Anti-angiogenic activity of chloride and potassium channel modulators: repurposing ion channel modulators

Abstract

Abstract Background Excessive angiogenesis can be the root cause of many pathological conditions. Various types of ion channels are found on the endothelial cells. These ion channels play a vital role in the multi-stepped process of angiogenesis. The study aims to investigate the anti-angiogenic effects of specific ion channel modulators mefloquine (volume-regulated chloride channel blocker), lubiprostone (ClC-2 channel agonist), and 4-aminopyridine (voltage-gated potassium channel blocker). Results The anti-angiogenic activity of ion channel modulators was screened by measuring its effects on the area of neovascularization and histopathological studies by in vivo (corneal neovascularization) method and by in vitro assays, endothelial cell proliferation assay, cell migration assay, and matrigel cord-like morphogenesis assay. The test and standard drug (bevacizumab) groups were compared with the control group using one-way ANOVA, followed by post hoc test, and Dunnett’s test to compare the mean of all the groups with the control mean. The results revealed that mefloquine at the dose of 0.6% w/v and 1.0% w/v, lubiprostone at the dose of 0.5% w/v and 1.0% w/v, and 4-aminopyridine at the dose of 2% w/v and 4% w/v showed significant anti-angiogenic property. In the studies on human umbilical vein endothelial cells, the test drugs (100 nM) showed significant inhibition of proliferation, migration, and decrease in network length of cord-like tubes. Conclusion The scientific findings indicate that the test drugs have potent anti-angiogenic activity by inhibiting the cell proliferation, inhibiting the cell volume increase, arresting the cell cycle progression and by causing membrane hyperpolarization. The potent anti-angiogenic drugs obtained by repurposing these ion channel modulators, in the further studies, will be able to treat the diseases due to excess angiogenesis from the root cause. Graphical abstract

Keywords

• Anti-angiogenesis
• Ion channel modulators
• Corneal neovascularization
• Mefloquine
• Lubiprostone
• 4-Aminopyridine