title: Thailandepsins: bacterial products with potent histone deacetylase inhibitory activities and broad-spectrum antiproliferative activities.
abstract: Histone deacetylase (HDAC) inhibitors have emerged as a new class of anticancer drugs, with one synthetic compound, SAHA (vorinostat, Zolinza; 1), and one natural product, FK228 (depsipeptide, romidepsin, Istodax; 2), approved by FDA for clinical use. Our studies of FK228 biosynthesis in Chromobacterium violaceum no. 968 led to the identification of a cryptic biosynthetic gene cluster in the genome of Burkholderia thailandensis E264. Genome mining and genetic manipulation of this gene cluster further led to the discovery of two new products, thailandepsin A (6) and thailandepsin B (7). HDAC inhibition assays showed that thailandepsins have selective inhibition profiles different from that of FK228, with comparable inhibitory activities to those of FK228 toward human HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, and HDAC9 but weaker inhibitory activities than FK228 toward HDAC4 and HDAC8, the latter of which could be beneficial. NCI-60 anticancer screening assays showed that thailandepsins possess broad-spectrum antiproliferative activities with GI50 for over 90% of the tested cell lines at low nanomolar concentrations and potent cytotoxic activities toward certain types of cell lines, particularly for those derived from colon, melanoma, ovarian, and renal cancers. Thailandepsins thus represent new naturally produced HDAC inhibitors that are promising for anticancer drug development.
authors.affiliation: Department of Biological Sciences, University of Wisconsin-Milwaukee, P.O. Box 413, Milwaukee, Wisconsin 53201, United States.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Leonhard M
authors.initials: LM
authors.lastname: Henkes
authors.forename: Leah B
authors.initials: LB
authors.lastname: Doughty
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.forename: Difei
authors.initials: D
authors.lastname: Wang
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Meyer-Almes
authors.forename: Yi-Qiang
authors.initials: YQ
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D019117:Burkholderia / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects*; D047630:Depsipeptides / Q000737:chemistry* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D054547:National Cancer Institute (U.S.); D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C529984:spiruchostatin B; C574693:thailandepsin A; C485419:spiruchostatin A; C087123:romidepsin