The vascular endothelium is one of the first barriers encountered by drugs and xenobiotics, which, once administered, enter the blood stream and diffuse to all organs through blood vessels. The continuous exposure of endothelial cells to drugs and chemical compounds turns out to be a huge risk for the cardiovascular system, as these substances could compromise endothelial vitality and function and create irreparable, localized or systemic damages. For this reason, a special attention should be paid to the safety of developing drugs on the cardiovascular system. In this study we focused our attention on carbonic anhydrase (CA)-IX inhibitors. CA-IX is an enzyme over-expressed in tumor cells in response to hypoxia, which is involved in pH control of the neoplastic mass microenvironment and in tumor progression. Specifically, we evaluated the safety on human umbilical vein endothelial cells (HUVEC) of CA-IX inhibitor AA-06-05, compared to its lead compound SLC-0111, for which the efficacy on tumor cells has already been proven. In this analysis we detected an impairment in viability and mitochondrial metabolism of HUVECs treated with AA-06-05 (but not with SLC-0111) in the concentration range 1-10 μM. These data were accompanied by an increase in the expression of the cell cycle negative regulator, p21, and a down-regulation of the pro-survival proteins ERK1/2 and AKT, both in their phosphorylated and total forms. The data obtained document the likelihood for CA-IX inhibitor AA-06-05 to be developed as new anticancer drug, but a particular attention should be paid to its potential side effects on endothelial cells due to its targeting on other CA isoforms as CA-I, with ubiquitous localization and physiological significance.
Keywords: Carbonic anhydrase inhibitors; Cardiovascular safety; Drug development; Endothelium; Hypoxic tumors; Vascular endothelial growth factor.
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