Celecoxib sensitizes imatinib-resistant K562 cells to imatinib by inhibiting MRP1-5, ABCA2 and ABCG2 transporters via Wnt and Ras signaling pathways.
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.
Department of Biotechnology, Sri Krishnadevaraya University, Anantapuramu 515003, A.P., India.
Gangappa
G
Dharmapuri
Department of Animal Biology, University of Hyderabad, Hyderabad 500046, Telangana, India.
Ravinder
R
Doneti
Department of Biotechnology, Sri Krishnadevaraya University, Anantapuramu 515003, A.P., India.
Gundala Harold
GH
Philip
Department of Animal Biology, University of Hyderabad, Hyderabad 500046, Telangana, India. Electronic address: arunasreemk@uohyd.ac.in.
Arunasree M
AM
Kalle
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D001483:Base Sequence; D001549:Benzamides / Q000494:pharmacology*; D000068579:Celecoxib; D017931:DNA Primers; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
C418186:ABCA2 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D017931:DNA Primers; D009363:Neoplasm Proteins; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; D051153:Wnt Proteins; D000068877:Imatinib Mesylate; D018631:ras Proteins; D000068579:Celecoxib
ABC transporters; Celecoxib; Chronic myeloid leukemia (CML); Cyclooxygenase-2 (COX-2); Imatinib mesylate