Staurosporine and conventional anticancer drugs induce overlapping, yet distinct pathways of apoptosis and caspase activation.
Apoptosis can be induced by various stimuli including DNA-damaging anticancer drugs and the protein kinase inhibitor staurosporine. It is generally believed that the molecular events during execution of apoptosis are shared, as both anticancer drugs and staurosporine derivatives induce mitochondrial damage, cytochrome c release and the activation of the caspase-9 proteolytic cascade. In the present study we show that overexpression of a dominant-negative caspase-9 mutant abolished the activation of endogenous caspase-9, caspase-3 and the cleavage of the caspase substrate Bid in response to anticancer drug treatment. Surprisingly, however, only marginal effects were observed during staurosporine-induced apoptosis. Furthermore, we describe a Jurkat T-cell clone that is completely resistant towards different anticancer drugs, but remains sensitive towards staurosporine-induced apoptosis. In these cells only staurosporine, but neither anti-CD95 nor anticancer drugs were able to trigger caspase activity and the cleavage of caspase substrates. Our results therefore suggest that the mechanism of staurosporine-induced apoptosis is more complex and at least partially differs from anticancer drug-induced caspase activation. These distinct features of staurosporine may allow to bypass chemoresistance of tumor cells and may encourage further clinical trials for the use of staurosporine derivatives in antitumor therapy.
Stepczynska
A
A
Department of Immunology and Cell Biology, University of Münster, Germany.
Lauber
K
K
Engels
I H
IH
Janssen
O
O
Kabelitz
D
D
Wesselborg
S
S
Schulze-Osthoff
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D006367:HeLa Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D015151:Immunoblotting; D019169:Jurkat Cells / Q000187:drug effects / Q000201:enzymology; D008928:Mitochondria / Q000502:physiology; D016685:Mitomycin / Q000494:pharmacology; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology; D019014:fas Receptor / Q000502:physiology
D000970:Antineoplastic Agents; D019014:fas Receptor; D016685:Mitomycin; D005047:Etoposide; D020169:Caspases; D019311:Staurosporine