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 cFLIPL, decrease of cFLIPS 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.
Vaculova
Alena
A
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden.
Kaminskyy
Vitaliy
V
Jalalvand
Elham
E
Surova
Olga
O
Zhivotovsky
Boris
B
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; D053221:TNF-Related Apoptosis-Inducing Ligand; D051028:bcl-2-Associated X Protein; D005047:Etoposide; D004317:Doxorubicin; D053181:Caspase 8