Casticin-Induced Inhibition of Cell Growth and Survival Are Mediated through the Dual Modulation of Akt/mTOR Signaling Cascade

The Akt/mTOR signaling cascade is a critical pathway involved in various physiological and pathological conditions, including regulation of cell proliferation, survival, invasion, and angiogenesis. In the present study, we investigated the anti-neoplastic effects of casticin (CTC), identified from the plant Vitex rotundifolia L., alone and/or in combination with BEZ-235, a dual Akt/mTOR inhibitor in human tumor cells. We found that CTC exerted a significant dose-dependent cytotoxicity and reduced cell proliferation in a variety of human tumor cells. Also, CTC effectively blocked the phosphorylation levels of Akt (Ser473) and mTOR (Ser2448) proteins as well as induced substantial apoptosis. Additionally treatment with CTC and BEZ-235 in conjunction resulted in a greater apoptotic effect than caused by either agent alone thus implicating the anti-neoplastic effects of this novel combination. Overall, the findings suggest that CTC can interfere with Akt/mTOR signaling cascade involved in tumorigenesis and can be used together with pharmacological agents targeting Akt/mTOR pathway.