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Multidrug Resistance Lab Report

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Introduction Multidrug resistance (MDR) is one of the major issues to be addressed in treating many diseases including cancers. One of the well-established causes for the multidrug resistance involves over expression of members of ATP binding cassette (ABC) proteins 1. The transporters play a key role in drug availability, metabolism and toxicity. Imatinib mesylate, a tyrosine kinase inhibitor, is a successful chemotherapeutic drug for the treatment of chronic myeloid leukemia (CML). However, resistance to imatinib therapy is frequently encountered in patients during the treatment and the resistance development is attributed to multiple drug efflux ABC transporters 2-4. Three major groups of ABC transporters are involved in multidrug …show more content…
In most tissues, COX-1 is expressed constitutively, whereas COX-2 is induced by growth factors, cytokines, and carcinogens. Epidemiologic and experimental studies have shown that COX-2 inhibitors are effective chemopreventive agents, reducing the risks of many types of tumors, including breast, colon, lung, prostate, and gastric cancers 10-12. Recently, COX-2 inhibitors have also gained attention, either alone or in combination with other chemotherapeutic agents and/or radiation therapy, in the treatment of cancer 13. For example, Celecoxib, a COX-2-selective inhibitor, exerted antitumor effects in a wide variety of cancers …show more content…
There was a significant increase in Ras, p-Raf, p-Mek, p-Erk and CREB proteins in IR-K562 cells indicating activation of the Ras pathway leading to downstream cell survival and cell proliferation signal transduction. However, celecoxib and imatinib treated IR-K562 cells showed down regulation of all these proteins.
We have further studied the Wnt-signaling pathway involving GSK3β, β-catenin, LEF-1 and TCF-4 by immunoblot and qPCR. The results were similar to that of Ras-Raf pathway where the combinatorial treatment of celecoxib and imatinib down regulated activated Wnt signaling pathway in IR-K562 cells. The results of the study clearly demonstrate that COX-2 regulates the expression of various ABC transporters by multiple pathways and that the combinatorial treatment of celecoxib and imatinib help in the reversal of imatinib resistance caused due to the overexpression of efflux pumps. The treatment strategy of the combinatorial treatment using celecoxib would be effective since multiple efflux pumps are downregulated via different signaling

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