Rapid Identification of a Protein Binding Partner for the Marine Natural Product Kahalalide F by Using Reverse Chemical Proteomics

✍ Scribed by Andrew M. Piggott; Peter Karuso

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 561 KB
• Volume: 9
• Category: Article
• ISSN: 1439-4227
• DOI: 10.1002/cbic.200700608

✦ Synopsis

Dedicated to the memory of Professor Paul J. Scheuer Kahalalide F (KF) is in phase II clinical trials as an anticancer drug against a range of difficult to treat solid tumors including prostate, breast and colon carcinomas, neuroblastomas, chondrosarcomas, and osteosarcomas and has relatively low toxicity to nontumor cells. KF was originally isolated by Hamann and Scheuer from the sacoglossan marine mollusk, Elysia rufescens, and subsequently from the sacoglossan's food source, the green alga Bryopsis sp. In phase I clinical trials, KF had a clinical benefit for patients with advanced androgen refractory prostate cancer and other advanced tumors. KF appears to act on cell lysosomes, with treated cells swelling dramatically and forming large vacuoles. Cell death is thought to occur via oncosis, with KF inducing sub G1 cell-cycle arrest and cytotoxicity independently of MDR, HER2, p53, and blc-2. A recent study by Janmaat et al. showed that sensitivity to KF in a variety of cell lines was positively correlated to receptor protein tyrosine kinase ErbB3 (HER3) levels and that KF efficiently inhibited the phosphatidylinositol 3-kinase-Akt signaling pathway in sensitive cell lines. These findings suggest that KF is involved in a hitherto unknown oncosis signaling pathway and that disruption of lysosomes is simply the final step in a series of cascading events. Despite numerous studies into the mode of action of KF, the actual cellular receptor for the molecule remains a mystery.

Chemical proteomics is a powerful tool for isolating and identifying cellular receptors for biologically active natural products, thereby facilitating subsequent rational drug design,