Phospho-sulindac (OXT-328), a novel sulindac derivative, is safe and effective in colon cancer prevention in mice.
OBJECTIVE
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.
Mackenzie
Gerardo G
GG
Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8173, USA.
Sun
Yu
Y
Huang
Liqun
L
Xie
Gang
G
Ouyang
Nengtai
N
Gupta
Ramesh C
RC
Johnson
Francis
F
Komninou
Despina
D
Kopelovich
Levy
L
Rigas
Basil
B
D000123:Acetyltransferases / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015317:Biogenic Polyamines / Q000032:analysis; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000517:prevention & control*; D015232:Dinoprostone / Q000096:biosynthesis; D000518:Eflornithine / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000970:Antineoplastic Agents; D015317:Biogenic Polyamines; D015232:Dinoprostone; D000518:Eflornithine; D016328:NF-kappa B; D009943:Organophosphorus Compounds; D013467:Sulindac; D000099228:Diamine N-Acetyltransferase; C553002:OXT-328