Quercetin induces endoplasmic reticulum stress to enhance cDDP cytotoxicity in ovarian cancer: involvement of STAT3 signaling.

ABSTRACT

There is an urgent need to make cisplatin (cDDP) more effective and less toxic in the treatment of ovarian cancer for its systemic side effects and high resistance rate. In this study, we investigated the effect of quercetin (Qu) pretreatment on the potentiation of cDDP in ovarian cancer. We found that Qu pretreatment significantly enhanced cDDP cytotoxicity in an ovarian cancer cell line and primary cancer cells. In addition, we demonstrated that Qu elicited obvious endoplasmic reticulum stress (ERS) and activated all three branches of ERS in ovarian cancer. Specific inhibitors of each ERS pathway, as well as the general ERS stabilizer tauroursodeoxycholic acid, notably diminished such enhancing effects. Furthermore, Qu notably suppressed STAT3 phosphorylation, leading to downregulation of the BCL-2 gene downstream of STAT3. Moreover, blocking ERS restored the protein levels of phosphorylated STAT3 as well as BCL-2 expression, thus abolishing the chemosensitization potency of Qu; these results revealed that Qu affected the STAT3 pathway to enhance cDDP cytotoxicity, and this effect involved ERS signaling. In a xenograft mouse model of ovarian cancer, Qu enhanced the antitumor effect of cDDP. Tumors from mice treated with cDDP in combination with Qu pretreatment had repressed STAT3 phosphorylation, lower BCL-2 and higher apoptosis levels compared with those from the other groups. Meanwhile, Qu markedly reduced the elevation of blood creatinine during cDDP intervention. These data indicate that Qu pretreatment potentiates the antitumor effects of cDDP in ovarian cancer while protecting the kidneys against damage. Therefore the strategy of Qu pretreatment may be beneficial in enhancing the therapeutic efficacy of cDDP against ovarian cancer.