Abstract 5614: Tandutinib (MLN518/CT53518) targeted to stem-like cells by inhibiting the function of ATP-binding cassette subfamily G member 2

Abstract

Abstract Tandutinib (MLN518/CT53518) is a novel quinazoline-based inhibitor of FMS-like tyrosine kinase 3, platelet-derived growth factor receptor, and KIT. In this study, we evaluated the possible interactions of tandutinib with P-glycoprotein (P-gp/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1), breast cancer resistance protein (BCRP/ABCG2) and MRP4/ABCC4. Our results showed that tandutinib reverses ABCG2-mediated drug resistance in ABCG2-transfected cell lines ABCG2-482-R2, ABCG2-482-G2 and ABCG2-482-T7 and mitoxantrone-induced ABCG2-overexpressing cell line S1-M1-80. On the other hand, tandutinib did not change the sensitivity of all tested ABCG2-overexpressing cell lines and their sensitive parental cell lines to cisplatin (non-substrate of ABCG2) and had no significant reversal effect on ABCB1-, ABCC1- and ABCC4-mediated drug resistance. Tandutinib increased doxorubicin and rhodamine 123 accumulation in S1-M1-80 cells in a dose-dependent manner, but did not change their accumulation in parental S1 cells. Similarly, tandutinib also enhanced [3H]mitoxantone accumulation in ABCG2-transfected cell lines, significantly inhibited mitoxantrone efflux in ABCG2-482-R2 cells, but not in HEK293/pcDNA 3.1 cells. However, tandutinib did not stimulate the ATPase activity of ABCG2 and significantly inhibit the photolabeling of ABCG2 with [125I]Iodoarylazidoprazosin. Tandutinib also did not affect the expression of ABCG2 at mRNA or protein levels. In addition, tandutinib did not block the phosphorylation of Akt and Erk1/2 in S1-M1-80 or S1 cells. Importantly, tandutinib targeted to A549 side population cells and enhanced their sensitivity to mitoxantrone, which was not altered in non-SP cells. Collectively, our results advocate the use of tandutinib as an ABCG2 modulator and stem cell targeted agent to increase efficiency of anticancer drugs in clinic therapy. 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 5614. doi:1538-7445.AM2012-5614