T-18, a stemonamide synthetic intermediate inhibits Pim kinase activity and induces cell apoptosis, acting as a potent anticancer drug

Abstract

Pim-3 kinase has been shown to be aberrantly expressed in premalignant and malignant lesions of endo-derm-derived organs such as the liver, pancreas, colon and stomach. Pim-3 kinase inactivates the Bad protein, a proapop-totic molecule, and improves the expression of Bcl-xL, an antiapoptotic molecule, to promote cell proliferation. Thus, blocking Pim-3 kinase activity may be a new strategy for the treatment of pancreatic cancer. In this study, we screened low molecular compounds and observed that the stemon-amide synthetic intermediate, T-18, potently inhibited Pim kinase activity. Moreover, T-18 inhibited the proliferation of human pancreatic, as well as that of hepatocellular and colon cancer cells in vitro. It also induced the apoptosis of human pancreatic carcinoma cells in vitro by decreasing the levels of phospho-Ser 112-Bad; the levels of Pim-3 kinase and total Bad protein were not altered. Furthermore, T-18 inhibited the growth of human pancreatic cancer cells in nude mice without apparent adverse effects when the tumor was palpable. These observations indicate that stemonamide synthetic intermediates may be novel drugs for the treatment of gastrointestinal cancers, particularly pancreatic cancer.