Sulfonamide anilides, a novel class of histone deacetylase inhibitors, are antiproliferative against human tumors

• Published in: Cancer research (Chicago, Ill.) Vol. 62; no. 15; pp. 4325 - 4330
• Main Authors: FOURNEL, Marielle, TRACHY-BOURGET, Marie-Claude, DELORME, Daniel, MACLEOD, A. Robert, BESTERMAN, Jeffrey M, ZUOMEI LI, YAN, P. Theresa, KALITA, Ann, BONFILS, Claire, BEAULIEU, Carole, FRECHETTE, Sylvie, LEIT, Silvana, ABOU-KHALIL, Elie, WOO, Soon-Hyung
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2002
• Subjects: Acetylation - drug effects; Anilides - pharmacology; Anilides - toxicity; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Benzamides - pharmacology; Benzamides - toxicity; Biological and medical sciences; Chemotherapy; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Cyclin A - biosynthesis; Cyclin B - biosynthesis; Cyclin B1; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - biosynthesis; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - toxicity; Female; G2 Phase - drug effects; Histone Deacetylase Inhibitors; Histones - metabolism; Humans; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Mitosis - drug effects; Pharmacology. Drug treatments; Pyridines - pharmacology; Pyridines - toxicity; Sulfonamides - pharmacology; Sulfonamides - toxicity; Xenograft Model Antitumor Assays; Antineoplastic agent; Human; Cell proliferation; Intraperitoneal administration; Sulfonamide; Rodentia; Enzyme inhibitor; Malignant tumor; In vitro; Biological activity; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Established cell line; Anilide; Tumor cell; Comparative study
• ISSN: 0008-5472; 1538-7445

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.