title: Inhibition of histone deacetylases 1 and 6 enhances cytarabine-induced apoptosis in pediatric acute myeloid leukemia cells.
abstract: BACKGROUND
  Pediatric acute myeloid leukemia (AML) remains a challenging disease to treat even with intensified cytarabine-based chemotherapy. Histone deacetylases (HDACs) have been reported to be promising therapeutic targets for treating AML. However, HDAC family members that are involved in chemotherapy sensitivities remain unknown. In this study, we sought to identify members of the HDAC family that are involved in cytarabine sensitivities, and to select the optimal HDACI that is most efficacious when combined with cytarabine for treating children with AML.
  
  
  METHODS
  Expression profiles of classes I, II, and IV HDACs in 4 pediatric AML cell lines were determined by Western blotting. Inhibition of class I HDACs by different HDACIs was measured post immnunoprecipitation. Individual down-regulation of HDACs in pediatric AML cells was performed with lentiviral shRNA. The effects of cytarabine and HDACIs on apoptosis were determined by flow cytometry analysis.
  
  
  RESULTS
  Treatments with structurally diverse HDACIs and HDAC shRNA knockdown experiments revealed that down-regulation of both HDACs 1 and 6 is critical in enhancing cytarabine-induced apoptosis in pediatric AML, at least partly mediated by Bim. However, down-regulation of HDAC2 may negatively impact cytarabine sensitivities in the disease. At clinically achievable concentrations, HDACIs that simultaneously inhibited both HDACs 1 and 6 showed the best anti-leukemic activities and significantly enhanced cytarabine-induced apoptosis.
  
  
  CONCLUSIONS
  Our results further confirm that HDACs are bona fide therapeutic targets for treating pediatric AML and suggest that pan-HDACIs may be more beneficial than isoform-specific drugs.
authors.affiliation: Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Xuelian
authors.initials: X
authors.lastname: Xu
authors.forename: Chengzhi
authors.initials: C
authors.lastname: Xie
authors.forename: Holly
authors.initials: H
authors.lastname: Edwards
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Steven A
authors.initials: SA
authors.lastname: Buck
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
mesh_terms: D017668:Age of Onset; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002648:Child; D003561:Cytarabine / Q000008:administration & dosage*; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering; D003561:Cytarabine; C110550:HDAC1 protein, human; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases