Cellular effects of olomoucine in human lymphoma cells differing in p53 function.
Olomoucine, a purine derivative, inhibits multiple cyclin-dependent kinases that play important roles in regulating the G1/S and G2/M transitions of the cell cycle. In this study we investigated the cellular effects of olomoucine in two human Burkitt's lymphoma cell lines, WMN (containing wild-type p53) and CA46 (containing mutant p53), and found that in consistency with its ability to block the activity of cyclin E/Cdk2 and cyclin B1/Cdc2 kinases, olomoucine caused cell cycle arrest at both G1/S and G2/S boundaries. Moreover, cell cycle arrest occurred equally well in these two cell lines bearing different p53 gene status, suggesting that p53 was not responsible for the cell cycle arrest by olomoucine. A similar p53-independent fashion was also observed in the cytotoxic potency and apoptosis induction of olomoucine, in contrast to ionizing radiation which caused more cytotoxic activity and apoptosis in the WMN cell line bearing wild-type p53 compared with CA46 cells bearing mutant p53. Such p53-independent cytotoxicity of olomoucine was also confirmed in other human Burkitt's lymphoma and lymphoid cell lines containing wild-type and mutant p53. Therefore, our results give an impetus to continued research into olomoucine that might be a very useful chemotherapeutic strategy in the treatment of patients with mutant p53 tumors, at least in lymphoma patients.
Fan
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Department of Radiation Oncology, Long Island Jewish Medical Center, New Hyde Park, NY 11042, USA. fan@lij.edu
Duba
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O'Connor
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D017209:Apoptosis / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019926:Cyclin B / Q000037:antagonists & inhibitors; D019927:Cyclin E / Q000037:antagonists & inhibitors; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D007701:Kinetin; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011687:Purines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D019926:Cyclin B; D019927:Cyclin E; D011687:Purines; C090046:olomoucine; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D007701:Kinetin