Afatinib reverses multidrug resistance in ovarian cancer via dually inhibiting ATP binding cassette subfamily B member 1

Oncotarget
Sheng-qi WangGuo-feng Li

Abstract

ABCB1-mediated multidrug resistance (MDR) remains a major obstacle to successful chemotherapy in ovarian cancer. Herein, afatinib at nontoxic concentrations significantly reversed ABCB1-mediated MDR in ovarian cancer cells in vitro (p < 0.05). Combining paclitaxel and afatinib caused tumor regressions and tumor necrosis in A2780T xenografts in vivo. More interestingly, unlike reversible TKIs, afatinib had a distinctive dual-mode action. Afatinib not only inhibited the efflux function of ABCB1, but also attenuated its expression transcriptionally via down-regulation of PI3K/AKT and MAPK/p38-dependent activation of NF-κB. Furthermore, apart from a substrate binding domain, afatinib could also bind to an ATP binding domain of ABCB1 through forming hydrogen bonds with Gly533, Gly534, Lys536 and Ala560 sites. Importantly, mutations in these four binding sites of ABCB1 and the tyrosine kinase domain of EGFR were not correlated with the reversal activity of afatinib on MDR. Given that afatinib is a clinically approved drug, our results suggest combining afatinib with chemotherapeutic drugs in ovarian cancer. This study can facilitate the rediscovery of superior MDR reversal agents from molecular targeted drugs to provide a more effect...Continue Reading

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Citations

Jun 19, 2017·Oncotarget·Ze-Ting YuanPei-Hao Yin
Jun 8, 2018·Current Medicinal Chemistry·Tijana StankovićMilica Pešić
Feb 6, 2016·International Journal of Oncology·Sheng-Qi WangGuo-Feng Li
Jun 8, 2017·Journal of Cellular Biochemistry·Yan ZhangKe-Xin Liu
Apr 5, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Chen-Yang ZhaoZhong-Min Tian
Nov 6, 2017·Archives of Gynecology and Obstetrics·Caihong LiWenjun Guo
May 7, 2021·Frontiers in Pharmacology·Huan XiaoQiu Sun
Apr 16, 2019·ACS Applied Materials & Interfaces·Alexander M CryerAndrew J Thorley

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Methods Mentioned

BETA
xenografts
nuclear translocation
confocal microscopy
transfecting
xenograft
flow cytometry
Assay
PCR
X-ray

Software Mentioned

PROSA
PROCHECK
MOE
CHARMM
ERRAT
Discovery Studio
AMBER
Kodak Molecular Imaging ( MI )
Molecular Operating Environment ( MOE

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