Dharmapuri Gangappa, Doneti Ravinder, Philip Gundala Harold, Kalle Arunasree M
Department of Biotechnology, Sri Krishnadevaraya University, Anantapuramu 515003, A.P., India.
Department of Animal Biology, University of Hyderabad, Hyderabad 500046, Telangana, India.
Leuk Res. 2015 Jul;39(7):696-701. doi: 10.1016/j.leukres.2015.02.013. Epub 2015 Apr 6.
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 K562 cells (IR-K562) via PGE2-cAMP-PKC-NF-κB 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.
甲磺酸伊马替尼是一种酪氨酸激酶抑制剂，在治疗慢性髓性白血病（CML）方面非常有效。然而，长期使用该药物时，对伊马替尼治疗产生耐药性也是一种非常常见的机制。我们之前的研究强调了环氧合酶-2（COX-2）在通过PGE2-cAMP-PKC-NF-κB途径调节伊马替尼耐药的K562细胞（IR-K562）中多药耐药蛋白-1（MDR1）即P-糖蛋白（P-gp）表达方面的作用，并且COX-2特异性抑制剂塞来昔布对COX-2的抑制可抑制该途径并逆转耐药性。研究已确定，不仅MDR1，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的发生。在此，我们试图研究COX-2在调节其他已被证明与伊马替尼耐药发生有关的ABC转运蛋白如MRP1、MRP2、MRP3、ABCA2和ABCG2中的作用。该研究结果清楚地表明，COX-2的过表达导致IR-K562细胞中MRP家族蛋白上调，而塞来昔布通过Wnt和MEK信号通路下调ABC转运蛋白。该研究表明，塞来昔布与伊马替尼联合使用可能是逆转伊马替尼耐药性的一种良好替代治疗策略。
