Resveratrol as a novel treatment for diseases with mTOR pathway hyperactivation.

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is hyperactivated in a variety of cancers and tumor syndromes. Therefore, mTORC1 inhibitors are being actively investigated for treatment of neoplasms. The concern with the monotherapy use of mTORC1 inhibitors, such as rapamycin, is that they cause upregulation of autophagy, a cell survival mechanism, and suppress the negative feedback loop to the oncogene Akt. In turn, Akt promotes cell survival, causing the therapy to be partially effective, but relapse occurs upon cessation of treatment. In this review, we describe the current literature on resveratrol as well as our work, which uses rapamycin in combination with resveratrol. We found that this combination treatment efficiently blocked upregulation of autophagy and restored inhibition of Akt in different cancer and tumor models. Interestingly, the combination of rapamycin and resveratrol selectively promoted apoptosis of cells with mTOR pathway hyperactivation. Moreover, this combination prevented tumor growth and lung metastasis when tested in mouse models. Finally, mass spectrometry-based identification of cellular targets of resveratrol provided mechanistic insight into the mode of action of resveratrol. The addition of resveratrol to rapamycin treatment may be a promising option for selective and targeted therapy for diseases with mTORC1 hyperactivation.