PXR-mediated P-glycoprotein induction by small molecule tyrosine kinase inhibitors
PXR-mediated P-glycoprotein induction by small molecule tyrosine kinase inhibitors
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DOI：
10.1016/j.ejps.2012.12.019
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发表时间：
2013-03-12
影响因子：
4.6
通讯作者：
Schellens, J. H. M.
中科院分区：
文献类型：
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作者：
Harmsen, S.;Meijerman, I.;Schellens, J. H. M.
由于暴露于小分子酪氨酸激酶抑制剂（TKI）而导致的耐药性的快速发展是这些药物在临床中成功使用的重要缺点。尽管细胞对抗癌药物产生耐药性的最既定机制之一是P-糖蛋白（PGP）等药物外排转运蛋白的上调，但目前尚不清楚TKI是否有诱导PGP的倾向。用临床相关浓度的TKI处理LS 180细胞后，评估TKI对PGP蛋白表达和活性的影响。此外，参与的核甾烷X受体（PXR），一个已知的调节PGP的表达，进行了测定。在9种受试TKI中，至少有5种（厄洛替尼、吉非替尼、尼洛替尼、索拉非尼、凡德他尼）能够在48 h内诱导LS 180细胞中PGP的表达。因此，这些TKI也显示会影响P-糖蛋白特异性探针底物的蓄积。此外，我们还发现，作为PGP诱导的重要调节因子，胆甾烷X受体（PXR）参与了暴露于这些TKI后PGP蛋白表达的上调。我们的数据表明，PXR介导的TKI上调PGP表达可能是癌细胞获得性耐药的潜在机制。(C)2013爱思唯尔有限公司版权所有。
The rapid development of drug resistance as a result of exposure to small molecule tyrosine kinase inhibitors (TKIs) is an important drawback to the successful use of these agents in the clinic. Although one of the most established mechanisms by which cells acquire drug resistance to anticancer drugs is the up regulation of drug efflux transporters such as P-glycoprotein (PGP), it is currently still unknown whether TKIs have the propensity to induce PGP. The effect of TKIs on the protein expression and activity of PGP was assessed after treatment of LS180 cells with clinically relevant concentrations of the TKIs. In addition, the involvement of the nuclear pregnane X receptor (PXR), a known regulator of PGP expression, was determined. At least five out of the nine tested TKIs (erlotinib, gefitinib, nilotinib, sorafenib, vandetanib) were able to induce the expression of PGP within 48 h in LS180 cells. Accordingly, these TKIs were also shown to affect the accumulation of a P-glycoprotein specific probe substrate. Furthermore, we showed that the pregnane X receptor (PXR), which is an important regulator of PGP induction, is involved in the upregulation of PGP protein expression following exposure to these TKIs. Our data show that PXR-mediated upregulation of PGP expression by TKIs might be a possible mechanism underlying acquired drug resistance in cancer cells. (C) 2013 Elsevier B.V. All rights reserved.