title: Marine-derived chromopeptide A, a novel class I HDAC inhibitor, suppresses human prostate cancer cell proliferation and migration.
abstract: Histone deacetylases (HDACs), especially HDAC1, 2, 3 and 4, are abundantly expressed and over-activated in prostate cancer that is correlated with the poor prognosis. Thus, inhibition of HDAC activity has emerged as a potential alternative option for prostate cancer therapy. Chromopeptide A is a depsipeptide isolated from the marine sediment-derived bacterium Chromobacterium sp. HS-13-94; it has a chemical structure highly similar to FK228, a class I HDAC inhibitor that is approved by FDA for treating T-cell lymphoma. In this study, we determined whether chromopeptide A, like FK228, acted as a class I HDAC inhibitor, and whether chromopeptide A could inhibit the growth and migration of human prostate cancer in vitro and in vivo. HDAC enzyme selectivity and kinetic analysis revealed that chromopeptide A selectively inhibited the enzymatic activities of HDAC1, 2, 3 and 8 in a substrate non-competitive manner with comparable IC50values for each HDAC member as FK228 in vitro. Importantly, chromopeptide A dose-dependently suppressed the proliferation of human prostate cancer cell lines PC3, DU145 and LNCaP with IC50values of 2.43±0.02, 2.08±0.16, and 1.75±0.06 nmol/L, respectively, accompanied by dose-dependent inhibition of HDAC enzymatic activity in PC3 and DU145 cells. Chromopeptide A (0.2-50 nmol/L) caused G2/M phase arrest and induced apoptosis in the prostate cancer cell lines. Moreover, chromopeptide A dose-dependently inhibited the migration of PC3 cells. In mice bearing PC3 prostate cancer xenografts, intravenous injection of chromopeptide A (1.6, 3.2 mg/kg, once a week for 18 d) significantly suppressed the tumor growth, which was associated with increased expression levels of Ac-H3 and p21 in tumor tissues. Our results identify chromopeptide A as a novel class I HDAC inhibitor and provide therapeutic strategies that may be implemented in prostate cancer.
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Sun
authors.affiliation: Zhejiang Hisun Pharmaceutical Company Ltd, Taizhou 318000, China.
authors.forename: Ji-Dong
authors.initials: JD
authors.lastname: Wang
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Hong-Chun
authors.initials: HC
authors.lastname: Liu
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Min-Min
authors.initials: MM
authors.lastname: Zhang
authors.affiliation: Shanghai ChemPartner Co, Ltd, Shanghai 201203, China.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Shanghai ChemPartner Co, Ltd, Shanghai 201203, China.
authors.forename: Chen-Hua
authors.initials: CH
authors.lastname: Zhang
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Su
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Shen
authors.affiliation: University of Chinese Academy of Sciences, Beijing 100049, China.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yue-Wei
authors.initials: YW
authors.lastname: Guo
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Ai-Jun
authors.initials: AJ
authors.lastname: Shen
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Geng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D064593:Heterografts; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C000622033:chromopeptide A