title: Novel analogs targeting histone deacetylase suppress aggressive thyroid cancer cell growth and induce re-differentiation.
abstract: To develop novel therapies for aggressive thyroid cancers, we have synthesized a collection of histone deacetylase (HDAC) inhibitor analogs named AB1 to AB13, which have different linkers between a metal chelating group and a hydrophobic cap. The purpose of this study was to screen out the most effective compounds and evaluate the therapeutic efficacy. AB2, AB3 and AB10 demonstrated the lowest half-maximal inhibitory concentration (IC50) values in one metastatic follicular and two anaplastic thyroid cancer cell lines. Treatment with each of the three ABs resulted in an increase in apoptosis markers, including cleaved poly adenosine diphosphate ribose polymerase (PARP) and cleaved caspase 3. Additionally, the expression of cell-cycle regulatory proteins p21(WAF1) and p27(Kip1) increased with the treatment of ABs while cyclin D1 decreased. Furthermore, AB2, AB3 and AB10 were able to induce thyrocyte-specific genes in the three thyroid cancer cell lines indicated by increased expression levels of sodium iodide symporter, paired box gene 8, thyroid transcription factor 1 (TTF1), TTF2 and thyroid-stimulating hormone receptors. AB2, AB3 and AB10 suppress thyroid cancer cell growth via cell-cycle arrest and apoptosis. They also induce cell re-differentiation, which could make aggressive cancer cells more susceptible to radioactive iodine therapy.
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Jang
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: X-M
authors.initials: XM
authors.lastname: Yu
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Odorico
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Clark
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: R
authors.initials: R
authors.lastname: Jaskula-Sztul
authors.affiliation: Department of Chemistry, University of Wisconsin School of Pharmacy, Madison, WI, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Schienebeck
authors.affiliation: Promega Corporation, Madison, WI, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Kupcho
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Harrison
authors.affiliation: Department of Chemistry, University of Wisconsin School of Pharmacy, Madison, WI, USA.
authors.forename: G N
authors.initials: GN
authors.lastname: Winston-McPherson
authors.affiliation: Department of Chemistry, University of Wisconsin School of Pharmacy, Madison, WI, USA.
authors.forename: W
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D058990:Molecular Targeted Therapy / Q000379:methods*; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D053148:Caspase 3