Abstract
BackgroundDrug resistance and disease progression are still the major obstacles in the treatment of chronic myeloid leukemia (CML). Increasing researches have demonstrated that autophagy becomes activated when cancer cells are subjected to chemotherapy, which is involved in the development of drug resistance. Therefore, combining chemotherapy with inhibition of autophagy serves as a new strategy in cancer treatment. Tigecycline is an antibiotic that has received attention as an anti-cancer agent due to its inhibitory effect on mitochondrial translation. However, whether combination of tigecycline with inhibition of autophagy could overcome drug resistance in CML remains unclear.MethodsWe analyzed the biological and metabolic effect of tigecycline on CML primary cells and cell lines to investigate whether tigecycline could regulate autophagy in CML cells and whether coupling autophagy inhibition with treatment using tigecycline could affect the viabilities of drug-sensitive and drug-resistant CML cells.ResultsTigecycline inhibited the viabilities of CML primary cells and cell lines, including those that were drug-resistant. This occurred via the inhibition of mitochondrial biogenesis and the perturbation of cell metabolism, which resulted in apoptosis. Moreover, tigecycline induced autophagy by downregulating the PI3K-AKT-mTOR pathway. Additionally, combining tigecycline use with autophagy inhibition further promoted the anti-leukemic activity of tigecycline. We also observed that the anti-leukemic effect of tigecycline is selective. This is because the drug targeted leukemic cells but not normal cells, which is because of the differences in the mitochondrial biogenesis and metabolic characterization between the two cell types.ConclusionsCombining tigecycline use with autophagy inhibition is a promising approach for overcoming drug resistance in CML treatment.
Highlights
Drug resistance and disease progression are still the major obstacles in the treatment of chronic myeloid leukemia (CML)
Tigecycline reduced the viabilities of the primary CML cells and cell lines Initially, we determined whether tigecycline could inhibit the viability of CML cells
The inhibitory effects of tigecycline were observed in primary CML cells obtained from the different patients (Fig. 1b, d)
Summary
Drug resistance and disease progression are still the major obstacles in the treatment of chronic myeloid leukemia (CML). Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm companied with the BCR-ABL fusion gene, which is encoded by the Philadelphia chromosome [1]. Other tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib have a higher anti-leukemic activity and are associated with fewer side effects. Acquired resistance to TKIs is one of the main obstacles to effective CML treatment and is involved in gene amplification of ABL tyrosine kinase point mutations [4]. Patients with these ABL tyrosine kinase point mutations generally have a poor prognosis and a higher mortality rate
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