Tigecycline and homoharringtonine synergistically target myeloid leukemia cells by inhibiting mitochondrial translation through mTOR/4EBP1 pathway

Abstract BackgroundTigecycline (TIG) is a tetracycline derivative antibiotic. Successive studies have shown that TIG is efficacious for the treatment of some solid tumors and hematological malignant diseases both in vivo and in vitro, and drug combinations appear to provide better inhibition. To explore new drug combinations for myeloid leukemia, we compared the differential combination efficacy of TIG with several anti-leukemia drugs, and explored the mechanisms of the combination of TIG and homoharringtonine (HHT) in myeloid leukemia cells both in vitro and in vivo.MethodsCell proliferation was assessed using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyph-enyl)-2-(4-sulfophenyl)-2H-tetrazolium) and CFU-GM (colony forming unit-granulocyte and macrophage) assays. Apoptosis was detected by flow cytometry. The combination of effects was confirmed in myeloid leukemia cells and tumor-bearing mouse model. The regulation of the AKT/mTOR (mammalian target of rapamycin)/4EBP1 (eukaryotic translation initiation factor 4E binding protein 1) pathway was assessed using a Western blot and immunohistochemistry.ResultsThe combination of TIG and HHT had a strong synergistic effect in myeloid leukemia cells. The use of the drug combination in vivo also effectively delayed myeloid tumor development in mice. The synergistic effect of this drug combination is likely to be achieved by inhibiting mitochondrial translation and down-regulating the AKT/mTOR/4EBP1 signaling pathway. Conclusion: The combination of TIG and HHT can synergistically enhance an anti-leukemia effect through downregulating anti-apoptotic proteins. Inhibiting mitochondrial translation through the AKT/mTOR/4EBP1 pathway might be an important mechanism.