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: Marielle Fournel, Marie-Claude Trachy-Bourget, P Theresa Yan, Ann Kalita, Claire Bonfils, Carole Beaulieu, Sylvie Frechette, Silvana Leit, Elie Abou-Khalil, Soon-Hyung Woo, Daniel Delorme, A Robert MacLeod, Jeffrey M Besterman, Zuomei Li
• Journal: Cancer research (Cancer Res) Vol. 62 Issue 15 Pg. 4325-30 (Aug 01 2002) ISSN: 0008-5472 [Print] United States
• PMID: 12154036 (Publication Type: Journal Article)

Chemical References

• Anilides
• Antineoplastic Agents
• Benzamides
• CCNB1 protein, human
• CDKN1A protein, human
• Ccnb1 protein, mouse
• Cdkn1a protein, mouse
• Cyclin A
• Cyclin B
• Cyclin B1
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Histones
• Pyridines
• Sulfonamides
• entinostat

Topics

• Acetylation (drug effects)
• Anilides (pharmacology, toxicity)
• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Benzamides (pharmacology, toxicity)
• Colonic Neoplasms (drug therapy, metabolism, pathology)
• Cyclin A (biosynthesis)
• Cyclin B (biosynthesis)
• Cyclin B1
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins (biosynthesis)
• Enzyme Inhibitors (pharmacology, toxicity)
• Female
• G2 Phase (drug effects)
• Histone Deacetylase Inhibitors
• Histones (metabolism)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitosis (drug effects)
• Pyridines (pharmacology, toxicity)
• Sulfonamides (pharmacology, toxicity)
• Xenograft Model Antitumor Assays