Navitoclax mediates Interleukin-3 induced human umbilical vein endothelial cells survival and angiogenesis

Abstract

Navitoclax is an effective pro-apoptotic agent against cancer cells. Uncontrolled cell survival is a hallmark of pathological angiogenesis in cancer and could promote plaque instability that contributes to atherosclerosis progression owing to intraplaque neovascularization. Cancer cell inhibition by navitoclax can restrain metastasis; therefore, it is possible to reduce endothelial cells survival and is expected to confer a novel therapeutic strategy for advanced atherosclerosis in regards to plaque instability. However, regulation of endothelial cell activity by navitoclax is yet to be examined. This study will analyze navitoclax efficacy in modulating human umbilical vein endothelial cells (HUVEC) viability, proliferation, migration and angiogenesis. Navitoclax concentrations ranging from 0.2 to 3.0µM at four-time points; 18-, 24-, 48- and 72-hours were used for MTT assay. The IC50 value for 18-hours post-treatment was undefined due to low efficacy at a limited time. While for 24-, 48- and 72-hours, the IC50 values were 0.91µM, 0.72µM, and 0.12µM, respectively. Navitoclax potency to inhibit HUVEC viability increased as the treatment time elevated. 0.9µM navitoclax for 24 hours treatment was selected for subsequent experiments. Next, 25 ng/ml IL-3 was used to induce the in-vitro angiogenesis model within 6 hours. Expectedly, navitoclax reduced the tube formation and migration of HUVEC induced by IL-3 in consistent with CXCL-8 released and MMP-3 expression in the cell. However, HUVEC proliferative activity was not affected by navitoclax treatment, as well as the BCL-2 gene expression. Therefore, an anti-angiogenic effect of navitoclax on HUVEC by preventing the cell motility through CXCL-8 and MMP-3 mechanism is determined.