Abstract
Overexpression of adenine triphosphate (ATP)-binding cassette (ABC) transporters is one of the main reasons of multidrug resistance (MDR) in cancer cells. Trametinib, a novel specific small-molecule mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, is currently used for the treatment of melanoma in clinic. In this study, we investigated the effect of trametinib on MDR mediated by ABC transporters. Trametinib significantly potentiated the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in cancer cells overexpressed ABCB1, but not ABCC1 and ABCG2. Furthermore, trametinib did not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, trametinib potently blocked the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. Importantly, trametinib remarkably enhanced the effect of vincristine against the xenografts of ABCB1-overexpressing cancer cells in nude mice. The predicted binding mode showed the hydrophobic interactions of trametinib within the large drug binding cavity of ABCB1. Consequently, our findings may have important implications for use of trametinib in combination therapy for cancer treatment.
Highlights
Cancer cells with multidrug resistance (MDR) to chemotherapeutic drugs significantly reduces the efficacy of cancer chemotherapy [1]
To investigate the effects of trametinib on ABCB1mediated MDR in cancer cells, we firstly examined the cytotoxicity of trametinib in two ABCB1-overexpressing cells KBV200 and MCF-7/ADR and their parental cells KB and MCF-7 by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay
We detected the effects of trametinib on ABCC1 and ABCG2-mediated MDR, and found that trametinib at 10 μM did not reduce the resistances of vincristine in ABCC1overexpressing cells KB-CV60 and doxorubicin in ABCG2-overexpressing cells S1M1-80 (Supplementary Figure 1)
Summary
Cancer cells with multidrug resistance (MDR) to chemotherapeutic drugs significantly reduces the efficacy of cancer chemotherapy [1]. ABCB1 can transport multiple types of chemotherapeutic drugs out of cells, such as the taxanes (paclitaxel, docetaxel), epipodophyllotoxins (etoposide), vinca alkaloids (vincristine, vinblastine), and anthracyclines (doxorubicin, epirubicin), and this process is coupled to the energy of ATP hydrolysis on the ATPase domain [7,8,9,10] Inhibition of these transporters will restore the sensitivity of MDR cancer cells to chemotherapeutic agents, and may permit a successful chemotherapy to patients with MDR cancer [11, 12]. In a multicentre phase 1 dose-escalation trial of 206 patients with advanced solid tumors to assesse the safety, pharmacokinetics, pharmacodynamics, and efficacy data of trametinib, the maximum tolerated dose was 3 mg once daily, the effective half-life was around 4 days, and active pathway inhibition and clinical activity were recorded [16]. We demonstrate that trametinib significantly sensitizes ABCB1-medidated MDR cancer cells to chemotherapeutic agents in vitro and in vivo by directly antagonizing the drug-efflux activity of ABCB1
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