Doxorubicin and etoposide sensitize small cell lung carcinoma cells expressing caspase-8 to TRAIL

Background: TRAIL is considered as a promising anti-cancer agent, because of its ability to induce apoptosis in cancer but not in most normal cells. However, growing evidence exist that many cancer cells are resistant to its apoptotic effects. SCLC is a typical example of tumor entity where TRAIL monotherapy is not efficient. Results: We demonstrated that doxorubicin and etoposide markedly sensitized SCLC cells expressing caspase-8 to apoptotic effects of TRAIL. The drug-mediated sensitization of these cells was associated with increase of surface and total DR5 protein level, specific cleavage of cFLIP(L), decrease of cFLIP(S) level, and a strong activation of caspase-8. The involvement of mitochondria-mediated pathway was demonstrated by enhanced Bid cleavage, Bax activation, and cytochrome c release. Activation of caspase-8 induced by combined treatment was shown to occur upstream of mitochondria and effector caspases. Conclusions: Our results highlight significant applicability of doxorubicin and etoposide in sensitization of SCLC cells expressing caspase-8 to treatment with TRAIL.