title: Sulfonamide anilides, a novel class of histone deacetylase inhibitors, are antiproliferative against human tumors.
abstract: Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. We have designed and synthesized novel nonhydroxamate sulfonamide anilides that can inhibit human HDAC enzymes and can induce hyperacetylation of histones in human cancer cells. These compounds selectively inhibit proliferation and cause cell cycle blocks in various human cancer cells but not in normal cells. The growth inhibitory activity of sulfonamide anilides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. One of these compounds (Compound 2) can significantly reduce tumor growth of implanted human colon tumors in nude mice. Unlike another anilide-based HDAC inhibitor, MS-275, which decreases both red and white blood counts and reduces spleen weights in mice, Compound 2 does not exhibit noticeable toxicity. By using cDNA array analysis, we have identified downstream genes whose expression is altered by Compound 2 in human cancer cells. In correlation with its antitumor activity both in vitro and in vivo, Compound 2 induces expression of p21(WAF1/Cip1), gelsolin, and keratin 19, while down-regulating expression of cyclin A and cyclin B1 in human cancer cells in a dose-dependent manner. Our results suggest that sulfonamide anilides are novel HDAC inhibitors and may be useful as antiproliferative agents in cancer chemotherapy.
authors.affiliation: MethylGene, Inc., St. Laurent, Quebec, H4S 2A1 Canada.
authors.forename: Marielle
authors.initials: M
authors.lastname: Fournel
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Trachy-Bourget
authors.forename: P Theresa
authors.initials: PT
authors.lastname: Yan
authors.forename: Ann
authors.initials: A
authors.lastname: Kalita
authors.forename: Claire
authors.initials: C
authors.lastname: Bonfils
authors.forename: Carole
authors.initials: C
authors.lastname: Beaulieu
authors.forename: Sylvie
authors.initials: S
authors.lastname: Frechette
authors.forename: Silvana
authors.initials: S
authors.lastname: Leit
authors.forename: Elie
authors.initials: E
authors.lastname: Abou-Khalil
authors.forename: Soon-Hyung
authors.initials: SH
authors.lastname: Woo
authors.forename: Daniel
authors.initials: D
authors.lastname: Delorme
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Besterman
authors.forename: Zuomei
authors.initials: Z
authors.lastname: Li
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000813:Anilides / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D001549:Benzamides / Q000494:pharmacology / Q000633:toxicity; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019925:Cyclin A / Q000096:biosynthesis; D019926:Cyclin B / Q000096:biosynthesis; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000633:toxicity; D013449:Sulfonamides / Q000494:pharmacology* / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D001549:Benzamides; C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; C534700:Ccnb1 protein, mouse; C493957:Cdkn1a protein, mouse; D019925:Cyclin A; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011725:Pyridines; D013449:Sulfonamides; C118739:entinostat