title: Valproic acid synergistically enhances the cytotoxicity of clofarabine in pediatric acute myeloid leukemia cells.
abstract: BACKGROUND
  Acute myeloid leukemia (AML) remains a major therapeutic challenge in pediatric oncology even with intensified cytarabine (ara-C)-based chemotherapy. Therefore, new therapies are urgently needed to improve treatment outcome of this deadly disease. In this study, we evaluated antileukemic interactions between clofarabine (a second-generation purine nucleoside analog) and valproic acid (VPA, a FDA-approved agent for treating epilepsy in both children and adult and a histone deacetylase inhibitor), in pediatric AML.
  
  
  METHODS
  In vitro clofarabine and VPA cytotoxicities of the pediatric AML cell lines and diagnostic blasts were measured by using MTT assays. The effects of clofarabine and VPA on apoptosis and DNA double strand breaks (DSBs) were determined by flow cytometry analysis and Western blotting, respectively. Active form of Bax was measured by Western blotting post-immunoprecipitation.
  
  
  RESULTS
  We demonstrated synergistic antileukemic activities between clofarabine and VPA in both pediatric AML cell lines and diagnostic blasts sensitive to VPA. In contrast, antagonism between the two agents could be detected in AML cells resistant to VPA. Clofarabine and VPA cooperate in inducing DNA DSBs, accompanied by Bax activation and apoptosis in pediatric AML cells.
  
  
  CONCLUSIONS
  Our results document synergistic antileukemic activities of combined VPA and clofarabine in pediatric AML and suggest that this combination could be an alternative treatment option for the disease.
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Chengzhi
authors.initials: C
authors.lastname: Xie
authors.forename: Holly
authors.initials: H
authors.lastname: Edwards
authors.forename: Salvatore B
authors.initials: SB
authors.lastname: Lograsso
authors.forename: Steven A
authors.initials: SA
authors.lastname: Buck
authors.forename: Larry H
authors.initials: LH
authors.lastname: Matherly
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Taub
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
mesh_terms: D000227:Adenine Nucleotides / Q000008:administration & dosage*; D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001087:Arabinonucleosides / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D003561:Cytarabine; D004249:DNA Damage / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000008:administration & dosage*
chemical_list: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D056572:Histone Deacetylase Inhibitors; D003561:Cytarabine; D014635:Valproic Acid; D000077866:Clofarabine