The nonsteroidal anti-inflammatory
drug (
NSAID)
sulindac and the
ornithine decarboxylase (ODC) antagonist
difluoromethylornithine (DFMO), individually and together, are effective inhibitors of colon
carcinogenesis. However, chronic use of
sulindac is associated with significant side effects. We evaluated the chemopreventive efficacy of phospho-
sulindac (P-S, OXT-328), an apparently safe derivative of
sulindac, together with DFMO, in HT-29 human
colon cancer xenografts. Nude mice were divided into four groups as follows: group 1 received vehicle (
corn oil); group 2 received P-S (100 mg/kg/d) by oral gavage; group 3 received DFMO (2% in
drinking water); and group 4 received P-S (100 mg/kg/d) by gavage plus DFMO (2% in
drinking water; P-S/DFMO). Eighteen days after implantation, compared with controls,
tumor volume was inhibited 65.9% by P-S, 52.9% by DFMO, and 70.9% by P-S/DFMO (P < 0.01 for all). P-S/DFMO reduced cell proliferation 27.1% and increased apoptosis 38.9% compared with controls (P < 0.05 for both). Compared with controls, P-S reduced the levels of
thioredoxin-1 (Trx-1) and
thioredoxin reductase (TrxR), whereas DFMO reduced
polyamine content (
putrescine and
spermidine) and TrxR levels. Importantly, P-S/DFMO decreased
putrescine and
spermidine levels and the expression of Trx-1, TrxR, and
cyclooxygenase (COX) 2. Of these molecular targets, TrxR most consistently correlated with
tumor growth. Study results show that P-S/DFMO is an efficacious
drug combination for
colon cancer prevention and also show the safety of P-S, which may overcome the limiting side effects of conventional
sulindac. P-S/DFMO has an intricate mechanism of action extending beyond
polyamines and including the
thioredoxin system, an emerging regulator of
chemoprevention. P-S/DFMO merits further evaluation.