Abrogation of ionizing radiation-induced G2 checkpoint and inhibition of nuclear export by Cryptocarya pyrones.
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.
Sturgeon
Christopher M
CM
Department of Biochemistry and Molecular Biology, Life Sciences Centre, University of British Columbia, Vancouver, BC, Canada.
Cinel
Bruno
B
Díaz-Marrero
Ana R
AR
McHardy
Lianne M
LM
Ngo
Michelle
M
Andersen
Raymond J
RJ
Roberge
Michel
M
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism* / Q000528:radiation effects*; D031369:Cryptocarya / Q000378:metabolism* / Q000528:radiation effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D016195:G2 Phase / Q000528:radiation effects*; D005720:Gamma Rays; D017930:Genes, Reporter / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D028884:Karyopherins / Q000502:physiology; D010936:Plant Extracts / Q000494:pharmacology; D011753:Pyrones / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D000097606:Exportin 1 Protein
D005231:Fatty Acids, Unsaturated; D049452:Green Fluorescent Proteins; D054303:HIV Reverse Transcriptase; D028884:Karyopherins; D010936:Plant Extracts; D011753:Pyrones; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C038753:leptomycin B