title: 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 endoderm-derived organs such as the liver, pancreas, colon             and stomach. Pim-3 kinase inactivates the Bad protein, a proapoptotic 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 stemonamide 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-Ser112-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.
authors: Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, PR China.
authors: Zhen
authors: Z
authors: Wang
authors: Xing-Min
authors: XM
authors: Li
authors: Kun
authors: K
authors: Shang
authors: Peng
authors: P
authors: Zhang
authors: Chao-Fu
authors: CF
authors: Wang
authors: Yu-Hu
authors: YH
authors: Xin
authors: Lu
authors: L
authors: Zhou
authors: Ying-Yi
authors: YY
authors: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000737:chemistry; D013141:Spiro Compounds / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D013141:Spiro Compounds; C587683:T-10 stemonamide; C587682:T-18 stemonamide; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt