title: Anticolon cancer activity of largazole, a marine-derived tunable histone deacetylase inhibitor.
abstract: Histone deacetylases (HDACs) are validated targets for anticancer therapy as attested by the approval of suberoylanilide hydroxamic acid (SAHA) and romidepsin (FK228) for treating cutaneous T cell lymphoma. We recently described the bioassay-guided isolation, structure determination, synthesis, and target identification of largazole, a marine-derived antiproliferative natural product that is a prodrug that releases a potent HDAC inhibitor, largazole thiol. Here, we characterize the anticancer activity of largazole by using in vitro and in vivo cancer models. Screening against the National Cancer Institute's 60 cell lines revealed that largazole is particularly active against several colon cancer cell types. Consequently, we tested largazole, along with several synthetic analogs, for HDAC inhibition in human HCT116 colon cancer cells. Enzyme inhibition strongly correlated with the growth inhibitory effects, and differential activity of largazole analogs was rationalized by molecular docking to an HDAC1 homology model. Comparative genomewide transcript profiling revealed a close overlap of genes that are regulated by largazole, FK228, and SAHA. Several of these genes can be related to largazole's ability to induce cell cycle arrest and apoptosis. Stability studies suggested reasonable bioavailability of the active species, largazole thiol. We established that largazole inhibits HDACs in tumor tissue in vivo by using a human HCT116 xenograft mouse model. Largazole strongly stimulated histone hyperacetylation in the tumor, showed efficacy in inhibiting tumor growth, and induced apoptosis in the tumor. This effect probably is mediated by the modulation of levels of cell cycle regulators, antagonism of the AKT pathway through insulin receptor substrate 1 down-regulation, and reduction of epidermal growth factor receptor levels.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, 1600 SW Archer Road, P.O. Box 100485, Gainesville, FL 32610, USA.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Liu
authors.forename: Lilibeth A
authors.initials: LA
authors.lastname: Salvador
authors.forename: Seongrim
authors.initials: S
authors.lastname: Byeon
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Ying
authors.forename: Jason C
authors.initials: JC
authors.lastname: Kwan
authors.forename: Brian K
authors.initials: BK
authors.lastname: Law
authors.forename: Jiyong
authors.initials: J
authors.lastname: Hong
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D047630:Depsipeptides / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D015536:Down-Regulation; D004355:Drug Stability; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D020411:Oligonucleotide Array Sequence Analysis; D011994:Recombinant Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D011994:Recombinant Proteins; D013844:Thiazoles; C527895:largazole; D006655:Histone Deacetylases