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

摘要: // Nagaraju Anreddy 1, * , Atish Patel 1 Yun-Kai Zhang Yi-Jun Wang Suneet Shukla 2 Rishil J. Kathawala Priyank Kumar Pranav Gupta Suresh V. Ambudkar John N. D. Wurpel Zhe-Sheng Chen Huiqin Guo 3, Department of Pharmaceutical Sciences, College Pharmacy and Health St. John’s University, Queens, NY 11439, USA Laboratory Cell Biology, Center for Cancer Research, National Institute, Institutes Health, Bethesda, MD 20892, 3 Thoracic Surgery, Peking Union Medical Hospital, Beijing 100730, P.R. China These authors have contributed equally to this work Correspondence to: Guo, e-mail: guohuiqin2@163.com Chen, chenz@stjohns.edu Keywords: multidrug resistance, ABCG2, ABC transporters, non-small cell lung cancer Received: July 22, 2015      Accepted: October 09, Published: 2015 ABSTRACT ATP-binding cassette subfamily G member (ABCG2) is a the transporter superfamily proteins, which has been implicated in development resistance (MDR) cancer, apart from its physiological role remove toxic substances out cells. The diverse range substrates ABCG2 includes many antineoplastic agents such as topotecan, doxorubicin mitoxantrone. expression reported be significantly increased some solid tumors hematologic malignancies, correlated poor clinical outcomes. In addition, distinguishing feature stem cells, whereby membrane facilitates chemotherapeutic drugs. To enhance chemosensitivity attention focused on MDR modulators. study, we investigated effect tetrodotoxin-resistant sodium channel blocker, A-803467 ABCG2-overexpressing drug selected transfected lines. We found that at non-toxic concentrations, could increase cellular sensitivity drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies demonstrated (7.5 μM) intracellular accumulation [ H]-mitoxantrone by inhibiting transport activity without altering levels. stimulated ATPase membranes overexpressed with murine model system, combination treatment (35 mg/kg) topotecan (3 inhibited tumor growth mice xenografted Our findings indicate may potentially novel therapeutic ABCG2-positive resistant cancers.