Abstract 812: Identification of novel anticancer drugs as substrates of organic anion transporting polypeptide 1B3 using a cell viability assay

Abstract

Abstract Organic anion transporting polypeptide 1B3 (OATP1B3) belongs to a superfamily of transport proteins that mediate the uptake of a wide range of endogenous and exogenous compounds into cells. Under normal conditions OATP1B3 is selectively expressed at the basolateral membrane of human hepatocytes. Recently, OATP1B3 expression has been detected in a variety of different cancers and because of its multispecificity OATP1B3 is thought to be a potential therapeutic target to enhance drug delivery into cancer cells. Thus far, only a few anticancer drugs have been identified as substrates of OATP1B3 including docetaxel, paclitaxel, methotrexate and imatinib. Given that OATP1B3 can potentially be used as a target for anticancer drug delivery we need to identify additional anticancer drug substrates of OATP1B3. Therefore, we aimed at establishing a cell based high throughput assay to screen the NCI approved oncology drug set for novel cytotoxic substrates of OATP1B3. Using a luminescent cell viability assay, we measured the viability of wild-type and OATP1B3-expressing Chinese Hamster Ovary (CHO) cells in the absence or presence of the anticancer drugs. After we identified positive hits we further characterized them with respect to concentration dependencies. We identified etoposide, bleomycin, oxaliplatin and plicamycin as compounds that kill OATP1B3-expressing CHO cells at much lower concentrations than wild-type CHO cells suggesting that these compounds are substrates of OATP1B3. Using secondary assays we confirmed that etoposide is a substrate of OATP1B3 and we are currently testing the remaining compounds for direct uptake by OATP1B3. In conclusion, this cell-based viability assay is a good tool to identify novel cytotoxic OATP1B3 substrates that can potentially be used to treat OATP1B3-expressing cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 812. doi:1538-7445.AM2012-812