Quercetin combined with shTERT induces apoptosis in ovarian cancer via the P53/Bax pathway, and RGD-MSN/QR/shTERT nanoparticles enhance the therapeutic efficacy.

Abstract

Background: Ovarian cancer (OC) is a highly malignant gynecological tumor with poor current treatment effects. Telomerase reverse transcriptase (TERT) is an important component of telomerase and plays an important role in the progression of ovarian cancer. Quercetin(QR) has been shown to inhibit the cell cycle and induce the apoptosis in various types of tumors. However, the mechanism of quercetin in ovarian cancer and whether it can be applied in the treatment of ovarian cancer has not been fully understood.

Results: OC cells were intervened with QR in vitro and it was found that QR only inhibited the cell cycle but not induced cell apoptosis. By conducting network pharmacology, proteomics and TCGA-OV database analysis, we found that QR inhibited the cell cycle by binding to P53 and P21. However, in this study, overexpressed TERT in OC could bind to P53 and inhibit the binding of QR to P53, failing to induce tumor cell apoptosis. After TERT was knocked down, QR significantly suppressed the cell cycle of OC cells and induced apoptosis.To realize high drug delivery efficiency and drug targeting to improve the effect of inhibiting OC, we designed and prepared RGD-MSN/QR/shTERT nanoparticles for the combined administration of QR and shTERT. As confirmed by the in vivo experiments, RGD-MSN/QR/shTERT possessed good targeting ability and significant OC inhibiting effect, with no adverse reactions, and improved the survival benefits.

Conclusions: This study demonstrated the mechanistic and therapeutic advantages of combining QR with shTERT in the treatment of OC. Based on this mechanism, we synthesized the novel nanoparticles (RGD-MSN/QR/shTERT) and verified the favorable OC inhibiting effect in vivo, providing a novel strategy for the treatment of OC.