruption of the mitochondrial transmembrane potential (ΔΨ(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 ΔΨ(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 ΔΨ(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 ΔΨ(m) disruption and apoptosis, although cytokine response modifier A dues prevent the ΔΨ(m) collapse and posterior nuclear apoptosis triggered by cross- linking of Fas/Apo-1/CD95. In conclusion, ΔΨ(m) disruption seems to be an obligatory step of early (pre-nuclear) apoptosis, and ΔΨ(m) is stabilized by two members of the bcl-2 gene family conferring resistance to chemotherapy.