Inhibition of p53 protein phosphorylation by 9-hydroxyellipticine: a possible anticancer mechanism.
Abnormality of p53, a tumor suppressor gene, is considered to be a potential cause of malignancy. We found that ellipticine and 9-hydroxyellipticine (9HE), antitumor alkaloids, caused selective inhibition of p53 protein phosphorylation in Lewis lung carcinoma and SW480 (human colon cancer cell line) in a concentration-dependent manner from 0.1 to 100 microM. 9HE suppressed cdk2 kinase activity concentration-dependently from 1 to 100 microM. By contrast, the inhibition of p53 protein phosphorylation by elliptinium and elliprabin (N2 substituted derivatives of 9HE) was very weak. A good correlation was observed between p53 phosphorylation inhibition and cytotoxic activity of these agents in terms of concentration-response relationships, suggesting that inhibition of p53 protein phosphorylation via kinase inhibition may be involved in the anticancer mechanism of these agents. In addition, this study demonstrated that brief exposure to 9HE caused apoptosis of cancer cells. It is suggested that accumulation of dephosphorylated mutant p53 may induce apoptosis.
Ohashi
M
M
Lead Optimization Laboratory, Tanabe Seiyaku Co., Ltd., Saitama.
Sugikawa
E
E
Nakanishi
N
N
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D042846:CDC2-CDC28 Kinases; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004611:Ellipticines / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D004611:Ellipticines; D004791:Enzyme Inhibitors; D006657:Histones; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; C034192:ellipticine; C008009:9-hydroxyellipticine; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases