Inhibitors of Proteinases as Potential Anti-Cancer Agents

Abstract

Cancer is a collection of over 100 devastating diseases that share a number of characteristics, a primary hallmark of which is out-of-control growth. However, in reality there are significant differences among these diseases, a fact that underlies the difficulties in the past few decades in their chemotherapeutic intervention. It is becoming evident that there are multiple routes to development of cancer, in part because so many distinct metabolic and biochemical steps can be altered to give rise to uncontrolled cell growth. There is a positive correlation between the aggressiveness of a tumor and the secretion of various proteinases. Using bioinformatic analysis approximately 600 proteinases have been determined in human and mouse genomes (2-4% of the genome), many of which are orthologous (Puente et al., 2003). Only some of them are involved in tumor progression and growth, both at the primary and metastatic sites. As tumor progresses towards increased malignancy, it passes through several important stages that require the action of proteinases. First, the induction of angiogenesis requires degradation of the vascular basement membrane and the release of matrix-bound proangiogenic growth factors. Second, invasion of cancer cells into the surrounding tissue involves the dissolution of cell-cell junctions, degradation of the epithelial basement membrane and remodeling of extracellular matrix to allow cancer cells to be released from the primary tumor mass. Third, at least two key steps in metastasis require proteolysis: intravasation of cancer cells into the blood or lymphatic circulation at the primary site and then extravasation at the secondary site, where proteinases can play a part in promoting the colonization and growth of cancer. Proteinases may co-operatively mediate these steps with individual ones having distinct roles. Therefore, inhibition of their activity might be one of the means to combat the development of cancer. Despite of the described facts, recent findings have revealed that the functions of proteinases in tumors are significantly more complex and varied. For example, they are now seen as extremely important signaling molecules that are involved in numerous vital processes. Proteinase signaling pathways are strictly regulated, and the deregulation of their activities can lead to various pathologies, including cancer. Thus, construction of the inhibitor, which should have an impact on tumor progression and metastasis, cannot be done without placing certain proteinase in the proper metabolic context. Inhibitor therapy design is further complicated because different types of cancers utilize diverse proteinases at varying stages of cancer development.