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Am. J. Biomed. Sci. 2016, 8(3), 228-236; doi: 10.5099/aj160300228 |
The
Active Metabolite of UTL-5g, 5-Methylisoxazole-3-Carboxylic Acid, is
Anti-Inflammatory and Reduces Doxorubicin-Induced Cardiac Toxicity |
Yiguan Zhang1,2, Yongxin Tang1, Ben Chen3, Frederick
Valeriote2, Subhash Gautam2, Xiaohua Gao2, Jiajiu
Shaw2,3,* |
1New Phiaring
Bio-medical Science Co., Ltd, Chengdu, China |
2Henry Ford Health System,
Internal Medicine, Detroit, Michigan, USA |
321st Century
Therapeutics, Detroit, Michigan, USA |
*Corresponding
Author |
Jiajiu Shaw |
21st Century Therapeutics |
440 Burroughs St., Suite 447 |
Detroit, Michigan48105 |
USA |
Abstract UTL-5g is a small-molecule TNF-α modulator that is anti-inflammatory in a carrageenan-induced edema animal model and chemoprotective against anticancer drug-induced side effects. Recently, it was shown that UTL-5g is a prodrug and its active metabolite is 5-methylisoxazole-3-carboxylic acid (Isox). We set out to investigate the anti-inflammatory and cardioprotective effects of Isox, and two of its esterified analogues, methyl ester (Isox-Me), and ethyl ester (Isox-Et). First, the carrageenan-induced edema animal model was employed to compare their anti-inflammatory effects. Briefly, Wistar rats were randomly divided into 5 groups and pretreated with vehicle, leflunomide, Isox, Isox-Me, and Isox-Et respectively before carrageenan treatment. The results showed that the anti-inflammatory effect of Isox was essentially the same as that of leflunomide. However, the anti-inflammatory effects of Isox-Me and Isox-Et were lower than that of Isox. In the second study, cardioprotective effects of Isox, Isox-Me, and Isox-Et on doxorubicin (DOX)-induced toxicity were investigated. SD rats were randomly divided into five groups. Rats in groups 1 and 2 were pretreated with vehicle; rats in groups 3-5 were pretreated with Isox, Isox-Me, and Isox-Et respectively for 5 consecutive days. One hr after the last treatment, animals in group 2-5 were treated with DOX. Twenty four hr later, effects of test compounds on cardioprotection were examined. The results showed that Isox significantly reduced the cardiotoxicity, but Isox-Me and Isox-Et did not show much cardioprotective effect. A subsequent in vitro MTT study confirmed that Isox, but not Isox-Me or Isox-Et, protected cardiomyocytes from the injury induced by DOX. In summary, Isox is anti-inflammatory against carrageenan-induced edema and the anti-inflammatory effect of Isox is at least partially responsible for its chemoprotective effect against DOX-induced cardiac injury; esterification of Isox significantly reduces its anti-inflammatory effect and cardioprotective effect. Keywords: Isox, cardioprotective effect, doxorubicin, cardiac toxicity Abbreviations: ALT: alanine aminotransferase; AST:
aspartate aminotransferase; BNP: brain natriuretic peptide; BUN: blood urea
nitrogen; CMC: carboxymethyl cellulose; DOX:
doxorubicin; Isox: 5-methylisoxazole-3-carboxylic
acid; Isox-Et: Ethyl 5-methylisoxazole-3-carboxylate;
Isox-Me: Methyl 5-methylisoxazole-3-carboxylate;
TNF-α: tumor necrosis factor alpha. Download the full article (PDF)
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