title: Identification of a phenanthrene derivative as a potent anticancer drug with Pim kinase inhibitory activity.
abstract: Pim-3, a proto-oncogene with serine/threonine kinase activity, is aberrantly expressed in malignant lesions, but not in normal tissues, of endoderm-derived organs, including the pancreas, liver, colon, and stomach. Furthermore, the development of hepatocellular carcinoma is accelerated in mice expressing Pim-3 transgene selectively in the liver when these mice are treated with a hepatocarcinogen. These observations suggest that a chemical targeting Pim-3 kinase may be a novel type of anticancer drug. In the present study, we screened low molecular weight chemicals and observed that the phenanthrene derivative T26 potently inhibited Pim-3 and Pim-1, but only weakly inhibited Pim-2. Moreover, T26 markedly inhibited the in vitro growth of human pancreatic cancer cell lines by inducing apoptosis and G(2) /M arrest. The growth inhibitory effects of T26 were reversed by overexpression of Pim-3 cDNA in human pancreatic cancer cells, indicating that T26 acts primarily on Pim-3. Furthermore, T26 inhibited the growth of a human pancreatic cancer cell line in nude mice without causing apparent adverse effects when it was administered after tumor formation was evident. These observations imply that the chemical and its related compounds may be effective for the treatment of cancers in which there is aberrant Pim-3 expression.
authors: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa.
authors: Ying-Ying
authors: YY
authors: Wang
authors: Tsuyoshi
authors: T
authors: Taniguchi
authors: Tomohisa
authors: T
authors: Baba
authors: Ying-Yi
authors: YY
authors: Li
authors: Hiroyuki
authors: H
authors: Ishibashi
authors: Naofumi
authors: N
authors: Mukaida
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010616:Phenanthrenes / Q000737:chemistry* / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: C000715470:MAS1 protein, human; D010616:Phenanthrenes; D000090063:Proto-Oncogene Mas; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim; D017868:Cyclic AMP-Dependent Protein Kinases