Extracellular acidification is known to be a driving force in pancreatic cancer growth and metastasis. Thus, manipulation of acidic peritumoral pH or blockage of key proteins stimulated by acidic extracellular microenvironment may offer considerable potential for pancreatic cancer therapy. Cathepsin S, also known as CTSS or CatS, is a critical proteolytic enzyme found to be up-regulated in malignant cells and secreted into the extracellular milieu to degrade surrounding matrix components. By examining the effect of low pH (6.7) on various pancreatic tumor cell lines, we detected a consistently increased CTSS expression associated with augmented cell migration and invasion. Other features such as CTSS-mediated proteolysis and ECM degradation were also observed under mildly acidic condition. Based on these findings, we designed and synthesized some new small molecules bearing an α-ketoamide warhead to evaluate their ability to inhibit CTSS. Kinetic study revealed these compound inhibitors possess very low Ki values and high specificity against target CTSS enzyme. Further in vitro and in vivo analyses demonstrated these agents not only could protect fibronectin from CTSS-mediated degradation but also induce tumor cell autophagy under extracellular acidification. Together these results indicate the potential of α-ketoamide derivatives as antitumor agents against pancreatic cancer.
Date:
2014-10
Relation:
Cancer Research. 2014 Oct;74(19 Suppl.):Abstract No. 4982.
