Upregulation of bcl‐2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines

Chemotherapeutic drugs eliminate cancer cells by induction of apoptosis. Resistance to chemotherapy is partly due to a decreased apoptosis rate. Here we investigated resistance to anticancer drugs in 9 small cell lung cancer (SCLC) cell lines. Apoptosis was induced by cisplatin, doxorubicin and etoposide and was found to be independent of caspase‐8 expression. Since caspase‐8 is essential for signal transduction of death receptor‐mediated apoptosis, all known death receptor systems are thus not required for drug‐induced apoptosis in SCLC. Furthermore, we found that anticancer drugs could activate the mitochondrial pathway of apoptosis without involvement of upstream caspases. Finally, by culturing 3 sensitive cell lines in subtherapeutic concentrations of etoposide, resistant cells were generated that exhibit cross‐resistance to cisplatin and doxorubicin. Drug resistance was paralleled by strong upregulation of Bcl‐2, which diminished apoptosis by inhibiting the loss of the mitochondrial transmembrane potential and the release of cytochrome c. The role of bcl‐2 in these processes was supported by bcl‐2 transfection and antisense inhibition. These results indicate that Bcl‐2 contributes to drug resistance in SCLC, a finding that has profound therapeutic implications. © 2001 Wiley‐Liss, Inc.