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Abrogation of ionizing radiation-induced G(2) checkpoint and inhibition of nuclear export by Cryptocarya pyrones

TitleAbrogation of ionizing radiation-induced G(2) checkpoint and inhibition of nuclear export by Cryptocarya pyrones
Publication TypeJournal Article
Year of Publication2008
AuthorsSturgeon, CM, Cinel, B, Diaz-Marrero, AR, McHardy, LM, Ngo, M, Andersen, RJ, Roberge, M
JournalCancer Chemotherapy and Pharmacology
Volume61
Pagination407-413
Date PublishedMar
ISBN Number0344-5704
Abstract

G(2) checkpoint inhibitors can force cells arrested in G(2) phase by DNA damage to enter mitosis. In this manner, several G(2) checkpoint inhibitors can enhance killing of cancer cells by ionizing radiation and DNA-damaging chemotherapeutic agents, particularly in cells lacking p53 function. All G(2) checkpoint inhibitors identified to date target protein phosphorylation by inhibiting checkpoint kinases or phosphatases. Using a phenotypic cell-based assay for G(2) checkpoint inhibitors, we have screened a large collection of plant extracts and identified Z-Cryptofolione and Cryptomoscatone D2 as highly efficacious inhibitors of the G(2) checkpoint. These compounds and related pyrones also inhibit nuclear export. Leptomycin B, a potent inhibitor of Crm1-mediated nuclear export, is also a very potent G(2) checkpoint inhibitor. These compounds possess a reactive Michael acceptor site and do not appear promising as a radiosensitizing agents because they are toxic to unirradiated cells at checkpoint inhibitory concentrations. Nevertheless, the results show that inhibition of nuclear export is an alternative to checkpoint kinase inhibition for abrogating the G(2) checkpoint and they should stimulate the search for less toxic nuclear export inhibitors.

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