Interaction of Tyrosine Kinase Inhibitors with the MDR-Related ABC Transporter Proteins

Wang, Xiao Kun; Li, Fu

doi:10.2174/138920010792927316

Cited by 42 publications

(30 citation statements)

References 128 publications

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“…The broad or polyspecificity of P-gp is legendary (or infamous), and the list of compounds known to interact with this transporter is well in excess of 300 (Wang et al, 2011;. It is apparent that many of the much touted "new generation" anticancer compounds (e.g., kinase inhibitors) are also substrates for transport by P-gp (Hegedus et al, 2002;Wang and Fu, 2010). There is a clear need to generate compounds, or strategies, to overcome the actions of P-gp in 1) limiting the effectiveness of chemotherapy in cancer and 2) influencing the pharmacokinetic profile of a vast number of clinically prescribed drugs.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy?

2014

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P-glycoprotein (P-gp) is a key player in the multidrug-resistant phenotype in cancer. The protein confers resistance by mediating the ATP-dependent efflux of an astonishing array of anticancer drugs. Its broad specificity has been the subject of numerous attempts to inhibit the protein and restore the efficacy of anticancer drugs. The general strategy has been to develop compounds that either compete with anticancer drugs for transport or act as direct inhibitors of P-gp. Despite considerable in vitro success, there are no compounds currently available to "block" P-gp-mediated resistance in the clinic. The failure may be attributed to toxicity, adverse drug interaction, and numerous pharmacokinetic issues. This review provides a description of several alternative approaches to overcome the activity of P-gp in drug-resistant cells. These include 1) drugs that specifically target resistant cells, 2) novel nanotechnologies to provide high-dose, targeted delivery of anticancer drugs, 3) compounds that interfere with nongenomic transfer of resistance, and 4) approaches to reduce the expression of P-gp within tumors. Such approaches have been developed through the pursuit of greater understanding of resistance mediators such as P-gp, and they show considerable potential for further application.

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Section: Introductionmentioning

confidence: 99%

Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy?

2014

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“…In recent years, TKIs have been identified as inhibitors of several ATP-binding cassette (ABC) efflux transporters that are commonly upregulated in cancer cells including P-glycoprotein (multidrug resistance protein 1), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein (MRP) 1 [10][11][12][13][14][15][16][17][18]. ABC efflux transporters consist of a large family of membrane-spanning proteins involved in the active extrusion of substrates such as endogenous molecules, drugs, and drug metabolites from the cell through hydrolysis of ATP [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

et al. 2016

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Tyrosine and aurora kinases are important effectors in signal transduction pathways that are often involved in aberrant cancer cell growth. Tyrosine (TKI) and aurora (AKI) kinase inhibitors are anti-cancer MRP4: alisertib, danusertib, erlotinib, lapatinib, neratinib, nilotinib, pazopanib, sorafenib, and tozasertib. The potentially clinically relevant inhibition of BCRP was much more extensive and included alisertib, barasertib, danusertib, enzastaurin, erlotinib, gefitinib, imatinib, neratinib, nilotinib, pazopanib, selumetinib, sorafenib, sunitinib, tozasertib, and vandetanib Keywords ABC transporters; transport inhibition ADMET & DMPK 4(4) (2016) 302-313TKIs and AKIs diminish transport of function of MRP4 and BCRP

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“…A large number of TKIs targeting different oncogenic signaling pathways have been developed, and are currently used in the clinic or being tested in clinical trials. Interestingly, it has been reported that several TKIs, such as gefitinib, imatinib, and lapatinib can interact with ABCG2, thereby inhibiting its drug transport activity and enhancing the anticancer efficacy of conventional chemotherapeutic agents (4). Importantly, various recent studies have reported favorable clinical outcome by combining TKIs with conventional cytotoxic agents or monoclonal antibody in cancer chemotherapy (5,6).…”

Section: Introductionmentioning

confidence: 99%

Afatinib Enhances the Efficacy of Conventional Chemotherapeutic Agents by Eradicating Cancer Stem–like Cells

Wang

et al. 2014

Cancer Research

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Cancer stem cells (CSC) have garnered significant attention as a therapeutic focus, based on evidence that they may represent an etiologic root of treatment-resistant cells. Indeed, expression of the multidrug resistance protein ATP-binding cassette subfamily G member 2 (ABCG2) confers chemoresistance to CSCs, where it serves as a potential biomarker and therapeutic target. Here, we show that afatinib, a small-molecule inhibitor of the tyrosine kinases EGFR, HER2, and HER4, preferentially eliminated side population cells with CSC character, in both cell lines and patient-derived leukemia cells, by decreasing ABCG2 expression. In these cells, afatinib also acted in parallel to suppress self-renewal capacity and tumorigenicity. Combining afatinib with the DNA-damaging drug topotecan enhanced the antitumor effect of topotecan in vitro and in vivo. Mechanistic investigations suggested that ABCG2 suppression by afatinib did not proceed by proteolysis through the ubiquitin-dependent proteosome, lysosome, or calpain. Instead, we found that afatinib increased DNA methyltransferase activity, thereby leading to methylation of the ABCG2 promoter and to a decrease in ABCG2 message level. Taken together, our results advocate the use of afatinib in combination with conventional chemotherapeutic drugs to improve efficacy by improving CSC eradication. Cancer Res; 74(16); 4431-45. Ó2014 AACR.

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Interaction of Tyrosine Kinase Inhibitors with the MDR-Related ABC Transporter Proteins

Cited by 42 publications

References 128 publications

Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy?

Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy?

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

Afatinib Enhances the Efficacy of Conventional Chemotherapeutic Agents by Eradicating Cancer Stem–like Cells

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