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Prevention of Carcinogenesis by Protease Inhibitors¹

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Protease inhibitors are very effective in their ability to suppress carcinogenesis in many different in vivo and in vitro assay systems. One particularly effective protease inhibitor, the soybean-derived Bowman-Birk inhibitor, has been extensively studied in our laboratory. Our results have indicated that Bowman-Birk inhibitor suppresses carcinogenesis 1) induced by several different types of carcinogens, 2) in three different species (mice, rats, and hamsters), 3) in several different tissues/organs [colon, liver, lung, esophagus, and cheek pouch (oral epithelium)], 4) when administered to animals by several different routes (including the diet), 5) involving several different types of tumors (squamous cell carcinomas, adenocarcinomas, angiosarcomas, etc.), and 6) in different cell types [epithelial cells (in the colon, liver, lung, esophagus, and cheek pouch) as well as connective tissue cells (fibroblasts, both in vitro and those in the liver which give rise to angiosarcomas)]. Thus, the remarkable ability of Bowman-Birk inhibitor to serve as an anticarcinogenic agent has been demonstrated in a variety of different carcinogenesis assay systems.

Although the mechanism of action of protease inhibitors as anticarcinogenic agents is unknown, many hypotheses have been presented. Our results suggest that anticarcinogenic protease inhibitors are capable of reversing the initiating event in carcinogenesis, presumably by stopping an ongoing process begun by carcinogen exposure. We have observed several effects of protease inhibitors which are thought to be related to their anticarcinogenic activity; these include 1) the ability to affect the expression of certain oncogenes (e.g., c-myc and c-fos) and 2) the ability to affect the levels of certain types of proteolytic activities (e.g., N-t-butoxycarbonyl-Val-Pro-Arg-7-amino-4-methylcoumarin-hydrolyzing activity) which are elevated in carcinogen-exposed tissues.

We have also observed other effects of anticarcinogenic protease inhibitors which may be related to carcinogenesis. For example, we have reported that the inhibitors can reduce the carcinogen-induced, elevated levels of gene amplification to nearly normal levels. While all of these effects of protease inhibitors may contribute to the prevention of carcinogenesis, the mechanism by which protease inhibitors prevent cancer cannot be determined with certainty until the mechanisms involved in cancer induction are known. While the mechanism remains unclear, it is clear that protease inhibitors can reverse a number of carcinogen-induced cellular changes which may play important roles in carcinogenesis.