Abstract 983: A dual inhibitor of MDR-1 and ABCG2,elacridar, enhances cytotoxic effects of sunitinib on RCC cell lines.

Abstract

Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) and currently approved for use in advanced renal cell carcinoma (RCC). It is really attractive drug for patients who cannot have surgical treatment. However, it is reported that TKI might be substrates of ATP-binding cassette (ABC) transporters, which are able to mediate the efflux of anti-tumor drugs from the tumor cells. In this study, we suggested that inhibition of MDR transporters by elacridar (dual inhibitor of MDR-1 and ABCG2) might overcome sunitinib resistance in experimental RCC. We used 786-O and Caki-1 RCC cell lines. The cells were treated with sunitinib alone, elacridar alone or the combination, then cytotoxicity was measured by the MTT cytotoxicity method. The expression of MDR-1 and ABCG2 mRNA and their protein were detected by real time RT-PCR or Western blotting. Additionally, P-gp function was analyzed by using 99mTc-MIBI. MCF-7 cells were used as negative control for P-gp functional assay. Our results showed that elacridar significantly enhanced sunitinib cytotoxicity in RCC cells. High P-gp expression was especially observed in 786-O, though that of ABCG2 was almost the same among cells. Additionally P-gp assay revealed that the protein would be active and elacridar blocked its function in 786-O, where the accumulation of the 99mTc-MIBI increased 7 folds compared to the control (non-treatment group). These findings suggest that sunitinib resistance is partly mediated by gene and protein expression of MDR transporters. Therefore combination with elacridar could reverse its resistance in MDR sensitive cancer cells, as it did in 786-O. Citation Format: Hiromi Sato, Sana Siddig, Rina Suzuki, Miaki Uzu, Sayumi Suzuki, Yuki Nomura, Yuko Sekine, Tomoya Uehara, Yasushi Arano, Koichi Ueno. A dual inhibitor of MDR-1 and ABCG2,elacridar, enhances cytotoxic effects of sunitinib on RCC cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 983. doi:10.1158/1538-7445.AM2013-983