Abrogation of ionizing radiation-induced G2 checkpoint and inhibition of nuclear export by Cryptocarya pyrones

Christopher M. Sturgeon, Bruno Cinel, Ana R. Díaz-Marrero, Lianne M. McHardy, Michelle Ngo, Raymond J. Andersen, Michel Roberge

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

G2 checkpoint inhibitors can force cells arrested in G 2 phase by DNA damage to enter mitosis. In this manner, several G2 checkpoint inhibitors can enhance killing of cancer cells by ionizing radiation and DNA-damaging chemotherapeutic agents, particularly in cells lacking p53 function. All G2 checkpoint inhibitors identified to date target protein phosphorylation by inhibiting checkpoint kinases or phosphatases. Using a phenotypic cell-based assay for G2 checkpoint inhibitors, we have screened a large collection of plant extracts and identified Z-Cryptofolione and Cryptomoscatone D2 as highly efficacious inhibitors of the G2 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 G2 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 G2 checkpoint and they should stimulate the search for less toxic nuclear export inhibitors.

Original languageEnglish
Pages (from-to)407-413
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume61
Issue number3
DOIs
StatePublished - Mar 2008

Keywords

  • Checkpoint inhibitor
  • DNA damage
  • Leptomycin B
  • Nuclear export
  • Z-Cryptofolione

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