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

Gerardo Mackenzie, Yu Sun, Liqun Huang, Gang Xie, Nengtai Ouyang, Ramesh C. Gupta, Francis Johnson, Despina Komninou, Levy Kopelovich, Basil Rigas

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45 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1320-1332
Number of pages13
JournalGastroenterology
Volume139
Issue number4
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

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Keywords

  • Colon Cancer
  • Phospho-Sulindac
  • Polyamines
  • Reactive Oxygen Species
  • Sulindac

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Mackenzie, G., Sun, Y., Huang, L., Xie, G., Ouyang, N., Gupta, R. C., Johnson, F., Komninou, D., Kopelovich, L., & Rigas, B. (2010). Phospho-sulindac (OXT-328), a novel sulindac derivative, is safe and effective in colon cancer prevention in mice. Gastroenterology, 139(4), 1320-1332. https://doi.org/10.1053/j.gastro.2010.06.044