Cisplatin in combination with emetine and patulin showed dose and sequence dependent synergism against ovarian cancer

Abstract

Combating multiple drug resistant ovarian cancer is a major challenge. Combined chemotherapy of platinum drugs with phytochemicals (e.g. paclitaxel) introduce new options for oncologists in overcoming drug resistance. The objective of the present study was to investigate the activity of cisplatin in combination with emetine and patulin within ovarian cancer models. Antitumour activity of the cisplatin, emetine and patulin as a single drug was determined against human ovarian cancer cell lines (A2780 and A2780^CisR) by using the MTT reduction assay. Combination indices obtained from Chou-Talalay method were used to express combined drug actions. Proteomics was also carried out to identify the proteins which were responsible for the synergistic effects of the drug combinations. Cisplatin in combination with emetine produced synergism against ovarian cancer models depending on dose and sequence of drug administration. Patulin also demonstrated synergism when combined cisplatin at different doses and sequence of administrations. Eight proteins (e.g. VIME, ENPL, GRP78, CARL, NACA, COF1, PPIA and RSSA) were considered for combined drug actions of cisplatin plus emetine. Synergistic activity of the combination of cisplatin with patulin could be attributed to the downregulation of VIME, COF1 and CH10 as well as upregulation of CISY. Combinations of cisplatin with emetine and cisplatin with patulin led to dose reductions of cisplatin in the ovarian cancer cell line A2780. These combinations could be warranted for further evaluation using suitable in vitro and animal models in the context of overcoming drug resistance.