The cephalostatin way of apoptosis.
The cephalostatins, bis-steroidal natural products from the marine tube worm Cephalodiscus gilchristi, were isolated by Dr. G. R. Pettit and his group. These compounds show a unique cytotoxicity profile in the in vitro screen of the National Cancer Institute, suggesting a novel mechanism of action. Indeed, cephalostatin 1 ( 1) is an extremely powerful agent that acts via an unusual apoptosis pathway. It induces selective Smac/DIABLO, but no cytochrome c release from mitochondria. Nevertheless, caspase-9 is required for apoptosis induction. Interestingly, caspase-9 is activated without the participation of the apoptosome, leading to the question of its mechanism of activation. We found that endoplasmic reticulum stress-associated caspase-4 contributes to nonclassical cephalostatin-mediated caspase-9 activation, additionally pointing out the unusual pathway used by this substance. Cephalostatin 1 ( 1), therefore, provides a very good tool to discover novel apoptotic pathways, which might be important in the understanding and treatment of chemo-resistant cancer.
Rudy
Anita
A
Department of Pharmacy, University of Munich, Munich, Germany. anita.rudy@cup.uni-muenchen.de
López-Antón
Nancy
N
Dirsch
Verena M
VM
Vollmar
Angelika M
AM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001688:Biological Products / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism*; D002816:Chordata, Nonvertebrate / Q000737:chemistry; D006801:Humans; D008954:Models, Biological; D010619:Phenazines / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D013256:Steroids / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001688:Biological Products; D010619:Phenazines; D013141:Spiro Compounds; D013256:Steroids; C454806:cephalostatin I; D020169:Caspases