title: ZSTK474, a PI3K inhibitor, suppresses proliferation and sensitizes human             pancreatic adenocarcinoma cells to gemcitabine.
abstract: The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is important             in cell proliferation and survival, and it is frequently and aberrantly activated             in pancreatic adenocarcinoma. Potential anti-tumor effect(s) of ZSTK474, a PI3K/Akt             inhibitor, together with a key clinically relevant anti-tumor agent, gemcitabine             (GEM), have been reported in a human pancreatic cancer xenograft mouse model.             However, the precise molecular mechanism of these anti-tumor effects has not been             well elucidated. In this study, we investigated the molecular mechanism of GEM             plus ZSTK474 in reducing tumor cell survival in human pancreatic cancer cell lines.             Our study showed that ZSTK474 inhibited cell growth by arresting cells at the             G1 phase and by inducing apoptosis. ZSTK474 also inhibited the phosphorylation             of Akt, GSK3β and BAD. The combination of GEM and ZSTK474 demonstrated synergistic             anti-tumor effects on pancreatic cancer cells in both transient (3 days) and long-term             (14 days) clonogenic assays. Thus, we elucidated the potential molecular mechanism             leading to the enhanced anti-tumor effect when GEM and ZSTK474 are combined in             treatment.
authors: Department of Oncology, Lombardi Comprehensive Cancer Center,                     Georgetown University, Washington DC 20057, USA.
authors: Hong-Quan
authors: HQ
authors: Duong
authors: Hee Jeong
authors: HJ
authors: Kim
authors: Hyo Jin
authors: HJ
authors: Kang
authors: Yeon-Sun
authors: YS
authors: Seong
authors: Insoo
authors: I
authors: Bae
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014227:Triazines / Q000008:administration & dosage*; D000093542:Gemcitabine
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D014227:Triazines; C510150:ZSTK474; D003841:Deoxycytidine; D000093542:Gemcitabine