Activation of FOXO3a reverses 5-Fluorouracil resistance in human breast cancer cells

Breast cancer is the most frequently diagnosed tumor type and the primary leading cause of cancer deaths in women worldwide. Drug resistance is the major obstacle for breast cancer treatment improvement. TRAIL-inducing compound 10 (Tic10), a novel activator of FOXO3, exhibits potent antitumor efficacy both in vitro and in vivo. In the present study, we investigated the resistance reversal effect of Tic10 on multidrug-resistant breast cancer cells T47D/5Fu derived from T47D breast cancer cells. We found that FOXO3a was significantly decreased in T47D/5-Fu cells, whereas treatment of Tic10 enhances FOXO3a expression and nuclear translocation. Moreover, treatment of Tic10 could reverses 5-Fluorouracil resistance of T47D/5-Fu cells via induction of G0/G1 cell cycle arrest and apoptosis. Furthermore, we found that Tic10 decreased the expression of CDK4 via FOXO3a-dependment mechanism. In addition, our data showed that Tic10 could sensitize drug resistant T47D/5-Fu cells to 5-Fu in vivo. Taken together, these data suggested Tic10 as capable of restoring sensitivity for drug-resistant breast cancer cells.