Sulindac, 3,3'-diindolylmethane and curcumin reduce carcinogenesis in the Pirc rat, an Apc-driven model of colon carcinogenesis.
BACKGROUND
Recently, 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 carcinogenesis


METHODS
Pirc 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 studied


RESULTS
Colon 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 varied


CONCLUSIONS
The 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.
NEUROFARBA Department, Section of Pharmacology and Toxicology, University of Florence, 6 Viale Pieraccini, 50139, Florence, Italy. angelo.pietro@unifi.it.
Angelo Pietro
AP
Femia
Department of Pathology and Legal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil. soarespv@gmail.com.
Paulo Victoria
PV
Soares
NEUROFARBA Department, Section of Pharmacology and Toxicology, University of Florence, 6 Viale Pieraccini, 50139, Florence, Italy. cristina.luceri@unifi.it.
Cristina
C
Luceri
NEUROFARBA Department, Section of Pharmacology and Toxicology, University of Florence, 6 Viale Pieraccini, 50139, Florence, Italy. maura.lodovici@unifi.it.
Maura
M
Lodovici
Department of Pathology, General Hospital of Prato, Prato, Italy. agiannini@usl4.toscana.it.
Augusto
A
Giannini
NEUROFARBA Department, Section of Pharmacology and Toxicology, University of Florence, 6 Viale Pieraccini, 50139, Florence, Italy. giovanna.caderni@unifi.it.
Giovanna
G
Caderni
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D018890:Chemoprevention / Q000379:methods; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003474:Curcumin / Q000008:administration & dosage*; D004032:Diet; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D017491:Genes, APC; D007211:Indoles / Q000008:administration & dosage*; D007413:Intestinal Mucosa / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D013467:Sulindac / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D007211:Indoles; D013467:Sulindac; D003474:Curcumin; C016392:3,3'-diindolylmethane