Abstract
BackgroundRecently, we showed that Sulindac (SU; 320 ppm) reduces precancerous lesions in the colon of Pirc rats, mutated in the Apc gene. Surprisingly, previous data in Apc-mutated mice showed that SU, with reported efficacy in Familial Adenomatous Polyposis (FAP), increases colon carcinogenesis. Therefore, we assessed the effect of SU 320 ppm in a long-term carcinogenesis experiment in Pirc rats. Moreover, since side effects of SU hamper its chronic use and a combination of drugs could be more effective and less toxic than single agents, we also studied whether two natural compounds, 3,3’-diindolylmethane (DIM; 250 ppm) and curcumin (CUR; 2000 ppm), with or without lower doses of SU could affect carcinogenesisMethodsPirc rats were fed an AIN76 diet containing SU, DIM and CUR and sacrificed at 8 months of age to measure intestinal tumours. Apoptosis and proliferation in the normal colon mucosa, as well as gene expression profile were studiedResultsColon tumours were significantly reduced by SU 320 ppm (62 % reduction over Controls), by DIM and CUR without or with SU 80 and 160 ppm (50, 53 and 58 % reduction, respectively) but not by SU 80 ppm alone. Total tumours (colon and small intestine) were reduced by SU (80 and 320 ppm) and by DIM and CUR. Apoptosis in the normal mucosa was significantly increased by SU 320 ppm, and slightly increased by DIM and CUR with or without SU. A slight reduction in Survivin-Birc5 expression was observed with all the treatments compared to Controls. Proliferative activity was not variedConclusionsThe results on SU reinforce the validity of Pirc rats to identify chemopreventive products. Moreover, the efficacy of the DIM and CUR combination to lower colon tumours, suggests an alternative strategy to be exploited in patients at risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1627-9) contains supplementary material, which is available to authorized users.
Highlights
We showed that Sulindac (SU; 320 ppm) reduces precancerous lesions in the colon of Pirc rats, mutated in the Apc gene
Significant side effects associated with the use of non-steroidal anti-inflammatory drugs (NSAID) like Sulindac (SU) or Celecoxib, two of the most effective chemopreventive drugs, have argued against
Rats were maintained in polyethylene cages with wire tops and bottoms and maintained at a temperature of 22 °C, with a 12:12-h light–dark cycle, under an experimental protocol approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Florence and performed according to the Italian Law on Animal Welfare (DL 116/92)
Summary
We showed that Sulindac (SU; 320 ppm) reduces precancerous lesions in the colon of Pirc rats, mutated in the Apc gene. Previous data in Apc-mutated mice showed that SU, with reported efficacy in Familial Adenomatous Polyposis (FAP), increases colon carcinogenesis. 320 ppm in the diet) reduces precancerous lesions in the Pirc rat colon [9] This result, while suggesting that Pirc rats might be useful to identify chemopreventive drugs, needs to be assessed in a long-term carcinogenesis experiment. We have shown that the apparently normal colon mucosa (NM) of Pirc rats over-expresses Birc5 [9], suggesting that a combination of DIM with an apoptosis inducer like CUR may reduce colon carcinogenesis in these Apc-mutated rats. Experimental studies have shown that a combination of drugs is often more effective than individual agents [2, 3]
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