Involvement of CPP32/Yama-like protease in CPT-11-induced death signal transduction pathway

Toxicology in Vitro : an International Journal Published in Association with BIBRA
A SuzukiM Kato

Abstract

CPT-11, a derivative of camptothecin (CPT) that interacts with type-I DNA topoisomerase, induced apoptosis in HL60 and Daudi cells in vitro. This cytotoxic activity was time and dose dependent, and was prevented by cycloheximide (CHX), a protein synthesis inhibitor, indicating the requirement of new protein synthesis for CPT-11-induced apoptotic cell death. Ac-Tyr-Val-Ala-Asp-aldehyde (YVAD) and Ac-Asp-Glu-Val-Asp-aldehyde (DEVD), synthesized tetrapeptide inhibitors of interleukin(1beta)-converting enzyme (ICE)- and CPP32/Yama-like proteases, were used to examine the CPT-11-induced death signal transduction. These inhibitors blocked CPT-11-induced cytotoxicity in a time- and dose-dependent manner. Cytotoxic activity of SN-38, an active metabolite of CPT-11, was about 1000-fold that of CPT-11 and was also prevented by CHX, YVAD and DEVD. The doses of YVAD, however, were a little too high; the prevention by YVAD is then thought to be non-specific. In addition, lymphocytes obtained from normal and lpr(cg) mutant mice showed similar susceptibility to CPT-11 cytotoxicity. These results indicate the direct involvement of CPP32/Yama-like protease in the CPT-11-induced death signal transduction pathway, and no involvement of Fas antige...Continue Reading

References

Aug 30, 1994·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·S Nagata
Mar 10, 1995·Science·S Nagata, P Golstein
Jan 17, 1993·Biochimica Et Biophysica Acta·Y OnishiH Kizaki

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Citations

Jul 25, 2000·Toxicology in Vitro : an International Journal Published in Association with BIBRA·A Suzuki, Y Tsutomi

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