Solid
tumor growth is dependent on angiogenesis, the formation of neovasculature from existing vessels. Endothelial activation of the
extracellular signal-regulated kinase 1/2, c-jun NH(2)-terminal
kinase, and
p38 mitogen-activated protein kinase pathways is central to this process, and thus presents an attractive target for the development of
angiogenesis inhibitors.
Anthrax lethal toxin (LeTx) has potent catalytic
mitogen-activated protein kinase inhibition activity. Preclinical studies showed that LeTx induced potent
tumor growth inhibition via the inhibition of xenograft vascularization. However, LeTx receptors and the essential
furin-like activating
proteases are expressed in many normal tissues, potentially limiting the specificity of LeTx as an
antitumor agent. To circumvent nonspecific LeTx activation and simultaneously enhance
tumor vascular targeting, a substrate preferably cleaved by the
gelatinases class of
matrix metalloproteinases (
MMP) was substituted for the
furin LeTx activation site. In vivo efficacy studies showed that this
MMP-activated LeTx inhibited
tumor xenografts growth via the reduced migration of endothelial cells into the
tumor parenchyma. Here we have expanded on these initial findings by showing that this
MMP-activated LeTx reduces endothelial proangiogenic
MMP expression, thus causing a diminished proteolytic capacity for extracellular matrix remodeling and endothelial differentiation into capillary networks. Additionally, our data suggest that inhibition of the c-jun NH(2)-terminal
kinase and p38, but not
extracellular signal-regulated kinase-1/2, pathways is significant in the antiangiogenic activity of the
MMP-activated LeTx. Collectively, these results support the clinical development of the
MMP-activated LeTx for the treatment of solid
tumors.