Antiangiogenic effect of TW37, a small-molecule inhibitor of Bcl-2
Dr. Benjamin D. Zeitlin: 0000-0003-0110-0188
Bcl-2 is an antiapoptotic protein that is up-regulated in several tumor types, and its expression levels have strong correlation, to development of resistance to therapy and poor prognosis. We have shown recently that Bcl-2 also functions as a proangiogenic signaling molecule that activates a nuclear factor-kappa B-mediated pathway resulting in up-regulation of the angiogenic chemokines CXCL1 and CXCL8 by neovascular endothelial cells. Here, we evaluate the antiangiogenic effect of the novel small-molecule inhibitor of Bcl-2 (TW37) developed using a structure-based design strategy. We observed that TW37 has an IC50 of 1.8 mu mol/L for endothelial cells but showed no cytotoxic effects for fibroblasts at concentrations up to 50 mu mol/L. The mechanism of TW37-induced endothelial cell death was apoptosis, in a process mediated by mitochondrial depolarization and activation of caspase-9 and caspase-3. The effect of TW37 on endothelial cell apoptosis was not prevented by coexposure to the growth factor milieu secreted by tumor cells. Inhibition of the angiogenic potential of endothelial cells (i.e., migration and capillary sprouting assays) and expression of the angiogenic chemokines CXCL1 and CXCL8 were accomplished at sub-apoptotic TW37 concentrations (0.005-0.05 mu mol/L). Notably, administration of TW37 i.v. resulted in a decrease in the density of functional human microvessels in the severe combined immunodeficient mouse model of human angiogenesis. In conclusion, we describe functionally separate proapoptotic and antiangiogenic mechanisms for a small-molecule inhibitor of Bcl-2 and show the potential for Bcl-2 inhibition as a target for antiangiogenic therapy.
Zeitlin, B. D.,
Nör, J. E.
Antiangiogenic effect of TW37, a small-molecule inhibitor of Bcl-2.
Cancer Research, 66(17), 8698–8706.