Abstract
5-Fluorouracil (5-FU) is one of the most effective drugs for the treatment of colorectal cancer (CRC). However, there is an urgent need in reducing its systemic side effects and chemoresistance to make 5-FU-based chemotherapy more effective and less toxic in the treatment of CRC. Here, enalapril, a clinically widely used antihypertensive and anti-heart failure drug, has been verified as a chemosensitizer that extremely improves the sensitivity of CRC cells to 5-FU. Enalapril greatly augmented the cytotoxicity of 5-FU on the cell growth in both established and primary CRC cells. The combination of enalapril and 5-FU synergistically suppressed the cell migration and invasion in both 5-FU-sensitive and -resistant CRC cells in vitro, and inhibited angiogenesis, tumor growth, and metastasis of 5-FU-resistant CRC cells in vivo without increased systemic toxicity at concentrations that were ineffective as individual agents. Furthermore, combined treatment cooperatively inhibited NF-κB/STAT3 signaling pathway and subsequently reduced the expression levels of NF-κB/STAT3-regulated proteins (c-Myc, Cyclin D1, MMP-9, MMP-2, VEGF, Bcl-2, and XIAP) in vitro and in vivo. This study provides the first evidence that enalapril greatly sensitized CRC cells to 5-FU at clinically achievable concentrations without additional toxicity and the synergistic effect may be mainly by cooperatively suppressing proliferation, angiogenesis, and NF-κB/STAT3-regulated proteins.
Highlights
The incidence and mortality of colorectal cancer (CRC)are in the forefront of malignancies[1]
Enalapril combination with 5-FU extremely decreased cell viability in HCT116 cells by 87% and in SW620 cells by 83% at 72 h, which was much stronger than each agent alone in a time-dependent manner (Fig. 1b, c and Supplementary Fig. 1C), suggesting that the different susceptibility of 5-FU in both cell lines disappeared after the addition of enalapril in both moderately sensitive and resistant CRC cells
We for the first time demonstrated that enalapril, a clinically widely used antihypertensive drug, significantly enhanced the efficacy of 5-FU in suppressing tumor growth and metastasis in CRC without additional toxicity through inhibition of proliferation, angiogenesis, and nuclear factor-κB (NF-κB)/STAT3-regulated proteins, showing an attractive therapeutic strategy for CRC
Summary
The incidence and mortality of colorectal cancer (CRC)are in the forefront of malignancies[1]. The toxic side effects and therapeutic resistance of chemotherapy drugs are the main obstacles to successfully cure CRC2,3. 5-Fluorouracil (5-FU) is one of the most widely used chemotherapy drugs in CRC with an overall response rate. Angiotensin-converting enzyme (ACE) inhibitors are widely used antihypertensive and anti-heart failure drugs clinically clinically[7]. Yang et al Cell Death and Disease (2020)11:477 factors in activating nuclear factor-κB (NF-κB) signaling to upregulate vascular endothelial growth factor (VEGF) expression[8,9]. ACE inhibitors including enalapril have been confirmed to suppress tumorigenesis and angiogenesis in other cancer mouse models, and that suppression of the VEGF level may be involved in the mechanism of this inhibitory effect[8,12,13]. The underlying mechanisms of the antitumor effects of ACE inhibitors are still unknown
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