Muscarinic Receptors as Targets for Metronomic Therapy in Ovarian Cancer

Aim: In this study, the effects of muscarinic acetylcholine receptor (mAChR) agonist carbachol on the proliferation of cisplatin-resistant (A2780cis) and cisplatin-free (SKOV-3) ovarian cancer cell line were for the first time investigated to further evaluate the potential therapeutic effect of metronomic chemotherapy. Material and Methods: The inhibitory effect of carbachol on cell proliferation was detected using the xCELLigence Real-Time Cell Analyzer (RTCA) dual plate (DP) system. A preliminary study was conducted to determine the dose of carbachol 100 mu M, cisplatin 1 mu M, and two combination studies were carried out with 100 mu M carbachol + cisplatin 1 mu M and 100 mu M carbachol + 10 mu M atropine, over cancer cells without drugs was used as the control group. The cell proliferation curve was monitored for 96 hours. The cell index value of inhibition in cell proliferation was automatically measured every hour for each well using RTCA 1.2.1 software. Results: Co-administration of carbachol with cisplatin caused a decrease in cell number in both A2780cis and SKOV-3 cell lines in a time-dependent manner (p<0.001). Substantial cell death was observed in both cisplatin-resistant (A2780cis) and cisplatin-free (SKOV-3) cell lines within 24 hours after carbachol with cisplatin application and this continued at the 96th hour. Conclusion: The findings of this study confirm the notion that mAChRs can be considered as therapeutic targets for metronomic therapy in ovarian cancer, as well as the usefulness of a muscarinic agonist as a repositioning drug in the treatment of such tumors.