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ATP-binding family G2 (ABCG2) transporters are known to produce multidrug resistance (MDR) and limit successful cancer chemotherapy. Using molecular modeling, we obtained data indicating that highly potent and selective dopamine (DA) D3 receptor antagonists had significant docking scores for the active site of the ABCG2 transporter. In this in vitro study, we determined the effect of the D3 receptor antagonists (PG01037, NGB2904, SB-277011A, and U99194) on MDR resulting from the overexpression of ABCG2 transporters. The D3 receptor antagonists alone did not significantly affect the viability of HEK293/ABCG2, H460/MX-20, S1-M1-80 or A549-MX-10 cells, which overexpress ABCG2 transporters. However, the D3 receptor antagonists (PG01037, NGB2904, SB-277011A, and U99194) significantly increased the efficacy of the anticancer drugs mitoxantrone and doxorubicin in the above mentioned cell lines. Efflux studies indicated that both PG01037 and NGB2904 significantly decreased the efflux of rhodamine 123 from H460-MX20 cells. Interestingly, PG01037 and NGB2904 significantly decreased the expression levels of the ABCG2 protein levels as shown by immunocytochemical and Western blot analysis. This suggests that D3 antagonists inhibit both function and expression of ABCG2 transporters at relevant non-toxic concentrations. In conclusion, our in vitro results indicate that PG01037, NGB2904, SB-277011A, and U99194 reverse resistance to mitoxantrone and doxorubicin mediated by overexpression of ABCG2 transporters. Further mechanistic and animal studies are warranted to establish the clinical use of D3 receptor antagonists in reversing ABCG2-mediated MDR. Citation Format: Noor Hussein, Haneen Amawi, Charles R. Ashby, Karthikeyan Chandrabose, Roopali Mittal, Ryann Christman, Piyush Trivedi, Amit Tiwari. The dopamine (DA) D3 receptor antagonists (PG01037, NGB2904, SB-277011A, and U99194) significantly attenuate ABCG2-mediated multidrug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1191. doi:10.1158/1538-7445.AM2017-1191

It has been reported that gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has the ability to modulate the function of certain ATP-binding cassette (ABC) transporters and to reverse ABC subfamily B member 1 (ABCB1; P-glycoprotein)– and ABC subfamily G member 2 (ABCG2; breast cancer resistance protein/mitoxantrone resistance protein)–mediated multidrug resistance (MDR) in cancer cells. However, it is unknown whether other EGFR TKIs have effects similar to that of gefitinib. In the present study, we have investigated the interaction of another EGFR TKI, erlotinib, with selected ABC drug transporters. Our findings show that erlotinib significantly potentiated the sensitivity of established ABCB1 or ABCG2 substrates and increased the accumulation of paclitaxel or mitoxantrone in ABCB1- or ABCG2-overexpressing cells. Furthermore, erlotinib did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in all cells and was unable to reverse MRP1-mediated MDR and had no effect on the parental cells. However, erlotinib remarkably inhibited the transport of E217βG and methotrexate by ABCG2. In addition, the results of ATPase assays show that erlotinib stimulated the ATPase activity of both ABCB1 and ABCG2. Interestingly, erlotinib slightly inhibited the photolabeling of ABCB1 with [125I]iodoarylazidoprazosin (IAAP) at high concentration, but it did not inhibit the photolabeling of ABCG2 with IAAP. Overall, we conclude that erlotinib reverses ABCB1- and ABCG2-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1 and ABCG2. These findings may be useful for cancer combinational therapy with erlotinib in the clinic. [Cancer Res 2007;67(22):11012–20]

Paclitaxel displays clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multi-drug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. In this study, we show that masitinib, a small molecule stem-cell growth factor receptor (c-Kit) tyrosine kinase inhibitor, at non-toxic concentrations, significantly attenuates paclitaxel resistance in HEK293 cells transfected with ABCC10. Our in vitro studies indicated that masitinib (2.5 μM) enhanced the intracellular accumulation and decreased the efflux of paclitaxel by inhibiting the ABCC10 transport activity without altering the expression level of ABCC10 protein. Furthermore, masitinib, in combination with paclitaxel, significantly inhibited the growth of ABCC10-expressing tumors in nude athymic mice in vivo. Masitinib administration also resulted in a significant increase in the levels of paclitaxel in the plasma, tumors and lungs compared to paclitaxel alone. In conclusion, the combination of paclitaxel and masitinib could serve as a novel and useful therapeutic strategy to reverse paclitaxel resistance mediated by ABCC10. Citation Format: Rishil Kathawala, Kamlesh Sodani, Kang Chen, Atish Patel, Alaa Abuznait, Nagaraju Anreddy, Yue-Li Sun, Amal Kaddoumi, Charles R. Ashby, Zhe-Sheng Chen. Masitinib antagonizes ATP-binding cassette subfamily c member 10-mediated paclitaxel resistance: a preclinical study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1964. doi:10.1158/1538-7445.AM2014-1964

Over-expression of ABC transporters are involved in the extrusion of therapeutic drugs, leading to MDR, which can eventually produce cancer chemotherapy failure. Previously, it was shown that specific TKIs could modulate several human multidrug resistance (MDR) ATP-binding cassette (ABC) proteins. Recently discovered second generation, BCR-Abl tyrosine kinase inhibitor (TKI), Nilotinib was developed to surmount resistance or intolerance to imatinib in patients with Philadelphia positive chronic myelogenous leukemia. Here, we report for the first time that nilotinib not only potentiates the cytotoxicity of widely used therapeutic substrates of ABCB1, such as colchicine, vincristine, and paclitaxel, but also that of ABCG2 substrates such as mitoxantrone and doxorubicin. Nilotinib also significantly enhances the intracellular accumulation of methotrexate (MTX) in cells transfected with ABCG2. Similarly, nilotinib significantly increases the accumulation of paclitaxel in cell lines overexpressing ABCB1. Furthermore, nilotinib produces a concentration-dependent inhibition of the ABCG2-mediated transport of MTX, as well as E217βG a physiological substrate of ABCG2. Uptake studies in membrane vesicles over-expressing ABCG2 have indicated that nilotinib inhibits ABCG2 similar to other established TKIs as well as fumitremorgin C. In addition, the kinetic analysis demonstrated that nilotinib is a potent competitive inhibitor of MTX transport by ABCG2 with a Ki value of 0.69+/-0.083 μM. To sum it up, our results indicate that nilotinib could reverse ABCB1- and ABCG2-mediated MDR by blocking the efflux function of these transporters. These findings may be useful in clinical practice for cancer combination therapy with nilotinib and may be vital to the design of present and future clinical trials with nilotinib, elucidating potential pharmacokinetic interactions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1531.