Therapeutic Promise of Dabigatran Etexilate, an Oral Direct Thrombin Inhibitor in a Preclinical Model of Colon Carcinogenesis

Abstract

Clinical observations suggest that there is activation of the coagulation system in patients of colon cancer. The resulting thrombin is implied in further exacerbation in the progression of colon cancer. We evaluated the effect of dabigatran etexilate (DE), an oral direct thrombin inhibitor in a preclinical model of 1, 2-Dimethylhydrazine (DMH) induced colon carcinogenesis in rats. DE reduced carcinogenesis induced gross morphological changes and colonic edema as compared to induced control. DE treatment significantly reduced levels of VEGF and ERK/MAPK and displayed a significant increase in colonic E-cadherin and reduction in N-cadherin, Twist and mTOR expression. Histopathologically, DE prevented the DMH induced adenocarcinomatous changes in the rat colon. Dual treatment of DE+5FU provided an additive effect as compared to the single treatment schedules of DE and 5FU, respectively. The preclinical study provides preliminary evidences on the promise of DE in treating DMH induced colon carcinogenesis in rats. The study portrays the effective role of DE treatment schedules both alone and in combination with 5FU in abating the parameters associated with progression of colon carcinogenesis expressing amelioration of factors mediating EMT, an important prelude to disease aggression and metastasis. A temporal association was drawn between administration of DE and improvement in colon cancer associated clinical end points. This investigation strongly suggests the role of thrombin in progression of carcinogen induced colon cancer and substantiates the role of direct thrombin inhibitors in treating colon cancer.