Curcumin Dually Inhibits Both Mammalian Target of Rapamycin and Nuclear Factor-kappa B Pathways through a Crossed Phosphatidylinositol 3-Kinase/Akt/I kappa B Kinase Complex Signaling Axis in Adenoid Cystic Carcinoma

Adenoid cystic carcinoma (ACC) is a highly malignant tumor that is generally unresponsive or only weakly responsive to the currently available antineoplastic agents. Thus, novel therapeutic strategies and agents are urgently needed to treat this aggressive neoplasm. Curcumin, a component of turmeric (Curcuma longa), has been shown to have a diversity of antitumor activities. We show here that curcumin is a potent inhibitor of ACC progression in vitro and in vivo. Curcumin concentration-dependently inhibited the growth of ACC cells via induction of apoptosis. The ability of ACC cells to migrate/invade and induce angiogenesis was also significantly attenuated by curcumin, accompanied by the down-regulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 and -9. Moreover, our data also demonstrated that the inhibitory effects of curcumin on ACC cells were due to its dual inhibition of both mammalian target of rapamycin (mTOR) and nuclear factor-kappa B (NF-kappa B) pathways through a crossed phosphatidylinositol 3-kinase/Akt/I kappa B alpha kinase signaling axis. Most importantly, curcumin effectively prevented the in vivo growth and angiogenesis of ACC xenografts in nude mice, as revealed by the induction of cell apoptosis and reduction of microvessel density in tumor tissues. In addition, we further assessed the nature activation status of both mTOR and NF-kappa B pathways in ACC tissues and confirmed the concurrent high activation of these two pathways in ACC for the first time. Taken together, our findings suggest that further clinical investigation is warranted to apply curcumin as a novel chemotherapeutic regimen for ACC because of its dual suppression of both mTOR and NF-kappa B pathways.