Abstract
Sitravatinib, also called MGCD516 or MG-516, is a broad-spectrum tyrosine kinase inhibitor (TKI) under phase III clinical evaluation. Herein, we explored the activity of sitravatinib toward multidrug resistance (MDR) by emphasizing its inhibitory effect on ATP-binding cassette super-family G member 2 (ABCG2). ABCG2 is a member of ATP-binding cassette (ABC) transporter family and plays a critical role in mediating MDR. Sitravatinb received an outstanding docking score for binding to the human ABCG2 model (PDB code: 6ETI) among thirty screened TKIs. Also, an MTT assay indicated that sitravatinib at 3 μM had the ability to restore the antineoplastic effect of various ABCG2 substrates in both drug-selected and gene-transfected ABCG2-overexpressing cell lines. In further tritium-labeled mitoxantrone transportation study, sitravatinib at 3 μM blocked the efflux function mediated by ABCG2 and as a result, increased the intracellular concentration of anticancer drugs. Interestingly, sitravatinib at 3 μM altered neither protein expression nor subcellular localization of ABCG2. An ATPase assay demonstrated that ATPase activity of ABCG2 was inhibited in a concentration-dependent manner with sitravatinib; thus, the energy source to pump out compounds was interfered. Collectively, the results of this study open new avenues for sitravatinib working as an ABCG2 inhibitor which restores the antineoplastic activity of anticancer drugs known to be ABCG2 substrates.
Highlights
Evidence from clinical studies showed that patients with multidrug resistant (MDR) tumors have a poorer prognosis and decreased likelihood of survival compared to cancer patients with drug sensitive tumors [1]
It is well-known that ATP-binding cassette (ABC) transporters contribute to multidrug resistance (MDR) and as a result, limit the anticancer efficacy of numerous chemotherapeutic agents in the clinical setting
Many researchers using in vivo and ex vivo models have demonstrated that tyrosine kinase inhibitor (TKI) have ability to restore the sensitivity of substrate antineoplastic drugs of ABC transporters for effective chemotherapy [40,41,42,43]
Summary
Evidence from clinical studies showed that patients with multidrug resistant (MDR) tumors have a poorer prognosis and decreased likelihood of survival compared to cancer patients with drug sensitive tumors [1]. Cancer patients develop cross-resistance to various structurally and functionally unrelated chemotherapeutic agents, resulting in treatment failure [2, 3]. Overexpression of ATP-binding cassette (ABC) transporters is a leading cause of MDR [4]. The overexpression of certain transporters leads to MDR, including, but not limited to, ABCB1 (P-glycoprotein, Pgp), ABCG2 (breast cancer resistance protein, BCRP/MXR) and ABCC1 (multidrug resistance-associated protein 1, MRP1) [4, 5]. ABCB1 and ABCG2 work as efflux pumps, and are located in the lipid raft of specific cell lines [1, 6], reducing the intracellular level of various antineoplastic agents accumulating in cancer cells
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