Phospho-sulindac (OXT-328), a novel sulindac derivative, is safe and effective in colon cancer prevention in mice.

Abstract

BACKGROUND & AIMS:

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective cancer chemopreventive agents. However, chronic administration of NSAIDs is associated with significant side effects, mainly of the gastrointestinal tract. Given these limitations, we synthesized phospho-sulindac (P-S; OXT-328), a novel sulindac derivative.

METHODS:

Here, we evaluated the safety and efficacy of P-S in preclinical models, including its mechanism of action with human colon cancer cell (HCCC) lines and animal tumor models.

RESULTS:

(1) Compared with sulindac, P-S is much more potent in inhibiting the growth of cultured HCCCs and more efficacious in preventing the growth of HT-29 xenografts in nude mice. P-S also prevents the growth of intestinal tumors in Apc/Min mice. (2) In combination with difluoromethylornithine (DFMO), P-S reduced tumor multiplicity in Apc/Min mice by 90%. (3) P-S is much safer than sulindac as evidenced by its in vitro toxicologic evaluation and animal toxicity studies. Mechanistically, P-S increases the intracellular levels of reactive oxygen and nitrogen species, which are key early mediators of its chemopreventive effect. Moreover, P-S induces spermidine/spermine N(1)-acetyltransferase enzymatic activity, and together with DFMO it reduces polyamine levels in vitro and in vivo.

CONCLUSIONS:

P-S displays considerable safety and efficacy, two pharmacologic properties that are essential for a potential cancer chemopreventive agent, and thus merits further evaluation.

• Authors: Gerardo G Mackenzie, Yu Sun, Liqun Huang, Gang Xie, Nengtai Ouyang, Ramesh C Gupta, Francis Johnson, Despina Komninou, Levy Kopelovich, Basil Rigas
• Journal: Gastroenterology (Gastroenterology) Vol. 139 Issue 4 Pg. 1320-32 (Oct 2010) ISSN: 1528-0012 [Electronic] United States
• PMID: 20600034 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Biogenic Polyamines
• NF-kappa B
• OXT-328
• Organophosphorus Compounds
• Sulindac
• Acetyltransferases
• diamine N-acetyltransferase
• Dinoprostone
• Eflornithine

Topics

• Acetyltransferases (biosynthesis)
• Animals
• Antineoplastic Agents (pharmacology)
• Biogenic Polyamines (analysis)
• Cell Line, Tumor
• Colonic Neoplasms (prevention & control)
• Dinoprostone (biosynthesis)
• Eflornithine (pharmacology)
• Female
• Humans
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Organophosphorus Compounds (pharmacology)
• Oxidative Stress (drug effects)
• Rats
• Rats, Sprague-Dawley
• Sulindac (analogs & derivatives, pharmacology)