Proteases, protease inhibitors and radiation carcinogenesis

Abstract

Purpose

The purpose of the studies described in this mini review article was to identify nontoxic compounds that could prevent or suppress the radiation induced malignant transformation of cells and be useful as human cancer preventive agents.

Conclusions

(1) Many different types of potential anticarcinogenic substances were evaluated initially for their abilities to prevent or suppress radiation induced malignant transformation in vitro, and certain anticarcinogenic protease inhibitors (APIs) were observed to be the most powerful anticarcinogenic agents at suppressing this surrogate endpoint biomarker of radiation carcinogenesis. (2) Within the category of APIs, those that inhibited the activity of chymotrypsin were effective at far lower molar concentrations than other APIs. The soybean-derived protease inhibitor known as the Bowman-Birk inhibitor (BBI) is a particularly powerful chymotrypsin inhibitor that is able to prevent radiation induced transformation in vitro (at concentrations down to nanomolar levels) as well as radiation induced carcinogenesis in vivo without toxicity. (3) There were many other unusual characteristics of APIs that led to the selection of one of these APIs, BBI, as the most appropriate compound for us to develop as a human cancer preventive agent. As one example, the APIs have an irreversible effect on carcinogenesis, while the effects are reversible for most anticarcinogenic agents when they are removed from carcinogenesis assay systems. (4) Numerous studies were performed in attempts to determine the potential mechanisms by which the APIs could prevent or suppress radiation induced carcinogenesis in in vitro and in vivo systems, and the results of these studies are described in this review article. The APIs and the proteases which interact with them appear to play important roles in radiation carcinogenesis. (5) Preparations for human trials using BBI began decades ago. The cost of preparing purified BBI was far too high to consider performing human trials with this agent, so BBI Concentrate (BBIC), a soybean extract enriched in BBI, was developed for the specific purpose of performing human trials with BBI. BBIC achieved Investigational New Drug (IND) Status with the Food and Drug Administration in April,1992, and human BBIC trials began at that time. (6) Several human trials were performed using BBIC and they indicated many potentially beneficial health effects produced by BBIC administration to people in various forms (e.g. tablets). 7) It is hypothesized that BBI takes the place of α-1-antichymotrypsin, an important regulatory compound in the human body, and helps to maintain homeostasis.

Keywords:

• Proteases
• protease inhibitors
• radiation carcinogenesis
• Bowman-Birk Inhibitor (BBI)

Acknowledgments

Numerous grants from the National Cancer Institute, NASA and the National Space Biomedical Research Institute (NSBRI) are acknowledged for providing funding for some of the studies on proteases and protease inhibitors discussed in this manuscript. It is also acknowledged that individuals from the National Cancer Institute and Central Soya Co. were extremely helpful in our efforts to obtain IND status from the FDA for BBIC so that several different trials involving the use of BBIC could be performed. The many highly skilled investigators in my laboratories at Harvard and the University of PA who contributed to the BBI research findings discussed in this paper are also acknowledged.

Disclosure statement

I am one of the inventors listed on a total of 11 patents related to the methods of production and effects of ‘Bowman-Birk Inhibitor Concentrate’ (BBIC); 9 of these patents are over 20 years old now, but the patents issued in 2004 and 2011 are currently within the 20 year patent protection period (these patents are related to the beneficial effects of BBIC in muscular dystrophy and multiple sclerosis). The owner of all 11 of the patents is the University of Pennsylvania. I am not now receiving any funds connected with these patents, and I do not expect to receive any funds related to these patents in the foreseeable future. (The Company that made BBIC available for the experiments described in these patents, Central Soya, is no longer in business and no other source for producing BBIC is available.)

Additional information

Notes on contributors

Ann R. Kennedy

Ann R. Kennedy is a Professor in the Department of Radiation Oncology at the University of Pennsylvania Perelman School of Medicine. She received her doctoral degree in Radiation Biology from Harvard University in 1973; her mentor at Harvard was John B. Little, MD. She remained at Harvard as a faculty member for many years before joining the faculty at the University of Pennsylvania in 1988. She has been performing research on mechanisms of radiation carcinogenesis and cancer prevention for her entire career, with research investigations including studies on molecular mechanisms involved in radiation effects in cells and animals. Much of the work in the Kennedy laboratory has focused on the soybean-derived protease inhibitor known as the Bowman-Birk inhibitor (BBI). BBI was originally identified as a cancer preventive agent from in vitro studies, and was then shown to prevent the development of cancer in many different models of animal carcinogenesis. BBI, as Bowman Birk Inhibitor Concentrate (BBIC), has been evaluated as a human cancer chemopreventive agent and as a therapeutic agent for several different human diseases. Much of her recent effort has been aimed at developing countermeasures for radiation induced adverse health effects which could occur in astronauts during space travel.