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Induction of apoptosis by enediyne antibiotic calicheamicin gammaII proceeds through a caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner

Item Type:Article
Title:Induction of apoptosis by enediyne antibiotic calicheamicin gammaII proceeds through a caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner
Creators Name:Prokop, A. and Wrasidlo, W. and Lode, H. and Herold, R. and Lang, F. and Henze, G. and Doerken, B. and Wieder, T. and Daniel, P.T.
Abstract:Calicheamicin {theta} variantII is a member of the enediyne class of antitumor antibiotics that bind to DNA and induce apoptosis. These compounds differ, however, from conventional anticancer drugs as they bind in a sequence-specific manner noncovalently to DNA and cause sequence-selective oxidation of deoxyriboses and bending of the DNA helix. Calicheamicin is clinically employed as immunoconjugate to antibodies directed against, for example, CD33 in the case of gemtuzumab ozogamicin. Here, we show by the use of the unconjugated drug that calicheamicin-induced apoptosis is independent from death-receptor/FADD-mediated signals. Moreover, calicheamicin triggers apoptosis in a p53-independent manner as shown by the use of p53 knockout cells. Cell death proceeds via activation of mitochondrial permeability transition, cytochrome c release and activation of caspase-9 and -3. The overexpression of Bcl-xL or Bcl-2 strongly inhibited calicheamicin-induced apoptosis. Knockout of Bax abrogated cell death after calicheamicin treatment. Thus, the activation of mitochondria and execution of cell death occur through a fully Bax-dependent mechanism. Interestingly, caspase inhibition by the pancaspase-inhibitor zVAD-fmk interfered with mitochondrial activation by calicheamicin. This places caspase activation upstream of the mitochondria and indicates that calicheamicin-triggered apoptosis is enhanced through death receptor-independent activation of the caspase cascade, that is, an amplification loop that is required for full activation of the mitochondrial pathway.
Keywords:Calicheamicin, Apoptosis, Caspase-3, Bax, Bcl-2, Cytochrome c, Mitochondria, BJAB, Jurkat, HCT116
Source:Oncogene
ISSN:0950-9232
Publisher:Nature Publishing Group (U.K.)
Volume:22
Number:57
Page Range:9107-9120
Date:11 December 2003
Official Publication:https://doi.org/10.1038/sj.onc.1207196
PubMed:View item in PubMed

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