title: Suberoylanilide hydroxamic acid induces hypersensitivity to radiation therapy in acute myelogenous leukemia cells expressing constitutively active FLT3 mutants.
abstract: Histone deacetylase inhibitors (HDIs) have shown promise as candidate radiosensitizer for many types of cancers. However, the mechanisms of action are not well understood, and whether they could have clinical impact on radiotherapy for leukemia is unclear. In this study, we demonstrate that suberoylanilide hydroxamic acid (SAHA) can increase radiosensitivity of acute myeloid leukemia (AML) cells through posttranslational modification of Rad51 protein responses and selective inhibition of the homology-directed repair (HDR) pathway. Our data also showed that AML cells with mutant, constitutively active FMS-like tyrosine kinase-3 (FLT3) were more radiation sensitive, caused by compromised non-homologous end joining (NHEJ) repair. Furthermore, SAHA-induced radiosensitization were enhanced in AML cells with expression of these FLT3 mutants. The results of this study suggest that SAHA, a recently approved HDI in clinical trials, may act as a candidate component for novel conditioning regimens to improve efficacy for AML patients undergoing radiotherapy and chemotherapy.
authors.affiliation: Department of Radiation Oncology, City of Hope Cancer Center, Duarte, California, United States of America ; Department of Radiation Oncology, The First People's Hospital of Hangzhou Medical Group, Hangzhou, Zhejiang, China.
authors.forename: Xufeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, City of Hope Cancer Center, Duarte, California, United States of America.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Radany
authors.affiliation: Department of Radiation Oncology, City of Hope Cancer Center, Duarte, California, United States of America.
authors.forename: Patty
authors.initials: P
authors.lastname: Wong
authors.affiliation: Department of Radiation Oncology, The First People's Hospital of Hangzhou Medical Group, Hangzhou, Zhejiang, China.
authors.forename: Shenglin
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Radiation Oncology, The First People's Hospital of Hangzhou Medical Group, Hangzhou, Zhejiang, China.
authors.forename: Kan
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, The First People's Hospital of Hangzhou Medical Group, Hangzhou, Zhejiang, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, City of Hope Cancer Center, Duarte, California, United States of America.
authors.forename: Jeffrey Y C
authors.initials: JY
authors.lastname: Wong
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D009154:Mutation; D011493:Protein Kinase C / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D000077337:Vorinostat; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: D006877:Hydroxamic Acids; D000077337:Vorinostat; D051941:fms-Like Tyrosine Kinase 3; D011493:Protein Kinase C; D051135:Rad51 Recombinase