The flavonoid hyperoside attenuates the toxic effect of cisplatin on the human ovarian granulosa cells: in vitro model study

Abstract

Premature ovarian insufficiency/failure is a well-known long-term risk of chemotherapy including CDDP in women. Granulosa cells (GCs) are an essential ovarian cell type that promotes oocyte growth and is crucial for ovarian reproductive function. Hyperoside (HYP) is a flavonoid known for its beneficial pharmacological properties, including anti-inflammatory and antiapoptotic effects. Hence the current work aimed to evaluate the potential cytoprotective impact of HYP on CDDP-induced cytotoxicity in a human ovarian GCs cell line model via a wide range of assays including MTT, hormones secretion, ATP and mitochondrial membrane potential, reactive oxygen species, lipid peroxidation as well as antioxidant enzymes, Caspases, and Akt kinase activities. Forty-eight-hour exposure to 5-10µM CDDP resulted in reduction of GCs viability in a dose-dependent manner. HYP (40 µM) was found to ameliorate this CDDP -induced effect on GCs viability. CDDP in a concentration-dependent way, dramatically reduced cellular ATP, mitochondrial activities, cellular progesterone, and estradiol secretion. It also increased oxidative stress markers, cytochrome c levels, caspase -3.-8.-9, and Bax/Bcl2 ratio with decreased Akt kinase activity and its coding genes expression. These cytotoxic effects of CDDP on the treated GCs, were mitigated to varying degrees by HYP (40 µM). In conclusion, CDDP-induced cytotoxic effects on GCs seem to be the possible underlying cellular and molecular mechanisms of CDDP-induced ovarian insufficiency/failure. The study also demonstrated the therapeutic potential of HYP in mitigating CDDP-induced ovarian injury. Further studies are warranted to investigate the potential benefit of HYP as an adjuvant to CDDP treatment protocols to avoid adverse ovarian effects.

Keywords: Cisplatin; granulosa cells; hyperoside; mitochondria; premature ovarian failure.