Inibição do mTOR agrava a mucosite intestinal induzida por irinotecano

Abstract

INTRODUCTION. Colorectal cancer (CRC) is one of the most prevalent neoplasms worldwide, being one of the leading causes of death from cancer. In Brazil, it is the third most frequent cancer in men and second in women. In the last decades new drugs incorporated into the clinical protocols for the treatment of mCRM have provided a significant increase in the survival of patients with this type of malignancy. Among these drugs, irinotecan occupies a prominent place and is commonly used as the first line in the treatment of metastatic RCC. However, since all chemotherapy treatments have a burden, a quarter of patients receiving irinotecan have a severe intestinal mucositis as a more noticeable side effect. Deregulation of cell signaling pathways is certainly one of the main reasons for the development of cancer. The mammalian rapamycin target protein (mTOR) is responsible for cell growth and the PI3K / Akt / mTOR axis is often dysregulated in several types of cancer. Thus, this work focused on investigating the role of mTOR during experimental intestinal mucositis induced by irinotecan. METHODS. C57BL / 6 male mice (n = 6 / group) were given intraperitoneally with saline or irinotecan (75 mg / kg or 45 mg / kg) for four consecutive days and treated with rapamycin or everolimus (mTOR inhibitors, 1.5 mg / Kg and 3 mg / kg, respectively) followed by irinotecan administration. Periodically the body weight variation and scores were evaluated for the degree of diarrhea. After euthanasia of the animals, ileus samples were collected for determination of myeloperoxidase activity (MPO), histopathology and morphometric analysis and cytokine levels measurement [KC (human IL-8 analogue chemokine), IL-1β, TGF-β And IFN-γ]. Gene expression of the mRNA of the PI3K / Akt / mTOR pathway proteins was performed by qRT-PCR. Blood was also collected from the animals to evaluate the total white blood cell count. The ANOVA / Bonferroni or Kruskal-Wallis / Dunn tests were used for statistical analysis. P <0.05 was accepted as significant. The present work was approved by the ethics committee of UFC (protocol number 100/14). RESULTS. Animals injected with irinotecan 75 mg / kg showed an increase in the gene expression of PI3K, Akt and mTOR mRNA evidencing the participation of the pathway in iatrogeny. Irinotecan 75 mg / kg significantly reduced body weight, total leukocyte count, villus / crypt ratio and promoted a characteristic intestinal lesion when compared to the saline control group. In addition, inhibition of mTOR with rapamycin or everolimus generally aggravated most of these parameters, such as weight loss, diarrhea, histopathology, neutrophil infiltration, and inflammatory mediators such as TGF-β and IFN-γ. CONCLUSION. Inhibition of mTOR aggravates irinotecan-induced intestinal mucositis probably by increasing the pro-inflammatory response via TGF-β and IFN-γ with important involvement of Paneth's Cells. Financial support: CNPq.