Protease inhibitors and carcinogenesis: a review

This brief review article deals with the subject of anticarcinogenic activity of protease inhibitors (PI). Three basic premises are made: (1) Although PI are prevalent constituents of dietary staples such as soy products, which have been epidemiologically associated with reduced cancer incidences at multiple target sites, they are unlikely to be the active anticarcinogenic entities. Cooked soy products, which are devoid of PI activity, are equally as effective at reducing cancer development as raw soy products. Isoflavones are likely to represent major chemopreventive agents in soy, although other constituents may well contribute. (2) Although supplementation of diets with PI (natural or synthetic), or direct topical administration, results in lower cancer incidences in many experimental models in vivo, this effect appears to be indirect. Dietary PI are, in general, poorly absorbed from the GI tract, and never reach target organs in any measurable quantity. The most attractive hypothesis is that dietary PI could induce synthesis and distribution of endogenous PI (acute-phase reactants), which have widespread effects on cell growth and behavior. Effects of topical administration of PI also encompass prominent anti-inflammatory effects. (3) A spectrum of PI inhibit in vitro transformation induced by a variety of carcinogenic agents. Their effects can be grouped into three basic categories, affecting: (a) signal transduction pathways; (b) DNA repair processes; and (c) nuclear proteases. I suggest that the nuclear multicatalytic protease activity, in particular the chymotrypsin-like activity, represents an important cellular target for which considerable anecdotal support can be garnered.