Abstract
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is characterized by overexpression of Akt signaling pathway, which has been shown to be associated with aggressive behaviour and chemoresistance. Aims: The aim of this study was to evaluate the therapeutic potential of perifosine, as a novel Akt inhibitor, in combination with gemcitabine in PDAC. Materials &methods: In vitro studieswere performed in 14 pancreaticcancer-cells, including seven primary PDAC cultures. Growth inhibitory effects of perifosine and gemcitabine were evaluated in PDAC cells, whereas modulation of Akt and phospho-Akt was investigated by Western-blotting and ELISA. Cell-cycle perturbation, apoptosis-induction and anti-migratory behaviors of perifosine were studied by flow-cytometry, AnnexinV, membrane potential, and migration assay, while pharmacological interaction with gemcitabine was determined with combination index (CI) method. Results: Akt expression was detected by quantitative-RT-PCR in 14 PDAC cells, including 7 primary cell cultures. Perifosine (IC50s, 2-hourexposure) modulated the expression of Akt, phospho-Akt, mTOR, Bcl-2, Bad and PARP proteins, and synergistically enhanced the antiproliferative activity of gemcitabine, with combination index values of 0.1 (CFPAC-1), 0.45 (PANC-1) and 0.75 (PP109). The drug combination reduced the percentages of cells in G2/M phase (e.g., from 28 to 16% in PANC-1, P<0.05), and significantly increased apoptosis compared to gemcitabine-alone. Moreover, perifosine decreased cell migration, which was additionally reduced by perifosine/gemcitabine combination (e.g., -20% in PP109, after 8hr exposure, P<0.05). Conclusion: These data show the ability of perifosine to specifically target Akt, interfere with cell-proliferation, induce apoptosis, reduce migration and synergistically interact with gemcitabine, supporting further studies on this novel therapeutic approach for treatment of pancreatic cancer
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