Myricetin, a natural inhibitor of CD147, increases sensitivity of cisplatin in ovarian cancer.

Abstract

Background: Ovarian cancer (OC) is the most lethal gynecological tumor, but it currently lacks effective therapeutic targets. CD147, which is overexpressed in OC, plays a crucial role in promoting malignant progression and is associated with poor prognosis in patients. Therefore, CD147 has been identified as a potential therapeutic target. However, there is a limited amount of research on the development of CD147 inhibitors.

Methods: Surface plasmon resonance (SPR) assay and virtual molecular docking analysis were performed to identify potential natural compounds targeting CD147. The anti‑tumor effects of myricetin were evaluated using various assays, including CCK8, Alkaline comet, immunofluorescence and xenograft mouse models. The underlying mechanism was investigated through western blot analysis and lentivirus short hairpin RNA (LV-shRNA) transfection.

Results: Myricetin, a flavonoid commonly found in plants, was discovered to be a potent inhibitor of CD147. Our findings demonstrated that myricetin exhibited a strong affinity for CD147 and down-regulated the protein level of CD147 by facilitating its proteasome-dependent degradation. Additionally, we observed synergistic antitumor effects of myricetin and cisplatin both in vivo and in vitro. Mechanistically, myricetin suppressed the expression of FOXM1 and its downstream DNA damage response (DDR) genes E×O1and BRIP1, thereby enhancing the DDR induced by cisplatin.

Conclusion: Our data demonstrate that myricetin, a natural inhibitor of CD147, may have clinical utility in the treatment of OC due to its ability to increase genomic toxicity when combined with cisplatin.