Candesartan induces tumor vascular normalization to improve the efficacy of radiotherapy in the therapeutic window

Abstract

Background: This study sought to examine whether candesartan induces tumor vascular normalization in a narrow therapeutic window to increase perfusion and oxygen content, and thus enhance the effect of radiotherapy (RT). Methods: Candesartan was administered to tumor-bearing mice to induce the normalization of tumor vessels, and the time window for normalization was determined. Then, tumor vascular density, perfusion, pericyte coverage, hypoxia of tumor-bearing mice was detected at 3, 6, 9, 12 days, respectively. In the treatment window, RT was administered to enhance the anti-tumor effect, which was evaluated based on relevant anti-tumor indicators. The tumor volume and tumor weight were recorded. Next, tumor growth inhibition rate was calculated according to the tumor weight. The Tunnel and Ki-67 expression of the tumor tissues of every group was measured to evaluate the effects on tumor proliferation and apoptosis. Results: Based on tumor vascular density, perfusion, pericyte coverage, hypoxia, and other indicators, the tumor vascular normalization window occurred 9 days after the administration of candesartan. The antitumor results showed that administering RT during the therapeutic window enhanced anti-tumor efficacy, with a tumor growth inhibition rate of 66.67%. The results of Tunnel and Ki-67 expression showed that window-period RT significantly promoted tumor cell apoptosis and limited proliferation compared to the control group (P<0.05 in Tunnel expression and P<0.01 in Ki-67 expression). Conclusions: Candesartan regulates the normalization of tumor vessels and increases the sensitivity of RT in the therapeutic window.

The potential of vascular normalization for sensitization to radiotherapy

“…Additionally, HIF-1 regulates the expression of several other angiogenic factors, including placental growth factor, platelet-derived growth factor β (PDGF-β), and angiopoietin-1 and -2 (Ang-1 and Ang-2) [ 57 ]. For example, the angiotensin II receptor antagonist candesartan modulates tumor vascular normalization and improves the sensitivity of radiotherapy during the therapeutic window [ 60 ].…”

Tumor Microenvironment‐Related Sonodynamic Therapy Mediates Tumor Therapy

“…Vascular normalization therapy can inhibit the leakage of blood components, increase the drug concentration of tumor cells, and reduce cancer metastasis. [ 121 ]…”

“…Vascular normalization therapy can inhibit the leakage of blood components, increase the drug concentration of tumor cells, and reduce cancer metastasis. [121] Vascular normalization is beneficial for increasing the intratumor perfusion of nanodrugs by changing angiogenic factors to reshape the tumor's internal vascular system. However, this will increase the coverage of vascular pericytes and reduce the penetration ability of large nanoparticles.…”

Induced Vascular Normalization—Can One Force Tumors to Surrender to a Better Microenvironment?

“…There are two main classes of drugs on the market that target RAAS to decrease blood pressure, either by directly competing with Angt II binding to AT1R (AT1R blockers: ARBs) or by inhibiting the angiotensin-converting enzyme (ACE) to prevent the production of Angt II. ARBs and angiotensin-converting enzyme inhibitors (ACE-Is) are gaining more attention for their potential to create TVN as a way to treat cancer [ 111 ]. In some retrospective studies, researchers found that cancer patients that were using previously prescribed ARB or ACE-I medication while receiving standard cancer treatments including chemotherapy, radiotherapy, or ICIs had better PFS and OS across various cancer types [ 112 , 113 ].…”