The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines.
Suberoylanilide hydroxamic acid (SAHA) is a hydroxamic acid-containing hybrid polar molecule; SAHA specifically binds to and inhibits the activity of histone deacetylase. Although SAHA, like other inhibitors of histone deacetylase, exhibits antitumor effects by increasing expression of genes regulating tumor survival, we found that SAHA reduces the production of proinflammatory cytokines in vivo and in vitro. A single oral administration of SAHA to mice dose-dependently reduced circulating TNF-alpha, IL-1-beta, IL-6, and IFN-gamma induced by lipopolysaccharide (LPS). Administration of SAHA also reduced hepatic cellular injury in mice following i.v. injection of Con A. SAHA inhibited nitric oxide release in mouse macrophages stimulated by the combination of TNF-alpha plus IFN-gamma. Human peripheral blood mononuclear cells stimulated with LPS in the presence of SAHA released less TNF-alpha, IL-1-beta, IL-12, and IFN-gamma (50% reduction at 100-200 nM). The production of IFN-gamma stimulated by IL-18 plus IL-12 was also inhibited by SAHA (85% at 200 nM). However, SAHA did not affect LPS-induced synthesis of the IL-1-beta precursor, the IL-1 receptor antagonist, or the chemokine IL-8. In addition, IFN-gamma induced by anti-CD3 was not suppressed by SAHA. Steady-state mRNA levels for LPS-induced TNF-alpha and IFN-gamma in peripheral blood mononuclear cells were markedly decreased, whereas IL-8 and IL-1-beta mRNA levels were unaffected. Because SAHA exhibits antiinflammatory properties in vivo and in vitro, inhibitors of histone deacetylase may stimulate the expression of genes that control the synthesis of cytokines and nitric oxide or hyperacetylate other targets.
Leoni
Flavio
F
Italfarmaco, SpA., 20092 Cinisello Balsamo, Italy. f.leoni@italfarmaco.com
Zaliani
Andrea
A
Bertolini
Giorgio
G
Porro
Giulia
G
Pagani
Paolo
P
Pozzi
Pietro
P
Donà
Giancarlo
G
Fossati
Gianluca
G
Sozzani
Silvano
S
Azam
Tania
T
Bufler
Philip
P
Fantuzzi
Giamila
G
Goncharov
Igor
I
Kim
Soo-Hyun
SH
Pomerantz
Benjamin J
BJ
Reznikov
Leonid L
LL
Siegmund
Britta
B
Dinarello
Charles A
CA
Mascagni
Paolo
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017252:CD3 Complex / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000293:injuries; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D000077337:Vorinostat
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D017252:CD3 Complex; D016207:Cytokines; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008934:Mitogens; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D018664:Interleukin-12; D009569:Nitric Oxide; D000077337:Vorinostat; D007371:Interferon-gamma