RESUMO
Colorectal cancer (CRC), associated with an increased intake of processed red meats, saturated fats, and simple carbohydrates accompanied by low dietary fiber, fruits, and vegetables consumption, presents a high epidemiological burden. Connexin43 (Cx43) protein, which forms gap junctions or hemichannels, has tumor suppressor or oncogenic activities in a cancer type- and stage-dependent manner. Cx43 expression varies during colon carcinogenesis, and its functional role is not fully understood. Thus, we evaluated the implications of Cx43 heterologous deletion (Cx43+/-) during the early stages of a chemically induced model of colon carcinogenesis. Female C57BL/6J mice (wild-type or Cx43+/-) were submitted to a colon carcinogenesis model induced by 1,2 dimethylhydrazine (DMH). Mice were euthanized eight hours (week 7) or 30 weeks (week 37) after the last DMH administration to evaluate subacute colon toxicity outcomes or the burden of (pre)neoplastic lesions, respectively. At week 7, Cx43 deficiency inferred no alterations in the DMH-induced increase in systemic (peripheral blood), in situ (colonocytes) DNA damage, and apoptosis in the colonocytes. At week 30, Cx43+/- mice presented an increase in preneoplastic aberrant crypt foci (ACF) multiplicity, while no alterations were observed in colorectal adenoma (CRA) occurrence, multiplicity, volume, proliferation, growth, and ß-catenin immunoexpression. Similarly, an in silico analysis of human CRA showed decreased mRNA expression of Cx43 with no correlation with proliferation, apoptosis, and ß-catenin markers. These findings indicate the discrete role of Cx43 in the early stages of chemically induced mouse colon carcinogenesis.
RESUMO
Benzo(a)pyrene (BaP) is a polycyclic aromatic hydrocarbon widespread in the environment and closely associated to tobacco use, which is an important risk factor for highly incident stomach cancer. Menthol, a monoterpene extracted from Mentha genus species, has multiple biological properties, including anti-inflammatory and gastroprotective properties, but its effects on carcinogenesis are still to be fully understood. Thus, we evaluated the modifying effects of Ment against BaP-induced forestomach carcinogenesis. Female Swiss mice received BaP by intragastrical (i.g.) administration (50 mg/kg of body weight [b wt], 2×/week), from weeks 1-5 weeks. Concomitantly, mice received Menthol at 25 (Ment25) or 50 (Ment50) mg/kg b wt (i.g, 3×/week). Animals were euthanized at weeks 5 (n = 5 mice/group) or 30 (n = 10 mice/group). At week 5, both Ment doses reduced peripheral leukocyte blood genotoxicity 4 h after the last BaP administration, but only Ment50 attenuated this biomarker 8 h after the last BaP administration. In accordance to these findings, both Ment interventions attenuated BaP-induced increase in the percentage of H2A.X-positive forestomach epithelial cells. Moreover, Ment50 reduced cell proliferation and apoptosis (i.e., Ki-67 and caspase-3, respectively) in forestomach epithelium but exerted no significant effects on NFκB, and Nrf2 protein levels. At week 30, Ment50 reduced by ~55% the incidence of BaP-induced forestomach diffuse hyperplasia and multiplicity of forestomach tumors (squamous cell papillomas and carcinomas). Our findings indicate that Ment50, administered during initiation phase, attenuates forestomach carcinogenesis by reducing early genotoxicity, cell proliferation, and apoptosis induced by BaP.