title: Superior activity of a new histone deacetylase inhibitor (ZYJ-34c) in inhibiting growth of human leukemia cells by inducing p21WAF1 expression and cell cycle arrest.
abstract: Histone deacetylase inhibitors are a new class of anticancer agents that inhibit cancer cell proliferation and induce apoptosis and cell cycle arrest in various cancer cells. Recently, we identified ZYJ-34c, a modified histone deacetylase inhibitor that showed significantly higher antitumor activity in vivo than the FDA-approved drug suberoylanilide hydroxamic acid. We aimed to investigate its exact mechanism of action. Activity of ZY-34c against human erythroleukemic (K562) cells, human myeloid leukemia (HL-60) cells, and primary leukemic cells were investigated in vitro using proliferation assays, cell cycle assays, apoptosis assays, RNA interference, promoter acetylation assays, and assays of transcription of related molecules. ZYJ-34c strongly inhibited the proliferation of leukemia cells compared with suberoylanilide hydroxamic acid. Primary leukemic cells isolated from patients with acute myeloid leukemia were more sensitive to ZYJ-34c. The 50% growth-inhibitory concentrations of ZYJ-34c and suberoylanilide hydroxamic acid were 2.95±0.75 and 4.45±0.29 μmol/l for K562 cells treated for 48 h, respectively. We found that ZYJ-34c caused more significant G1 cell cycle arrest than suberoylanilide hydroxamic acid, in a time-dependent manner. ZYJ-34c-induced hyperacetylation of histone H3 and H4 around the promoter region of p21. P21 RNA interference markedly impaired ZYJ-34c-induced or suberoylanilide hydroxamic acid-induced G1 cell cycle arrest. In addition, levels of bcr-abl mRNA and protein in K562 cells decreased after treatment with either suberoylanilide hydroxamic acid or ZYJ-34c; moreover, ZYJ-34c had a higher inhibition activity. ZYJ-34c could represent a novel pharmacological agent with potential benefit for patients with leukemia.
authors.affiliation: aInstitute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences bDepartment of Medicinal Chemistry, School of Pharmacy, Shandong University, Jinan cDepartment of Immunology, Taishan Medical University, Tai'an, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Wenfang
authors.initials: W
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Peixiang
authors.initials: P
authors.lastname: Lan
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhang
authors.forename: Cai
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D007938:Leukemia / Q000473:pathology*; D015854:Up-Regulation
chemical_list: C561594:2-(2-(3,3-dimethylbutanamido)-3-methylpentanoyl)-7-(2-(hydroxyamino)-2-oxoethoxy)-N-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007546:Isoquinolines; D016044:Fusion Proteins, bcr-abl