title: The histone deacetylase inhibitor SAHA sensitizes acute myeloid leukemia cells to a combination of nucleoside analogs and the DNA-alkylating agent busulfan.
abstract: Fludarabine (Flu), clofarabine (Clo) and busulfan (Bu) are used in allogeneic hematopoietic stem cell transplant (allo-HSCT). We reported that combining [Flu + Clo + Bu] had a synergistic cytotoxicity in AML cells. We hypothesized that combining [Flu + Clo + Bu] with the histone deacetylase inhibitor SAHA will further enhance cytotoxicity. We exposed the acute myeloid leukemia (AML) cell lines KBM3/Bu250(6) and OCI-AML3 to Flu, Clo, Bu and SAHA alone and in various combinations. [Flu + Clo + Bu + SAHA] resulted in synergistic cytotoxicity, which can be attributed to (1) activated DNA-damage response and cell cycle checkpoint activation through the ATM-CHK2-P53 (or P73) pathway or ATM-CHK2-cdc25-cdc2 pathway, (2) histone modifications and (3) activated apoptosis pathway. The [Flu + Clo + Bu + SAHA] combination causes mitochondrial outer membrane permeabilization, leakage of cytochrome c and Smac/Diablo into the cytosol with caspase activation, and release of apoptosis-inducing factor (AIF) into the nucleus resulting in nuclear fragmentation and cell death. These results provide a mechanistic basis for using SAHA in future clinical trials with double nucleoside analog-busulfan combinations in pretransplant conditioning therapy.
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M. D. Anderson Cancer Center , Houston, TX , USA.
authors.forename: Guiyun
authors.initials: G
authors.lastname: Song
authors.forename: Benigno C
authors.initials: BC
authors.lastname: Valdez
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Jose R
authors.initials: JR
authors.lastname: Dominguez
authors.forename: Paul
authors.initials: P
authors.lastname: Corn
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.forename: Borje S
authors.initials: BS
authors.lastname: Andersson
mesh_terms: D000227:Adenine Nucleotides / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001087:Arabinonucleosides / Q000494:pharmacology; D002066:Busulfan / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077866:Clofarabine; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000227:Adenine Nucleotides; D018906:Antineoplastic Agents, Alkylating; D001087:Arabinonucleosides; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000077866:Clofarabine; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine
keywords: AML; DNA alkylator; SAHA; drug cytotoxicity; nucleoside analog