Celecoxib sensitizes imatinib-resistant K562 cells to imatinib by inhibiting MRP1-5, ABCA2 and ABCG2 transporters via Wnt and Ras signaling pathways
Celecoxib sensitizes imatinib-resistant K562 cells to imatinib by inhibiting MRP1-5, ABCA2 and ABCG2 transporters via Wnt and Ras signaling pathways
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DOI：
10.1016/j.leukres.2015.02.013
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发表时间：
2015-07-01
影响因子：
2.7
通讯作者：
Kalle, Arunasree M.
中科院分区：
文献类型：
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作者：
Dharmapuri, Gangappa;Doneti, Ravinder;Kalle, Arunasree M.
甲磺酸伊马替尼是一种酪氨酸激酶抑制剂，治疗慢性粒细胞白血病（CML）非常有效。然而，对伊马替尼治疗产生耐药性也是长期给药观察到的一种非常常见的机制。我们的前期研究发现环氧合酶-2（cyclooxygenase-2，考克斯-2）通过PGE 2-cAMP-PKC-NF-κ B途径调节伊马替尼耐药1（562）细胞的多药耐药蛋白1（multidrug resistant protein-1，MDR 1）P-gp的表达，而塞来昔布（celecoxib）是考克斯-2的特异性抑制剂。研究发现，不仅MDR 1，而且其他ATP结合盒转运蛋白（ABC转运蛋白）也参与了伊马替尼耐药性的发展。在此，我们试图研究考克斯-2在调节其他ABC转运蛋白如MRP 1、MRP 2、MRP 3、ABCA 2和ABCG 2中的作用，这些转运蛋白已经与伊马替尼耐药性的发展有关。研究结果清楚地表明，考克斯-2过表达导致MRP家族蛋白在IR-K562细胞中上调，塞来昔布通过Wnt和MEK信号通路下调ABC转运蛋白。该研究表明，塞来昔布联合伊马替尼可以成为逆转伊马替尼耐药的良好替代治疗策略。(C)2015爱思唯尔有限公司版权所有。
Imatinib mesylate, a tyrosine kinase inhibitor, is very effective in the treatment of chronic myeloid leukemia (CML). However, development of resistance to imatinib therapy is also a very common mechanism observed with long-term administration of the drug. Our previous studies have highlighted the role of cyclooxygenase-2 (COX-2) in regulating the expression of multidrug resistant protein-1 (MDR1), P-gp, in imatinib-resistant 1(562 cells (IR-K562) via PGE2-cAMP-PKC-NF-kappa B pathway and inhibition of COX-2 by celecoxib, a COX-2 specific inhibitor, inhibits this pathway and reverses the drug resistance. Studies have identified that not only MDR1 but other ATP-binding cassette transport proteins (ABC transporters) are involved in the development of imatinib resistance. Here, we tried to study the role of COX-2 in the regulation of other ABC transporters such as MRP1, MRP2, MRP3, ABCA2 and ABCG2 that have been already implicated in imatinib resistance development. The results of the study clearly indicated that overexpression of COX-2 lead to upregulation of MRP family proteins in IR-K562 cells and celecoxib down-regulated the ABC transporters through Wnt and MEK signaling pathways. The study signifies that celecoxib in combination with the imatinib can be a good alternate treatment strategy for the reversal of imatinib resistance. (C) 2015 Elsevier Ltd. All rights reserved.