The Angiotensin-Converting Enzyme Inhibitor 'Enalapril' Increases the Anti-Proliferative Activity of 5-Fluorouracil in Colorectal Cancer Cells

Objectives:The dysregulation of angiotensin-converting enzyme inhibitor (ACE-I) and its pathway has been reported to be associated with oncogenesis and poor prognosis in colorectal cancer (CRC). Methods: We explored the therapeutic potential of targeting ACE-I through the use of enalapril and investigated its pharmacological interaction with 5-FU in CT26, HT29, a nd SW480 cells. The anti-proliferative and anti-migratory effects as well as apoptotic activity of this agent on cell cycle have been evaluated by MTT, wound healing assay, and FACS, while the expression of genes was determined through mRNA or protein levels. Results: According to the observations, enalapril has inhibited cell proliferation in a dose-dependent manner and affected the anti-tumor properties of 5-FU via increasing the levels of apoptosis and ROS, as well as through the modulation of antioxidant/oxidant markers. Enalapril has also suppressed cell migration by the perturbation of MMP3/MMP-9 and E-cadherin. The combination of enalapril and 5FU has resulted in decrease in the expression levels of ACE, AT1R, and SMAD-3. Conclusion: Our findings suggested that targeting ACE-I by applying the modulation of angiotensin pathway could increase the activity of 5-FU due to interfering with cell-proliferation, apoptosis, and inflammatory markers, which is indicative of its potential value as a therapeutic option for the treatment of CRC.