5-Lipooxygenase Antagonist Promotes Tyrosine Kinase Inhibitor Induced Apoptosis And Downregulates Multidrug Resistance In Chronic Myeloid Leukemia Cells

Abstract

The first tyrosine kinase inhibitor (TKI), imatinib, has been utilized successfully in clinical settings to treat chronic myeloid leukaemia (CML).However, most patients develop TKI-resistance. Herein we investigate the effect of combining zileuton and imatinib on enhancing imatinib therapeutic potential and overcoming cancer cells resistance. K562 CML cells were assigned into four groups: Group (1) untreated cells. Group (2) cells treated with zileuton. Group (3) cells treated with imatinib and Group (4) cells treated with zileuton followed by imatinib. Cell cytotoxicity was determined by MTT assay, cell cycle arrest was analysed by flow cytometry and apoptotic and drug resistance genes expression were carried out by real-time PCR. Administration of zileuton and/or imatinib induced cytotoxic effect on K562 CML cells and combined therapy resulted in higher cytotoxic effect than single drug administration. The combination index for all combinations being less than one indicated synergistic effect between zileuton and imatinib against CML cells and decreased proliferation by inducing cell cycle arrest at the G2/M phase. Zileuton enhanced the anticancer effect of imatinib through triggering apoptotic genes caspase 3 and p53, curbing antiapoptotic Bcl2 gene expression, and downregulating multi drug resistance gene MDR1 and MAPK1.  Co-administration of zileuton may be an effective method to promote the cytotoxic antitumor effects of imatinib on chronic myeloid leukemia cells.