Antitumor drug fostriecin inhibits the mitotic entry checkpoint and protein phosphatases 1 and 2A.
In most eukaryotic cells, entry into mitosis is tightly controlled and requires completely replicated and undamaged DNA. We show that the antitumor drug, fostricin, interferes with this control; it induces cycling cells to enter mitosis prematurely, and it can overcome the mitotic entry checkpoint, forcing into mitosis cells that were arrested in the division cycle by treatment with the DNA replication inhibitor aphidicolin or with the DNA-damaging agents camptothecin and teniposide. This effect was observed in all rodent, simian, and human cell lines tested. Fostriecin also hampers progression through the later stages of mitosis as determined by the absence of normal half-spindles, anaphase figures, and telophase figures. The only previously known target for fostriecin is topoisomerase II, which is inhibited in vitro with a 50% inhibitory concentration of 40 microM (T. J. Boritzki, T. S. Wolfard, J. A. Besserer, R. C. Jackson, and D. W. Fry. Inhibition of type II topoisomerase by fostriecin. Biochem. Pharmacol., 37: 4063-4068, 1988). We show that fostriecin is a more potent inhibitor of protein phosphatase 1, with a 50% inhibitory concentration of 4 microM and protein phosphatase 2A, with a 50% inhibitory concentration of 40 nM. Inhibition of the mitotic entry checkpoint and inhibition of protein phosphatases are novel properties for antitumor drugs with potential or proven therapeutic value.
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada.
M
M
Roberge
C
C
Tudan
S M
SM
Hung
K W
KW
Harder
F R
FR
Jirik
H
H
Anderson
D000475:Alkenes / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002166:Camptothecin / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011090:Polyenes; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D011753:Pyrones; D013713:Teniposide / Q000494:pharmacology
D000475:Alkenes; D000903:Antibiotics, Antineoplastic; D011090:Polyenes; D011753:Pyrones; D013713:Teniposide; D016203:CDC2 Protein Kinase; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D002166:Camptothecin; C040313:fostriecin