title: Homoharringtonine and SAHA synergistically enhance apoptosis in human acute myeloid leukemia cells through upregulation of TRAIL and death receptors.
abstract: Single‑agent histone deacetylase (HDAC) inhibitors have exhibited marked antileukemic activity in preclinical and clinical studies and have undergone trials in combination with standard chemotherapeutics. However, the mechanisms of action of combination therapies are not completely understood. In the present study, a novel strategy for treatment of acute myeloid leukemia (AML) was identified, in which the chemotherapeutic agent, homoharringtonine (HHT), was combined with suberoylanilide hydroxamic acid (SAHA), a pan‑HDAC inhibitor. A synergistic effect was observed when HHT was added to SAHA to induce apoptosis in Kasumi‑1 and THP‑1 leukemia cells. This combination was found to significantly enhance the activation of caspase‑8 and ‑9 compared with treatment with each drug separately. Notably, while SAHA induced upregulation of death receptor 4 (DR4) and DR5, HHT upregulated tumor necrosis factor‑related apoptosis-inducing ligand (TRAIL) expression in a dose‑dependent manner. In addition, the synergistic effect between HHT and SAHA was blocked partially using a specific anti‑TRAIL antibody. The combination therapy was also found to significantly inhibit the growth of leukemia xenografts in vivo with enhanced apoptosis. These results indicate that, by regulating the induction of TRAIL and activation of the TRAIL apoptotic pathway, it is possible to administer HHT at low concentrations in combination with SAHA as an effective therapeutic approach for the treatment of AML.
authors.affiliation: Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zheijiang 310003, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Cao
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Cheng
authors.forename: Liangshun
authors.initials: L
authors.lastname: You
authors.forename: Jiejing
authors.initials: J
authors.lastname: Qian
authors.forename: Wenbin
authors.initials: W
authors.lastname: Qian
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006248:Harringtonines / Q000494:pharmacology* / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000077863:Homoharringtonine; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D053218:Receptors, Death Domain / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014183:Transplantation, Heterologous; D000077337:Vorinostat
chemical_list: D006248:Harringtonines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077337:Vorinostat; D000077863:Homoharringtonine; D053181:Caspase 8; D053453:Caspase 9