title: A novel class I histone deacetylase inhibitor, I-7ab, induces apoptosis and arrests cell cycle progression in human colorectal cancer cells.
abstract: Epigenetic mutations are closely associated with human diseases, especially cancers. Among them, dysregulations of histone deacetylases (HDACs) are commonly observed in human cancers. Recent years, HDAC inhibitors have been identified as promising anticancer agents; several HDAC inhibitors have been applied in clinical practice. In this study, we synthesized a novel N-hydroxyacrylamide-derived HDAC inhibitor, I-7ab, and examined its antitumor activity. Our investigations demonstrated that I-7ab exerted cytotoxicity toward and inhibited the growth of human cancer cell lines at micromolar concentrations. Among tested cells, HCT116 was the most sensitive one to the treatment of I-7ab. However, I-7ab displayed far less cytotoxicity in human normal cells. In HCT116 cells, I-7ab inhibited the expression of class I HDACs, especially that of HDAC3, and suppressed EGFR signaling pathway. With respect to the cytotoxic effect of I-7ab, it induced apoptosis via increasing the Bax/Bcl-2 ratio and suppressing the translocation of NF-κB. Other than inducing apoptosis, I-7ab inhibited the expression of cyclin B1 and thereby arrests cell cycle progression at G2/M phase. Further analyses revealed potential role of p53 and p21 in I-7ab-induced apoptosis and cell cycle arrest. According to our findings, I-7ab may serve as a lead compound for potential antitumor drugs.
authors.affiliation: Department of Molecular & Cellular Pharmacology, Biomedical Nanotechnology Center, State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Molecular & Cellular Pharmacology, Biomedical Nanotechnology Center, State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Qiannan
authors.initials: Q
authors.lastname: Liang
authors.affiliation: Department of Molecular & Cellular Pharmacology, Biomedical Nanotechnology Center, State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Shen
authors.affiliation: Department of Molecular & Cellular Pharmacology, Biomedical Nanotechnology Center, State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Molecular & Cellular Pharmacology, Biomedical Nanotechnology Center, State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: An
authors.affiliation: Department of Molecular & Cellular Pharmacology, Biomedical Nanotechnology Center, State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of General Surgery, Xinhua Hospital Chongming Branch, Shanghai Jiaotong University School of Medicine, 25 Nanmen Rd, Chengqiaozhen, Chongming, Shanghai 202150, PR China. Electronic address: zheweifei@xinhuamed.com.cn.
authors.forename: Zhewei
authors.initials: Z
authors.lastname: Fei
authors.affiliation: Department of Molecular & Cellular Pharmacology, Biomedical Nanotechnology Center, State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China. Electronic address: liujian@ecust.edu.cn.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000473:pathology*; D056744:Cyclin B1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D000970:Antineoplastic Agents; D016203:CDC2 Protein Kinase; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000099186:Histone Deacetylase 3; C000604789:N-hydroxy-3-(2-phenyl-4-((2-(piperidin-1-yl)ethyl)amino)-2H-pyrazolo(3,4-c)quinolin-8-yl)acrylamide
keywords: Apoptosis; Cell cycle arrest; Colorectal cancer; HDAC inhibitor; I-7ab