Identification of stemonamide synthetic intermediates as a novel potent anticancer drug with an apoptosis-inducing...

We previously demonstrated that Pim-3, a protooncogene with serine/threonine kinase activity, was aberrantly expressed in malignant lesions but not in normal tissues of endoderm-derived organs, including pancreas, liver, colon and stomach. Moreover, aberrantly expressed Pim-3 can prevent tumor cell apoptosis by inactivating a proapoptotic molecule, Bad, and enhancing the expression of an antiapoptotic molecule, Bcl-X(L). These observations prompted us to speculate that a chemical targeting Pim-3 kinase may be a good candidate for a novel type of anticancer drug. Hence, we screened various low-molecule compounds by examining their capacity to inhibit Pim-3 kinase activity in vitro. We observed that some synthetic intermediates of stemonamide can inhibit in vitro activities of Pim-3 kinase and its related kinases, such as Pim-1 and Pim-2. Moreover, these compounds inhibit in vitro cell proliferation of various human pancreatic, hepatocellular and colon cancer cell lines. Furthermore, the compounds can induce apoptosis of human pancreatic cancer cell lines in vitro by reducing the amount of phospho-Ser(112)-Bad, but not total amounts of Bad and Pim-3. Finally, when the compound was administered to nude mice injected with a human pancreatic cancer cell line, it retarded tumor growth by increasing apoptotic cell numbers and decreasing proliferating cell numbers without causing serious adverse effects on blood counts. These observations indicate that the chemicals and its related compounds may be effective for the treatment of tumors of endoderm-derived organs, particularly the pancreas.