The Experimental Study Of Olaparib Promotes Ferroptosis In BRCA-proficient Ovarian Cancer And Its Combined Effect With Erastin

Research background and purpose:Ovarian cancer（OC）is one of the most common malignant tumors of the female reproductive system.Due to the lack of effective screening and diagnostic methods in the early stage,many patients find that they are unwell,have local or distant metastases,and have missed the best treatment window.Even if patients with advanced ovarian cancer have received standard treatment,the survival rate has not significantly improved,and the recurrence rate is also high.In recent years,poly ADP-ribose polymers（PARP）inhibitors can be selectively targeted to ovarian cancer patients with BRCA1/2 mutations,but most patients have clinically BRCA wild-type ovarian cancer.Therefore,there is an urgent need to develop new strategies for PARP inhibitors that may kill BRCA wild-type ovarian cancer cells.Studies have shown that PARP inhibitors combined with ferroptosis inducers can inhibit the proliferation of BRCA wild-type ovarian cancer cells.Ferroptosis is an iron-dependent,programmed cell necrosis characterized by the accumulation of lipid peroxides and has been shown to inhibit tumor growth in a variety of cancer tumors.Erastin is a ferroptosis inducer,which can increase the sensitivity of ovarian cancer cells to chemotherapeutic drugs.Therefore,the purpose of this paper is to investigate whether a PARP inhibitor（Olaparib）can induce ferroptosis in BRCA wild-type ovarian cancer and its combined effect with Erastin in order to provide new ideas for the treatment of ovarian cancer.Methods1.The effects of different concentrations of Olaparib on the cell viability and proliferation of the ovarian cancer cell line A2780 were detected by the CCK-8 assay.2.The morphology and number of the ovarian cancer cell line A2780 were observed under an inverted optical microscope.3.The expression of ferroptosis markers in the ovarian cancer cell line A2780 treated with different concentrations of Olaparib was determined by reactive oxygen species（ROS）and malondialdehyde（MDA）detection kits.4.The expression of ferroptosis key protein SLC7A11 in the ovarian cancer cell line A2780 treated with different concentrations of Olaparib was detected by Western blot.5.Cell counting CCK-8 method was used to detect the effect of Erastin alone,Erastin combined with 5u M Olaparib and combined with 10u M Olaparib on the survival rate of A2780 cells and the change of IC₅₀.Results1.The CCK-8 assay showed that the cell viability and proliferation ability of the ovarian cancer cell line A2780 treated with different concentrations of Olaparib were significantly lower than those of the control group（P（27）0.05）,and the inhibition ability gradually increased with the prolongation of Olaparib action time and the increase in concentration.2.The results of the ROS assay and MDA assay showed that the production of ROS and MDA in the ovarian cancer cell line A2780 treated with 5 u M and 10 u M Olaparib was significantly higher than that in the control group（P（27）0.01）,and the production of ROS and MDA increased with the increase in Olaparib concentration.3.Western blot experiments confirmed that the expression of SLC7A11 protein in ovarian cancer cell line A2780 treated with 5 u M and 10 u M Olaparib was significantly lower than that in the control group（P（27）0.05）,and the expression of SLC7A11 decreased with the increase in Olaparib concentration.4.The CCK-8 assay showed that the cell viability and proliferation ability of the ovarian cancer cell line A2780 were significantly lower than those of the control group（P（27）0.01）,and the inhibition ability increased with the increase in Erastin concentration.5.The CCK-8 assay showed that the cell viability and proliferation ability of ovarian cancer cell line A2780 treated with Olaparib combined with Erastin were significantly lower than those of the single drug group.Conclusion1.Olaparib may inhibit cell viability and proliferation by inducing ferroptosis in BRCA wild-type ovarian cancer cells.2.Erastin can enhance the sensitivity of Olaparib to BRCA wild-type ovarian cancer cells,and the inhibitory effect is related to the concentration of Erastin.3.Olaparib has potential clinical application value for BRCA wild-type ovarian cancer cells and is expected to become a potential treatment for BRCA wild-type ovarian cancer patients.