Effects of carfi lzomib alone and in combination with cisplatin on the cell death in cisplatin-sensitive and cisplatin-resistant ovarian carcinoma cell lines

Abstract

BACKGROUND: Previous studies on the effi cacy of platinum-based drugs and selective inhibitors of proteasome have revealed promising outcomes. This study is aimed to evaluate the effects of the combination of cisplatin and carfi lzomib on the cell death induction and drug effl ux transporters expression in cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) ovarian cancer cells lines. METHODS: MTT cytotoxic assay was conducted to determine the cytotoxicity. Drug interactions were analyzed based on Chou-Talalay's principles and real-time PCR analysis was performed to determine possible alterations in mRNA levels of MRP1 and BCRP. RESULTS: A2780s cells were more susceptible to both cisplatin and carfi lzomib while analyses of drug interactions between the two agents showed synergistic effects in all affected fractions of drug-treated A2780s and A2780cp cells (CI < 0.9) with the combination indices being signifi cantly lower in A2780cp cells (p < 0.01). We also found that although mRNA levels of BCRP and MRP1 were signifi cantly altered in both cells exposed to each drug alone, only the combination regimen was able to signifi cantly reduce the mRNA levels of these genes in A2780cp cells (p < 0.001). CONCLUSION: This combination might be a potential strategy for suppressing cell growth via downregulating the drug effl ux transporters expression, especially in cisplatin-resistant ovarian cancer cells.