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New okadaic acid analogues from the marine sponge Merriamum oxeato and their effect on mitosis

TitleNew okadaic acid analogues from the marine sponge Merriamum oxeato and their effect on mitosis
Publication TypeJournal Article
Year of Publication2003
AuthorsBritton, R, Roberge, M, Brown, C, Van Soest, R, Andersen, RJ
JournalJournal of Natural Products
Volume66
Pagination838-843
Date PublishedJun
Type of ArticleArticle
ISBN Number0163-3864
KeywordsCELL-CYCLE CHECKPOINTS, DNA-DAMAGE CHECKPOINT, ELUCIDATION, INHIBITION, ISOGRANULATIMIDE, P53, PROTEIN-KINASES, TRANSFORMATION
Abstract

Inhibitors of the G2 DNA damage checkpoint can selectively sensitize cancer cells with impaired p53 tumor suppressor activity to killing by DNA-damaging drugs or ionizing radiation and have been proposed as a promising therapeutic strategy. An extract from the Northeastern Pacific marine sponge Merriamum. oxeato showed G2 checkpoint inhibitory activity, and fractionation identified the known dinoflagellate toxin dinophysistoxin 1 (1) and the two novel analogues 27-O-acetylokadaic acid (2) and 27-O-acetyldinophysistoxin 1 (3) as the active compounds. The mixture of 1, 2, and 3 was extremely potent at inhibiting the G2 checkpoint (IC50 = 1 ng/mL) and cellular protein Ser/Thr phosphatases (IC50 = 1 ng/mL), and it radiosensitized MCF-7 breast cancer cells expressing mutated p53 at all concentrations tested. However, the mixture of 1, 2, and 3 was also very toxic to cells not exposed to DNA damage (IC50 = 1 ng/mL), making these compounds poor candidates for therapeutic agents to augment the effectiveness of DNA-damaging therapies.

URL<Go to ISI>://000183814600019