The 2,6-disubstituted purine reversine induces growth arrest and polyploidy in human cancer cells.
Reversine (RV) is the synthetic purine identified from a protein kinase-based screen of purine mimetics and it has been shown to induce muscle myoblast differentiation into progenitor cells that can be further converted into other cell lineages. Since protein kinases play a pivotal role in cell cycle control, we hypothesize that RV might affect the proliferation of cancer cells. Herein we report that RV inhibited growth of cultured human tumor cells, respectively, PC-3, HeLa, CWR22Rv1, and DU-145 cells, and induced accumulation of polyploidal cells with > or =4N DNA content. However, RV was without effect on growth of normal prostate epithelial cells. RV-treated PC-3 cells showed enlarged nuclei and an estimated 100-fold increase in cell size. Moreover, PC-3 cells treated with RV for 2-4 days were accompanied by a marked increase in the expression of p21(WAF1), a modest elevation in the levels of cyclin D3 and CDK6 and concomitantly, also a substantial reduction in cyclin B and CDK1. These results suggest that RV may induce polyploidy and increase in cell size by up-regulating p21(WAF1) and cyclin D3/CDK6, while simultaneously suppressing the expression of cyclin B and CDK1.
Hsieh
Tze-Chen
TC
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Traganos
Frank
F
Darzynkiewicz
Zbigniew
Z
Wu
Joseph M
JM
D016203:CDC2 Protein Kinase / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000032:analysis; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis; D006801:Humans; D009025:Morpholines / Q000494:pharmacology*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D011123:Polyploidy; D011687:Purines / Q000494:pharmacology*
C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004273:DNA, Neoplasm; D009025:Morpholines; D011687:Purines; D016203:CDC2 Protein Kinase; C484369:2-(4-morpholinoanilino)-6-cyclohexylaminopurine