Development of the Bowman‐Birk inhibitor for oral cancer chemoprevention and analysis of neu immunohistochemical staining intensity with Bowman‐Birk inhibitor concentrate treatment

Abstract

ObjectiveslHypothesis: Cancer chemoprevention is a rapidly evolving approach to reverse or inhibit carcinogenesis, and there is active interest in development of effective chemopreventive agents against head and neck cancers. The retinoids are archetypal chemopreventive agents for oral premalignant lesions. They have significant clinical effect, but widespread use is limited by significant clinical toxicity. The Bowman-Birk Inhibitor is one of several nontoxic compounds exhibiting both potent anticarcinogenic activity and minimal toxicity. The purposes of the study were to summarize the preclinical and clinical development of Bowman-Birk Inhibitor and a Bowman-Birk Inhibitor concentrate against oral premalignant lesions and to evaluate Neu immunohistochemical staining intensity for lesions and simultaneously obtained biopsy specimens of normal-appearing mucosa from the Phase IIa Bowman-Birk Inhibitor concentrate oral leukoplakia chemoprevention trial. Study Design: Part I is a selected literature review. Part I1 is a retro- Methods: Thirty-two sets of biopsy specimens from lesions and uninvolved oral mucosa before and after treatment with Bowman-Birk Inhibitor concentrate in doses ranging from 200 to 1066 chymotrypsin inhibitory units were examined in blinded fashion for Neu immunohistochemical staining intensity using the 3B-5 monoclonal antibody. Staining intensity scores among the lesion and control biopsy specimens before and after Bowman-Birk Inhibitor concentrate treatment were analyzed and compared with previously obtained values for serum Neu, oral mucosal cell Neu, protease activity, and clinical response to treatment. Results: Mean Neu staining score was significantly higher in lesions compared with un-

Plant Protease Inhibitors in Therapeutics-Focus on Cancer Therapy

“…BBIC shows promise to become an effective nontoxic chemopreventive agent based on results of extensive preclinical studies, and Phase I and Phase IIa clinical trials. BBIC has dose-related clinical activity against oral leukoplakia and modulates levels of Neu (Neu immune histochemical staining intensity for lesions) and protease activity (Armstrong et al, 2003). Wan et al (1999a) have reported a specific substrate hydrolysis methodology to measure the protease activity of human oral mucosal cells.…”

Soy, phytoestrogens and their impact on reproductive health

“…Other proteins or peptides present in lower amounts include enzymes such as lipoxygenase, chalcone synthase and catalase. Peptides such as lunasin (a 43 amino acid protease inhibitor) and the Bowman-Birk inhibitor (a 71 amino acid protease inhibitor) have been reported to have an anticancer capacity or an in vitro chemopreventative effect (Armstrong et al, 2003;Galvez et al, 2001;Lam et al, 2003). Some of the health benefits attributed to soy may result from the release of biologically active peptides by enzymatic proteolysis during gastrointestinal digestion or during the fermentation of soy proteins.…”

The role of nutraceutical proteins and peptides in apoptosis, angiogenesis, and metastasis of cancer cells

“…The same study demonstrated the noncytotoxic effect of BBI when its protease inhibitor activity was removed. This protease inhibitor also demonstrated its in vitro chemopreventive effect on other types of cancer such as oral cavity [36,37] and lung cancer [38,39]. In contrast to previous studies, a [24,25] Suppressed proliferation of breast cancer cells through accumulation of MAPK phosphatase-1 and induction of apoptosis and lysosome membrane permeabilization (20 and 200 μM, in vitro) [26,29] Induced apoptosis in prostate cancer cells through upregulation of Cx43 (500 μg/ml and 2000 mg/kg/day, in vitro and in vivo) [31] Antiproliferative effects on human colon cancer cells μM, in vitro) [33][34][35] Kunitz trypsin inhibitor Suppressed cancer invasion and metastasis through inhibition of uPA expression (10 μM and 50 g/kg diet, in vitro and in vivo) [40,42] Suppressed LPS-induced and UV-induced cytokine production (5 μM, in vitro) [ 163,164] Inducted apoptosis in rat lymphoma cells (5 μg/ml, in vitro) [ Cx43 connexin 43, LPS lipopolysaccharide, UV ultraviolet, uPA urokinase plasminogen activator, MAPK mitogen-activated protein kinase recent study in MDA-MB-231 breast cancer xenograft mouse model showed that BBI given at 20 mg/kg body weight for 2 months at a frequency of three times per week was not able to reduce tumor incidence in mouse [155].…”