Quercetin enhanced the sensitivity of colorectal cancer cells to 5- fluorouracil by induction of autophagy and Drp-1 mediated mitochondrial fission

Abstract

Abstract Background: 5-fluorouracil (5-FU) is the main chemotherapeutic agent for colorectal cancer (CRC) treatment, while the emergence of drug resistance or insensitivity hindered the clinical benefit. Thus, it is impending to explore novel effective chemotherapeutic adjuvants to increase patients' survival rate. The anticancer activity of quercetin (Que) has been reported in various of cancer such as lung, gastric, breast and pancreatic cancer. Nevertheless, the underlying anti-cancer molecular mechanism of quercetin against colorectal cancer remains to be investigated. Methods: MTT assay and colony formation assay were performed to explore the growth inhibition of quercetin alone or combine with 5-FU on colorectal cancer cells. GFP-LC3 and mRFP-GFP-LC3 plasmids were applied to detect autophagy and autophagy flux. Hoechst staining, DCFH-DA, JC-1, Mito-Tracker red were used to evaluate apoptosis, ROS, mitochondrial membrane potential (MMP) and mitochondria fission. The expression of proteins was assessed by western blotting. Results: The results demonstrated that quercetin inhibited cell proliferation, induced apoptosis and autophagy in CRC cells in vitro. Autophagy blockage enhanced quercetin-induced cytotoxicity, indicating that quercetin induced protective autophagy. Quercetin induced excessive ROS accumulation and decreased mitochondrial membrane potential (MMP), which were associated with the imbalance of mitochondria dynamic. Quercetin promoted Drp-1 mediated mitochondria fission eventually caused mitochondrial dysfunction and cell death. Moreover, Quercetin synergistically increased the sensitivity of colorectal cancer cells to 5-fluorouracil by induction of autophagy and Drp-1 mediated mitochondria fission. Conclusion: Our results revealed that Quercetin induced apoptosis through Drp-l mediated mitochondria fission and promoted autophagy. Furthermore, Quercetin synergistically enhanced the sensitivity of colorectal cancer cells SW480 and HCT116 to 5-FU.