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Dolastatin 15 from a Marine Cyanobacterium Suppresses HIF‐1α Mediated Cancer Cell Viability and Vascularization
Author(s) -
Ratnayake Ranjala,
Gunasekera Sarath P.,
Ma Jia Jia,
Dang Long H.,
Carney Thomas J.,
Paul Valerie J.,
Luesch Hendrik
Publication year - 2020
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202000180
Subject(s) - biology , transcriptome , zebrafish , kras , cytotoxicity , angiogenesis , cancer cell , gene , microbiology and biotechnology , biochemistry , cancer research , cancer , in vitro , genetics , gene expression , mutation
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 an antivascularization effect in human endothelial cells and in zebrafish vhl mutants with activated Hif, thus signifying its clinical potential as a treatment for solid tumors with an angiogenic component. Global transcriptome analysis with RNA sequencing suggested that dolastatin 15 could affect other major cancer pathways that might not directly involve tubulin or HIF. The identification of the true producer of a clinically relevant agent is important for sustainable supply, as is understanding the biosynthesis, and future genetic manipulation of the biosynthetic gene cluster for analogue production.