Reversal Of Imatinib Resistance In Chronic Myeloid Leukemia Cells By Recombinant Mutant Human Tumor Necrosis Factor-related Apoptosis-inducing Ligand

Objective: Multidrug resistance is still the main cause of chemotherapy failure in myeloid leukemia.To study the effect of recombinant allosteric human tumor necrosis factor-related apoptosis inducing ligand(CPT)on Eph B4 gene and Mcl-1 gene in bone marrow cells of human chronic myeloid leukemia,and to further explore the mechanism of CPT reversing imatinib resistance of chronic myeloid leukemia.Methods: Leukemia monocytes were extracted from bone marrow cells of CML patients,and then the target genes Eph B4 and Mcl-1 were extracted from leukemia monocytes.The WB method was used to detect the protein expression changes of Eph B4 and Mcl-1 genes in CML patients’ bone marrow cells,and the CCK8 method was used to detect the changes of IM resistance of CML bone marrow cells.The nude mice model of drug-resistant K562-R cell line was established,and the changes of body weight and transplanted tumor volume were detected,and the survival time of nude mice treated with different drugs was compared.Results: Compared with the newly treated cells,Eph B4 and Mcl-1 protein were overexpressed in the refractory cells with IM resistance.The resistance of refractory cells to IM(IC50 = 5.36±0.62 mg/l)was significantly higher than that of newly treated cells(IC50 = 0.17±0.016 mg/l)(p < 0.001).The expression of Eph B4 and Mcl-1 in refractory-CPT cells after CPT treatment was significantly lower than that in untreated refractory cells,and IC50 value of refractory-CPT cells decreased to 1.270.16mg/l(p < 0.001).The relative tumor volume(RTV)of transplanted tumor in IM+CPT group was 4.17±0.54,which was significantly lower than that in IM group8.15±0.86(P < 0.05).The mean weight of tumor-bearing mice in IM+CPT group was22.95±0.09 g after 12 days,which was slightly higher than that in d1 21.33±0.26g(P <0.05),while that in IM group was 20.65±0.20 g after 12 days,which was slightly lower than that in d1 21.24±0.33g(P < 0.05).The mean survival time of nude mice in IM+CPT group was 19.33±2.05 days,which was significantly higher than that in IM group(13.33±1.25 days)(P<0.05).Conclusion: CPT can reverse the drug resistance of drug-resistant chronic myeloid leukemia cells.It can make IM therapy superior by inhibiting Eph B4/Mcl-1 pathway.