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.