Abstract 4432: A-803467, a tetrodotoxin-resistant sodium channel blocker, modulates ABCG2-mediated MDR in vitro and in vivo

Abstract

Abstract ABCG2 is a member of the ABC transporter superfamily, which has been implicated in the development of multidrug resistance (MDR) in cancer. Its diverse range of substrates includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been significantly increased in some solid tumors and hematologic malignancies, which is correlated to poorer clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter impacts resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the ability of a tetrodotoxin-resistant sodium channel blocker, A-803467 to reverse ABCG2-mediated MDR. We found that A-803467 at non-toxic concentration could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies indicated that A-803467 (7.5 μM) significantly increased the intracellular accumulation of mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression level. In addition, A-803467 stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that A-803467 might be a substrate of ABCG2. Binding interactions of A-803467 were found to be in transmembrane region of homology modeled human ABCG2. Interactions of A-803467 with ABCG2 were relatively stronger when compared to the interactions of topotecan with ABCG2. Furthermore, A-803467 (30 mg/kg) with topotecan (3 mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. Our findings indicate that A-803467 has the potential to be used in combination with ABCG2 chemotherapeutic substrates to improve the response in drug resistant cancers. Citation Format: Nagaraju Anreddy, Atish Patel, Yun-Kai Zhang, Yi-Jun Wang, Suneet Shukla, Rishil J. Kathawala, Priyank Kumar, Pranav Gupta, Suresh V. Ambudkar, John ND Wurpel, Zhe-Sheng Chen. A-803467, a tetrodotoxin-resistant sodium channel blocker, modulates ABCG2-mediated MDR in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4432. doi:10.1158/1538-7445.AM2015-4432