The cephalostatin way of apoptosis.

Abstract

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.

• Authors: Anita Rudy, Nancy López-Antón, Verena M Dirsch, Angelika M Vollmar
• Journal: Journal of natural products (J Nat Prod) Vol. 71 Issue 3 Pg. 482-6 (Mar 2008) ISSN: 0163-3864 [Print] United States
• PMID: 18257532 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antineoplastic Agents
• Biological Products
• Phenazines
• Spiro Compounds
• Steroids
• cephalostatin I
• Caspases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Biological Products (pharmacology)
• Caspases (metabolism)
• Chordata, Nonvertebrate (chemistry)
• Humans
• Models, Biological
• Phenazines (pharmacology)
• Spiro Compounds (pharmacology)
• Steroids (pharmacology)