Quercetin-3-O-glucuronide inhibits doxorubicin resistance by reducing endoplasmic reticulum stress in hepatocellular carcinoma cells

Abstract Hepatocellular carcinoma (HCC) is typically aggressive and is closely correlated with recurrence and poor survival. Endoplasmic reticulum (ER) stress is a critical problem because it causes drug resistance. Quercetin-3-O-glucuronide (Q3GA) has been shown to exhibit antiproliferative and antioxidant activities. However, the effects of Q3GA on ER stress-induced doxorubicin (DOX) resistance in human HCC cells have not been studied. The results of MTT assay and flow cytometry data indicated that pretreatment with tunicamycin (TM), an ER stress inducer, significantly reduced apoptosis induced by DOX in HepG2 cells. Moreover, Western blot analysis indicated that the induction of ER stress resulted in an increase in COX-2 expression and the phosphorylation of PI3K/Akt in HepG2 cells. In addition, Q3GA enhanced DOX-induced cytotoxicity and caspase-3 activation under ER stress. These results demonstrated that Q3GA attenuated ER stress-induced resistance to DOX in human HCC cells through the downregulation of the COX-2-mediated PI3K/Akt pathway.