【摘 要】
：
Background: Gemcitabine (GEM) is currently used as a standard anti-cancer drug with best evidence for pancreatic cancer.Recently we discovered that glycogen synthase kinase-3beta (GSK-3beta) promotes
【机 构】
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Department of Medical Oncology Kanazawa Medical University Japan
【出 处】
：
BIT Life Sciences 1st Annual World Cancer Congess-2008(2008中
论文部分内容阅读
Background: Gemcitabine (GEM) is currently used as a standard anti-cancer drug with best evidence for pancreatic cancer.Recently we discovered that glycogen synthase kinase-3beta (GSK-3beta) promotes survival and proliferation of cancer cells and that combination of gemcitabine (GEM) and GSK3beta inhibitor (GSKI) is a putative therapeutic strategy for pancreatic cancer.In this study, we investigated the anti-tumor effect and molecular mechanisms of treatment by a GSKI combined with GEM.Materials and Methods: GEM (10-100 mg/L) and GSKI (AR-A014418; 5 mg/L,16 microM) were added to the culture medium of a human pancreatic cancer cell line PANC-1 in vitro, and injected intraperitoneally to PANC-1 xenograft-burden nude mice.Results: Combination of GEM and SKI synergistically suppressed the growth of PANC-1 cells dose-dependently in vitro.Proliferation of PANC-1 xenografts in mice and expressions of PCNA and p53 in the tumors were significantly decreased in the GEM plus GSKI group, compared with the GEM alone group.cDNA mieroarray analysis demonstrated that expression of 372 genes was altered in GEM-treated PANC-1 cells.Ingenuity Pathways Analysis (IPA) revealed marked changes in the genes responsible for gene expression, cell death, DNA replication and cell cycle.In particular, IPA for GSKI-treated PANC-1 cells identified changes in expression of genes involved in bothp53-and myc-related molecular networks.Conclusions: These data indicate that GSK-3beta is a new therapeutic target in pancreatic cancer and that GSK3beta inhibition sensitizes pancreatic cancer cells to GEM by modulating p53 and myc pathways.
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