Enhanced imatinib uptake through influx transporters and its quantification based on LC-MS/MS in human leukemic cells

Chronic myeloid leukemia (CML) is a slowly progressing cancer of the blood cells that originates in the pluripotent hematopoietic stem cells. It is caused by the reciprocal translocation between chromosomes 9 and 22, which results in the formation of a chimeric chromosome referred to as the ‘Philadelphia (Ph) chromosome’. As per GLOBOCAN 2020, leukemia is the tenth most frequently occurring cancer across the world with an overall mortality rate of 3.1%. Among all the countries, India is ranked third in the incidence as well as mortality associated with leukemia. Tyrosine kinase inhibitors (TKIs) are the standard treatment drugs for CML. However, around 30% of CML patients have been observed to develop resistance against imatinib because of the reduced intracellular availability of the drug. Therefore, the present study was designed to enhance the imatinib import through the use of MayBridge fragment (MBF) compounds. Here we used the previously developed imatinib-resistant leukemia cells (K562-R) for further study. The gene expression analysis revealed that the effect of MBF compounds on imatinib treatment was probably due to the change in the expression of import transporters (OATP1A2 and OCT1). The metabolite profiling carried out by LC-MS/MS confirmed that the intracellular concentration of imatinib did increase in K562-R cells when treated with either of the MBFs and imatinib together in comparison to imatinib treatment alone. These results imply that MBF1 and MBF4 used in this study enhance the imatinib import in K562-R cells by altering the expression of membrane transporters in a better way.