Ratnayake, Ranjala, Gunasekera, Sarath P., Ma, Jia Jia, Dang, Long H., Carney, Thomas, Paul, Valerie J., and Luesch, Hendrik. 2020. "Dolastatin 15 from a Marine Cyanobacterium Suppresses HIF-1α Mediated Cancer Cell Viability and Vascularization." Chembiochem: A European Journal of Chemical Biology 21 (16):2356-2366. https://doi.org/10.1002/cbic.202000180
Chemical investigation of a benthic marine cyanobacterium yielded the anticancer agent dolastatin 15, originally isolated from a mollusk. Dolastatin 15 is a microtubule destabilizing agent with analogues undergoing clinical evaluation. Profiling against a panel of isogenic HCT116 colorectal cancer cells showed remarkable differential cytotoxicity against the parental cells over isogenic cells lacking HIF or other key players in the pathway, including oncogenic KRAS and VEGF. Dolastatin 15 displayed anti-vascularization effect in human endothelial cells and in zebrafish vhl mutants with activated Hif, signifying its clinical potential as a treatment for solid tumors with an angiogenic component. Global transcriptome analysis using RNA-sequencing suggested that dolastatin 15 could affect other major cancer pathways that may not directly involve tubulin or HIF. The identification of the true producer of a clinically relevant agent is important for sustainable supply, understanding the biosynthesis and future genetic manipulation of the biosynthetic gene cluster for analogue production.