Fig. 7.

Molecular mechanisms involved in the synergistic interaction of perifosine with gemcitabine. The main upstream activator of Akt is phosphatidylinositol-3 kinase (PI3K), which is activated in the response to a variety of growth stimuli through receptor tyrosine kinases and G protein-coupled receptors. This kinase phosphorylates phosphatidylinositol-4,5-diphosphate (PIP2), which results in generation of phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 interacts with the pleckstrin homology (PH) domain of Akt, leading to translocation of Akt to the cell membrane, and phosphorylation at Thr308 and Ser473. Perifosine inhibits Akt activation and enhances the growth inhibitory effects of gemcitabine through its pronounced pro-apoptotic, anti-invasive effects, as well as by inhibiting the cell proliferation, followed by modulation of ribonucleotide reductase (RR), potentially facilitating gemcitabine cytotoxicity. Moreover, Akt inhibition reduce Glut1 activity reducing glucose influx and thereby favouring apoptosis induction and sensitizing PDAc cells to treatment with cytotoxic agents