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One of the major problems being faced by researchers and clinicians in leukemic treatment is the development of multidrug resistance (MDR) which restrict the action of several tyrosine kinase inhibitors (TKIs). MDR is a major obstacle to the success of cancer chemotherapy. The mechanism of MDR involves active drug efflux transport of ABC superfamily of proteins such as Pglycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) that weaken the effectiveness of chemotherapeutics and negative impact on the future of anticancer therapy. In this review, the authors aim to provide an overview of various multidrug resistance (MDR) mechanisms observed in cancer cells as well as the various strategies developed to overcome these MDR. Extensive studies have been carried out since last several years to enhance the efficacy of chemotherapy by defeating these MDR mechanisms with the use of novel anticancer drugs that could escape from the efflux reaction, MDR modulators or chemosensitizers, multifunctional nanotechnology, and RNA interference (RNAi) therapy.

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Imatinib has been the first and most successful tyrosine kinase inhibitor (TKI) for chronic myeloid leukemia (CML), but many patients develop resistance to it after a satisfactory response. Glutathione (GSH) metabolism is thought to be one of the factors causing the emergence of imatinib resistance. Since hsa-miR-203a-5p was found to downregulate Bcr-Abl1 oncogene and also a link between this oncogene and GSH metabolism is reported, the present study aimed to investigate whether hsa-miR-203a-5p could overcome imatinib resistance by targeting GSH metabolism in imatinib-resistant CML cells. After the development of imatinib-resistant K562 (IR-K562) cells by gradually exposing K562 (C) cells to increasing doses of imatinib, resistant cells were transfected with hsa-miR-203a-5p (R+203). Thereafter, cell lysates from various K562 cell sets (imatinib-sensitive, imatinib-resistant, and miR-transfected imatinib-resistant K562 cells) were used for GC-MS-based metabolic profiling. L-alanine, 5-oxoproline (also known as pyroglutamic acid), L-glutamic acid, glycine, and phosphoric acid (Pi)—five metabolites from our data, matched with the enumerated 28 metabolites of the MetaboAnalyst 5.0 for the GSH metabolism. All of these metabolites were present in higher concentrations in IR-K562 cells, but intriguingly, they were all reduced in R+203 and equated to imatinib-sensitive K562 cells (C). Concludingly, the identified metabolites associated with GSH metabolism could be used as diagnostic markers.