PURPOSE: The pancreatic cancer has extremely low overall 5-year survival, and gemcitabine is the only approved single agent for pancreatic cancer treatment. METHODS: In the present study, we investigated the potential effect of perifosine, a novel Akt inhibitor on gemcitabine-induced anti-pancreatic cancer effect both in vivo and in vitro. RESULTS: We showed that sub-cytotoxic low concentration of perifosine dramatically enhanced gemcitabine-induced cytotoxicity in cultured pancreatic cancer cells. Perifosine inhibited Akt-mammalian target of rapamycin and Erk-mitogen-activated protein kinase activation in pancreatic cancer cells. Meanwhile, perifosine suppressed the hedgehog signaling, as it inhibited glioma-associated oncogenes (Gli) 1 activation and decreased its target protein patched 1 (PTCH1) expression. Our data demonstrated that perifosine blocked p70S6K1 (S6K1) activation, thus disrupting S6K1-Gli1 association and subsequent Gli1 activation. The reduction of S6K1 or Gli1 expression by target siRNAs inhibited PTCH1 expression and enhanced gemcitabine-induced cytotoxicity in pancreatic cancer cells. Significantly, perifosine dramatically enhanced gemcitabine-mediated antitumor effect in a PANC-1 xenograft severe combined immunodeficiency mice model. CONCLUSIONS: In summary, we conclude that perifosine sensitizes gemcitabine-mediated anti-pancreatic cancer efficiency through regulating multiple signaling pathways.
PURPOSE: The pancreatic cancer has extremely low overall 5-year survival, and gemcitabine is the only approved single agent for pancreatic cancer treatment. METHODS: In the present study, we investigated the potential effect of perifosine, a novel Akt inhibitor on gemcitabine-induced anti-pancreatic cancer effect both in vivo and in vitro. RESULTS: We showed that sub-cytotoxic low concentration of perifosine dramatically enhanced gemcitabine-induced cytotoxicity in cultured pancreatic cancer cells. Perifosine inhibited Akt-mammalian target of rapamycin and Erk-mitogen-activated protein kinase activation in pancreatic cancer cells. Meanwhile, perifosine suppressed the hedgehog signaling, as it inhibited glioma-associated oncogenes (Gli) 1 activation and decreased its target protein patched 1 (PTCH1) expression. Our data demonstrated that perifosine blocked p70S6K1 (S6K1) activation, thus disrupting S6K1-Gli1 association and subsequent Gli1 activation. The reduction of S6K1 or Gli1 expression by target siRNAs inhibited PTCH1 expression and enhanced gemcitabine-induced cytotoxicity in pancreatic cancer cells. Significantly, perifosine dramatically enhanced gemcitabine-mediated antitumor effect in a PANC-1 xenograft severe combined immunodeficiencymice model. CONCLUSIONS: In summary, we conclude that perifosine sensitizes gemcitabine-mediated anti-pancreatic cancer efficiency through regulating multiple signaling pathways.
Authors: Selvi Kunnimalaiyaan; Jose Trevino; Susan Tsai; T Clark Gamblin; Muthusamy Kunnimalaiyaan Journal: Mol Cancer Ther Date: 2015-04-17 Impact factor: 6.261
Authors: Nabila A El-Sheridy; Riham M El-Moslemany; Alyaa A Ramadan; Maged W Helmy; Labiba K El-Khordagui Journal: Drug Deliv Date: 2021-12 Impact factor: 6.819