Sulfonamide anilides, a novel class of histone deacetylase inhibitors, are antiproliferative against human tumors.
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.
Fournel
Marielle
M
MethylGene, Inc., St. Laurent, Quebec, H4S 2A1 Canada.
Trachy-Bourget
Marie-Claude
MC
Yan
P Theresa
PT
Kalita
Ann
A
Bonfils
Claire
C
Beaulieu
Carole
C
Frechette
Sylvie
S
Leit
Silvana
S
Abou-Khalil
Elie
E
Woo
Soon-Hyung
SH
Delorme
Daniel
D
MacLeod
A Robert
AR
Besterman
Jeffrey M
JM
Li
Zuomei
Z
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
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