Inhibition of Angiogenesis and Extracellular Matrix Remodeling: Role of Renin-Angiotensin System Inhibitors in Bevacizumab -induced Hypertension

Abstract Bevacizumab (Bev) is a humanized vascular endothelial growth factor monoclonal antibody that is used with chemotherapeutic drugs for the treatment of metastatic colorectal cancer (mCRC). Bev-induced hypertension (HT) is the most common adverse reaction during clinical practice. However, at present, appropriate antihypertensive agents for Bev-induced HT are unavailable. In this study, retrospective analysis of clinical data from mCRC patients who received renin-angiotensin system inhibitors (RASIs) showed significant survival benefits of overall survival (OS) and progression-free survival (PFS) over patients who received calcium channel blockers (CCBs) and patients who received no antihypertensive drug. An experiment in HCT116 colon cancer cell xenografts in mice confirmed that combined treatment with Bev and lisinopril (Lis), a RASI, synergistically inhibited subcutaneous tumor growth and enhanced the concentration of 5-fluorouracil (5-Fu) in tumor tissues. Our results showed that the addition of Lis did not interfere with the vascular normalization effect promoted by Bev, but also inhibited collagen and hyaluronic acid (HA) deposition and significantly downregulated the expression of TGF-β1 and downstream SMAD signaling components which were enhanced by Bev, ultimately remodeling primary ECM components. In conclusion, RASIs might be the optimal choice for the treatment of Bev-induced HT in mCRC patients.