title: Inhibition of autophagy enhances the selective anti-cancer activity of tigecycline to overcome drug resistance in the treatment of chronic myeloid leukemia.
abstract: 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.
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Da Dao North, Guangzhou, 510515, China.
authors.forename: Ziyuan
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Da Dao North, Guangzhou, 510515, China.
authors.forename: Na
authors.initials: N
authors.lastname: Xu
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Da Dao North, Guangzhou, 510515, China.
authors.forename: Bolin
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Da Dao North, Guangzhou, 510515, China.
authors.forename: Chengyun
authors.initials: C
authors.lastname: Pan
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Da Dao North, Guangzhou, 510515, China.
authors.forename: Yangqing
authors.initials: Y
authors.lastname: Lan
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Da Dao North, Guangzhou, 510515, China.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Da Dao North, Guangzhou, 510515, China. lxl2405@126.com.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
mesh_terms: D001343:Autophagy / Q000187:drug effects; D000071183:Autophagy-Related Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D008911:Minocycline / Q000031:analogs & derivatives* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000078304:Tigecycline
chemical_list: D000071183:Autophagy-Related Proteins; D008911:Minocycline; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000078304:Tigecycline; C546842:MTOR protein, human
keywords: Autophagy; Chronic myeloid leukemia; Drug resistance; Energy metabolism; Mitochondrial biogenesis; Tigecycline