mTORC1 inhibition by metformin synergizes with dendrosomal nano-curcumin to induce apoptosis via modulation of pro- and anti-apoptotic proteins in breast cancer cells.

Breast cancer often carries a poor short-term prognosis because of its strong tendency for early distant metastasis and recurrence. Effective treatment requires strategies that disrupt the anabolic pathways cancer cells use to overcome therapeutic resistance. In this study, we explored a synergistic combination of a well-tolerated anti-diabetic drug, Metformin, which is in a phase III clinical trial, and dendrosomal curcumin, DNC, to induce cell death in breast cancer MDA-MB-231 and MCF-7 cells. Intriguingly, Metformin and DNC exhibited positive synergistic effects, increased anticancer toxicity through S-phase cell growth arrest, enhanced activation of caspases, reduced expression of Bcl-2, cIAP1, cIAP2, and XIAP proteins, and morphological and biological changes consistent with apoptosis. The mechanism behind this synergism in MDA-MB-231 and MCF-7 cells was the result of a significantly higher ratio of Bax to Bcl-2 and the dramatic upregulation of active caspase-3, concomitant with the downregulation of XIAP. In addition to downregulation of anti-apoptotic proteins and upregulation of pro-apoptotic proteins, mTORC1 signaling was effectively hindered in the cells exposed to the drugs. Thus, induction of apoptosis by a combination of Metformin and DNC in MDA-MB-231 and MCF-7 cells is accompanied by the inhibition of anabolic pathways mediated by mTOR complex I.