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Inhibition of oral carcinogenesis by a protease inhibitor
Abstract:
The effect of the Bowman-Birk inhibitor (BBI) and soybean trypsin inhibitor (SBTI) on experimental 7,12-dimethylbenz[a]anthracene [(DMBA) CAS: 57-97-6]-induced oral carcinogenesis in Syrian male hamsters was examined. All treatments were applied topically on both cheek pouches for 20 weeks, and the animals were then sacrificed. Gross and microscopic evaluations revealed a statistically significant reduction in the number of invasive carcinomas, the total number of tumors, and the tumor mass for the DMBA + BBI treatment group compared to animals treated with DMBA alone, DMBA and autoclaved BBI (a preparation in which protease inhibitor activity is destroyed), or DMBA + SBTI. A protease activity (with the use of Boc-Val-Pro-Arg-MCA as substrate) was measured and found to be elevated about tenfold in tumorous and nontumorous tissue from DMBA-treated cheek pouches. This protease activity was found to be decreased in the DMBA and BBI treatment group but not in the DMBA + SBTI or DMBA and autoclaved BBI treatment groups, as compared to the protease activity in the DMBA treatment group. Partial characterization of the Boc-Val-Pro-Arg-MCA hydrolyzing activity with diisopropyl fluorophosphate suggests that the proteolytic activity is a serine protease. Iodoacetamide and diethyl pyrocarbonate also inhibit enzyme activity, suggesting that other residues may be necessary for catalysis, possibly including cysteine and histidine. Our results suggest that this protease activity may play a role in DMBA-induced cheek pouch carcinogenesis.
Insights
Bowman-Birk inhibitor (BBI) significantly reduced oral tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in hamsters. BBI also decreased elevated protease activity linked to DMBA carcinogenesis, unlike SBTI or inactivated BBI.
Area of Science:
- Biochemistry
- Oncology
- Protease Inhibitors
Background:
- 7,12-dimethylbenz[a]anthracene (DMBA) is a potent carcinogen used to induce oral tumors in experimental models.
- Protease activity is implicated in cancer progression and metastasis.
Purpose of the Study:
- To investigate the chemopreventive effects of Bowman-Birk inhibitor (BBI) and soybean trypsin inhibitor (SBTI) on DMBA-induced oral carcinogenesis.
- To assess the impact of these inhibitors on associated protease activity.
Main Methods:
- Syrian male hamsters were treated topically with DMBA, BBI, SBTI, or autoclaved BBI on cheek pouches for 20 weeks.
- Tumor incidence, number, and mass were evaluated grossly and microscopically.
- Protease activity using Boc-Val-Pro-Arg-MCA substrate was measured in cheek pouch tissues.
Main Results:
- BBI significantly reduced the number of invasive carcinomas, total tumors, and tumor mass compared to DMBA alone.
- Protease activity was elevated in DMBA-treated tissues and significantly decreased by BBI treatment.
- SBTI and autoclaved BBI did not show significant reduction in tumors or protease activity.
Conclusions:
- Bowman-Birk inhibitor demonstrates chemopreventive efficacy against DMBA-induced oral carcinogenesis.
- The reduction in protease activity by BBI suggests its role in the mechanism of chemoprevention.
- This protease activity, potentially a serine protease, may be a key factor in DMBA-induced oral cancer development.