Lu Ziyuan, Xu Na, He Bolin, Pan Chengyun, Lan Yangqing, Zhou Hongsheng, Liu Xiaoli
Department of Hematology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Da Dao North, Guangzhou, 510515, China.
J Exp Clin Cancer Res. 2017 Mar 10;36(1):43. doi: 10.1186/s13046-017-0512-6.
Drug 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.
We 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.
Tigecycline 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.
Combining tigecycline use with autophagy inhibition is a promising approach for overcoming drug resistance in CML treatment.
耐药性和疾病进展仍然是慢性粒细胞白血病（CML）治疗中的主要障碍。越来越多的研究表明，癌细胞在接受化疗时自噬会被激活，这与耐药性的产生有关。因此，将化疗与自噬抑制相结合是癌症治疗的一种新策略。替加环素是一种抗生素，由于其对线粒体翻译的抑制作用而作为抗癌药物受到关注。然而，替加环素与自噬抑制联合使用是否能克服CML的耐药性仍不清楚。
我们分析了替加环素对CML原代细胞和细胞系的生物学和代谢作用，以研究替加环素是否能调节CML细胞中的自噬，以及将自噬抑制与替加环素治疗相结合是否会影响药物敏感和耐药CML细胞的活力。
替加环素抑制了CML原代细胞和细胞系的活力，包括耐药细胞系。这是通过抑制线粒体生物合成和扰乱细胞代谢而发生的，从而导致细胞凋亡。此外，替加环素通过下调PI3K-AKT-mTOR通路诱导自噬。此外，将替加环素与自噬抑制联合使用进一步增强了替加环素的抗白血病活性。我们还观察到替加环素的抗白血病作用具有选择性。这是因为该药物靶向白血病细胞而非正常细胞，这是由于两种细胞类型之间线粒体生物合成和代谢特征的差异。
将替加环素与自噬抑制联合使用是克服CML治疗中耐药性的一种有前景的方法。
