Marine-derived chromopeptide A, a novel class Ⅰ HDAC inhibitor, suppresses human prostate cancer cell proliferation and migration

• 来源期刊: 中国药理学报（英文版）
• 关键词: HDAC chromopeptide A FK228 human prostate cancer cell cycle arrest apoptosis cancer cell migration PC3 xenograft model
• 年，卷（期）: 2017,（4）
• 页码范围: 551-560
• 页数: 10页
• 语种: 英文
• DOI: 10.1038/aps.2016.139

摘要

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 IC50 values 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.