Trypanosoma cruzi infection and/or administration of the nonsteroidal anti-inflammatory nimesulide increase the number of colonic crypts overexpressing metallothioneins in rat colon carcinogenesis

Abstract

Trypanosoma cruzi infection and nonsteroidal anti-inflammatory drugs inhibit colorectal carcinogenesis by mechanisms not completely known and metallothionein proteins (MTs) may be involved in this process. Sixty-six male Wistar rats weighing 90 to 120 g were randomly divided into seven groups (GI to GVII). GI, GII and GIII animals were subcutaneously infected with 200,000 trypomastigote forms of the Y strain of T. cruzi. After 8 weeks, GI, GII, GIV, and GVI were injected with one weekly subcutaneous dose of 12 mg/kg dimethylhydrazine for 4 weeks. In sequence, GI, GIV and GV were treated with nimesulide (10 mg/kg per dose, five times per week for 8 weeks). Groups I, III, IV, and VI had 12 animals, and each of the other groups had 6 animals. All the animals were euthanized 8 weeks after the last dimethylhydrazine injection. The colons were fixed and processed for MT immunohistochemistry. The index of MT-overexpressing colonic crypts (MTEC) was estimated as the percentage of MT-stained crypts in relation to the total number of crypts scored. Five hundred crypts per animal were scored. Data were analyzed by the Kruskal-Wallis test followed by the Dunn test. There was an increase in MTEC index in the groups either infected with T. cruzi or treated with nimesulide or both infected and treated when compared to control (401, 809, and 1011%, respectively). We suggest that the increased formation of MTEC may be related to the protection against carcinogenesis provided both by T. cruzi infection and nimesulide.

Expression of Metallothionein after Administration of Aspirin, Vitamin C or Zinc Supplement in the DMH Induced Colon Carcinoma in Rat

“…In the cancerous group there was a 24.6 fold increase in MT mRNA expression which was reflected in an increase in the MT immunohistochemical expression (200%) along with a concomitant increase in MT protein content (109%) as compared with the DMH only treatment group. Our study is in agreement with a study reported by Escalante et al, (2006), that ingestion of the NSAID -Nimesulide along with administration of DMH was associated with an increase in the number of MT-over expressing colonic epithelial cells, as measured by Immunohistochemistry, when compared to the DMH only treated rats. Comparison of the MT mRNA expression, protein expression and MT content in the large intestine in DMH treated rats without aspirin as shown in our previous study (Christudoss et al, 2016) and with aspirin therapy as observed in the present study demonstrates significant improvement in the metallothionein parameters in the aspirin co-treated group.…”

“…NSAIDs may inhibit colon carcinogenesis by mechanisms not known and metallothionein proteins (MTs) may be involved in this process as shown with administration of nimuselide in rats. Interestingly it has been shown that NSAIDs are reported to cause a marked increase in MT expression in rats (Escalante et al, 2006). Intracellular ascorbic acid can protect against 3238 oxidative DNA damage in a dose dependent manner.…”

Overexpression of metallothioneins, stem cell niches and field cancerization in experimental gliomagenesis

“…Finally, we and other authors have shown that the amount of MT overexpressing cells correlates well with factors that are known to influence colon carcinogenesis, such as the non-steroidal anti-inflammatory drugs and diet 4,7 . In case this occurs in the glia, the MT staining may provide a simple and reliable method to design short-term studies to verify factors that could influence gliomagenesis, by evaluating the number of MTOEC formation and proliferation.…”

“…The paraffin-mounted serial sections of the rat's spinal cord were used for MT immunohistochemistry staining. Immunohistochemical detection of MT protein in cold acetone-fixed paraffin embedded spine cord sections was performed by the streptavidin-avidin-biotin-immuno peroxidase complex method, as previously described 5,7 . Two investigators (SB Garcia and Vinicius) independently evaluated the immunohistochemistry.…”

Formas digestivas da doença de Chagas e carcinogênese: um estudo de associação

“…As metalotioneínas podem exercer funções protetoras durante o dano ao DNA, presumivelmente por atuarem como antioxidantes. Observou-se que a carcinogênese colorretal é caracterizada por uma diminuição significativa da expressão de MT 16 . A infecção pelo T. cruzi, por sua vez, causa um aumento pronunciado da expressão de MT, assim como ocorre na utilização de anti-inflamatórios não hormonais (AINH).…”