Novel pharmacological approach for the prevention of multidrug resistance (MDR) in a human leukemia cell line

• Published in: Leukemia research Vol. 109; p. 106641
• Main Authors: Gupta, Sonu Kumar, Singh, Priyanka, Chhabra, Ravindresh, Verma, Malkhey
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.10.2021
• Subjects: Bcr-Abl1; Chronic Myeloid Leukemia; Drug efflux pumps; Imatinib Mesylate; Maybridge compounds; RT-qPCR; Maybridge compounds; Bcr-Abl1; Chronic Myeloid Leukemia; Drug efflux pumps; Imatinib Mesylate; RT-qPCR
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2021.106641

•Multi drug resistance is a major obstacle to the success of cancer chemotherapy.•The mechanism of MDR involves active drug efflux transport by P-gp/ABCB1, MRP2/ABCC2 and BCRP/ABCG2 genes.•The drug efflux adversely effect chemotherapeutics and impart negative impact on the future of anticancer therapy.•The MBFs treatment with optimal dose of imatinib induced apoptosis of K562 cells.•MBFs assured the reduced efflux of imatinib through downregulating the drug efflux genes. Drug resistance mechanisms are the regulatory factors associated with drug metabolism and drug transport to inward and outward of the target cells. Maybridge fragment (MBF) library is a collection of pharmacophore rich compounds having affinity with membrane transporters. This study has been designed to evaluate the efficacy of MBFs in overcoming the leukemic cells’ resistance to imatinib. Imatinib resistant cells (K562-R) were prepared using myelogenous leukemia cell line (K562) by titration method. The four MBFs were prioritized for determining their effect on imatinib resistance. The cells were treated with imatinib and MBFs and the MTT assay was performed to evaluate the efficacy of MBFs in enhancing the imatinib mediated cell death. The transcript levels of Bcr-Abl1 gene and efflux transporter genes were determined by RT-qPCR analysis. The MBFs enhanced the imatinib mediated cell death of K562-R cells. There was also a significant decrease in the mRNA levels of the major drug efflux genes (ABCB1, ABCB10, ABCC1 and ABCG2) when treated with a combination of imatinib and MBF in comparison to imatinib treatment alone. The drug efflux is one of the mechanisms of multidrug resistance in cancer cells and the MBFs used in this study were all found to significantly overcome the imatinib resistance by limiting the expression of efflux genes. This study, therefore, highlights the potential of Maybridge compounds in treating the drug resistant leukemia.