Abstract 1270: Potential metabolic and molecular mechanisms of black raspberry-mediated oral cancer chemoprevention
Authors: Oghumu Steve , Knobloch Thomas J. , Weghorst Logan C. , Bruschweiler-Li Lei , Wang Cheng , Bruschweiler Rafael , Weghorst Christopher M. 
Published: August 2018

Oral cancer accounts for about 50,000 new cases and 10,000 new deaths in the U.S. every year. This amounts to about one person every hour every day. To combat this public health challenge, there is a need to identify agents that prevent oral cancer development and fully characterize their mechanisms of action. Preclinical and clinical studies demonstrate the ability of black raspberries (BRBs) to inhibit oral carcinogenesis. We recently showed that in an experimental model of rat oral carcinogenesis using the carcinogen 4 nitroquinoline-1-oxide (4NQO), BRBs reduce oral lesion incidence and multiplicity. However, understanding how the bioactive compounds in BRBs drive the metabolic and molecular pathways that lead to oral cancer chemoprevention remains unclear. In this study, we determined the potential metabolic and molecular mechanisms associated with BRB-mediated chemoprevention of oral carcinogenesis using the well-established carcinogen-induced rat oral cancer model. Male F344 rats were divided into 4 groups: sentinel group, 4NQO only group, 4NQO + 5% BRB group, and 4NQO + 10% BRB group. 4NQO was administered in drinking water (20ug/mL) for 10 weeks after which regular drinking water was provided for 6 weeks. BRBs were incorporated into rat diets at 5% or 10% concentrations and fed to the rat treatment groups for the last 6 weeks after 4NQO administration. Sentinel animals did not receive 4NQO or BRB. At terminal sacrifice, urine samples from all groups were harvested and analyzed by NMR-based metabolomics. We identified metabolites in rat urine samples by "Complex Mixture Analysis by NMR" (COLMAR) followed by 2D 13C-1H HSQC NMR quantitative analysis. RNA was extracted from rat tongue samples and used for RNA sequencing analysis. 4NQO only administered rats showed highest overall intensity, which was about 2.5 times higher than 4NQO + BRB treated rats. 171 metabolites were identified in urine samples of 4NQO only administered rats while 101 and 90 metabolites were identified in 4NQO administered rats that were treated with 10% and 5% BRB, respectively. About 31 "unique" metabolites were identified in 4NQO only administered rat urine samples but were absent in BRB treated groups. Fourteen additional metabolites were increased and 11 metabolites were decreased following BRB treatment of 4NQO administered rats compared to rats administered with 4NQO only. Our metabolomic and transcriptomic analyses reveal distinct molecular and metabolic markers and pathways that drive oral carcinogenesis and BRB-mediated oral chemoprevention, which can potentially be exploited in oral cancer treatment strategies.

Citation Format: Steve Oghumu, Thomas J. Knobloch, Logan C. Weghorst, Lei Bruschweiler-Li, Cheng Wang, Rafael Bruschweiler, Christopher M. Weghorst. Potential metabolic and molecular mechanisms of black raspberry-mediated oral cancer chemoprevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1270.