Chemopreventive efficacy of suberoylanilide hydroxamic acid (SAHA) against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in female A/J mice.
Histone deacetylase (HDAC) inhibitors, such as suberoylanilide hydroxamic acid (SAHA), represent a promising new class of chemopreventive agents. We have synthesized SAHA by an improved method and examined its efficacy as a dietary supplement at 450 ppm against lung tumor development in female A/J mice induced by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We observed significant inhibition (80%, p < 0.0001) of lung tumor multiplicity in mice treated with NNK plus SAHA compared to NNK-treated controls. SAHA inhibited the carbonyl reductive pathways of NNK in a dose-dependent manner in liver, but not lung microsomes, obtained from A/J mice. However, a significant inhibition of the a-hydroxylation pathway of NNK was observed in both lung and liver microsomes, suggesting that SAHA may act to inhibit the activation pathways of NNK metabolism. The results of this model study indicate that SAHA holds promise as a potential chemopreventive agent against lung cancer.
Desai
Dhimant
D
Institute for Cancer Prevention, American Helath Foundation Cancer Center, 1 Dana Road, Valhalla, NY 10595, USA. ddesai@ifcp.us
Das
Arunangshu
A
Cohen
Leonard
L
el-Bayoumy
Karam
K
Amin
Shantu
S
D000818:Animals; D002273:Carcinogens / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D005260:Female; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009602:Nitrosamines / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D000077337:Vorinostat
D002273:Carcinogens; D006877:Hydroxamic Acids; D009602:Nitrosamines; D000077337:Vorinostat; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone