Pharmacodynamic Modeling to Evaluate the Impact of Cimetidine, an OCT2 Inhibitor, on the Anticancer Effects of Cisplatin

Despite potent anticancer activity, the clinical utilization of cisplatin is limited due to nephrotoxicity. As Organic Cation Transporter 2 (OCT2) has been shown to be one of the key transporters involved in the uptake of cisplatin into renal proximal tubules, OCT2 inhibitors such as cimetidine have been explored to suppress cisplatin-induced nephrotoxicity. Nonetheless, the impact of OCT2 inhibition or cimetidine on the anti-cancer effects of cisplatin has not been extensively examined. The main objective of the present study was to quantitatively characterize the anticancer effects of cisplatin and cimetidine and determine their nature of interactions in two cancer cell lines, OCT2-negative hepatocellular carcinoma (HCC) cell line, Huh7, and OCT2-positive breast cancer cell line, MDA-MB-468. First, we determined the static concentration-response curves of cisplatin and cimetidine as single agents. Next, with the help of three-dimensional (3D) response surface analyses and a competitive interaction model, we determined their nature of interactions at static concentrations to be modestly synergistic or additive in Huh7 and antagonistic in MDA-MB-468. These results were consistent with the cell-level pharmacodynamic (PD) modeling analysis which leveraged the time-course effects of drugs as single agents and drug combinations. Our developed PD model can be further used to design future preclinical studies to further investigate the cisplatin and cimetidine combinations in different in vitro and in vivo cancer models.