VS-4718 Antagonizes Multidrug Resistance in ABCB1- and ABCG2-Overexpressing Cancer Cells by Inhibiting the Efflux Function of ABC Transporters
Overexpression of ATP-binding cassette (ABC) transporters is one of the most important mechanisms responsible for multi-drug resistance (MDR). VS-4718, a tyrosine kinase inhibitor targeting focal adhesion kinase (FAK) with a potential anticancer effect, is currently evaluated in clinical trials. In...
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Frontiers Media S.A.,
2018-10-01T00:00:00Z.
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|---|---|---|---|
| 001 | doaj_4f13e3c1a96b4ec4b366ac3ebd9bb4c0 | ||
| 042 | |a dc | ||
| 100 | 1 | 0 | |a Ning Ji |e author |
| 700 | 1 | 0 | |a Ning Ji |e author |
| 700 | 1 | 0 | |a Yuqi Yang |e author |
| 700 | 1 | 0 | |a Chao-Yun Cai |e author |
| 700 | 1 | 0 | |a Zi-Ning Lei |e author |
| 700 | 1 | 0 | |a Jing-Quan Wang |e author |
| 700 | 1 | 0 | |a Pranav Gupta |e author |
| 700 | 1 | 0 | |a Qiu-Xu Teng |e author |
| 700 | 1 | 0 | |a Zhe-Sheng Chen |e author |
| 700 | 1 | 0 | |a Dexin Kong |e author |
| 700 | 1 | 0 | |a Dong-Hua Yang |e author |
| 245 | 0 | 0 | |a VS-4718 Antagonizes Multidrug Resistance in ABCB1- and ABCG2-Overexpressing Cancer Cells by Inhibiting the Efflux Function of ABC Transporters |
| 260 | |b Frontiers Media S.A., |c 2018-10-01T00:00:00Z. | ||
| 500 | |a 1663-9812 | ||
| 500 | |a 10.3389/fphar.2018.01236 | ||
| 520 | |a Overexpression of ATP-binding cassette (ABC) transporters is one of the most important mechanisms responsible for multi-drug resistance (MDR). VS-4718, a tyrosine kinase inhibitor targeting focal adhesion kinase (FAK) with a potential anticancer effect, is currently evaluated in clinical trials. In this study, we investigated whether VS-4718 could reverse MDR mediated by ABC transporters, including ABCB1, ABCG2, and ABCC1. The results showed that VS-4718 significantly reversed ABCB1- and ABCG2-mediated MDR, but not MDR mediated by ABCC1. Treatment of VS-4718 did not alter the protein level and subcellular localization of ABCB1 or ABCG2. Mechanism studies indicated that the reversal effects of VS-4718 were related to attenuation of the efflux activity of ABCB1 and ABCG2 transporters. ATPase analysis indicated that VS-4718 stimulated the ATPase activity of ABCB1 and ABCG2. Docking study showed that VS-4718 interacted with the substrate-binding sites of both ABCB1 and ABCG2, suggesting that VS-4718 may affect the activity of ABCB1 and ABCG2 competitively. This study provided a novel insight for MDR cancer treatment. It indicated that combination of VS-4718 with antineoplastic drugs could attenuate MDR mediated by ABCB1 or ABCG2 in ABCB1- or ABCG2-overexpressing cancer cells. | ||
| 546 | |a EN | ||
| 690 | |a VS-4718 | ||
| 690 | |a multidrug resistance (MDR) | ||
| 690 | |a ATP-binding cassette (ABC) transporter | ||
| 690 | |a P-glycoprotein (P-gp/ABCB1) | ||
| 690 | |a breast cancer resistance protein (BCRP/ABCG2) | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Frontiers in Pharmacology, Vol 9 (2018) | |
| 787 | 0 | |n https://www.frontiersin.org/article/10.3389/fphar.2018.01236/full | |
| 787 | 0 | |n https://doaj.org/toc/1663-9812 | |
| 856 | 4 | 1 | |u https://doaj.org/article/4f13e3c1a96b4ec4b366ac3ebd9bb4c0 |z Connect to this object online. |