Oral squamous cell carcinoma (OSCC) is the most common cancer of the head and neck region; in the USA, over 45,000 cases and about 11,000 deaths from the disease occur annually. Progress in the prevention and control of OSCC has been hampered by the lack of appropriate animal models that would reflect human exposure. Tobacco smoking is considered a major etiological factor in the development of oral cancer. An attractive animal model would be one where tumors resulting from chronic exposure of the animal to chemical carcinogens present in cigarette smoke, would recapitulate the biochemical, molecular and cellular alterations observed in human OSCC during the development of the disease. We have developed such a model and propose to apply it to chemoprevention. Previous studies have demonstrated the ability of diets containing 5-10% freeze-dried black raspberry (BRB) powder to inhibit the development of chemically-induced cancers in multiple organ sites in rodents including the oral cavity. 7,12-Dimethylbenz(a)anthracene (DMBA) induced squamous cell carcinomas (SCC) in the hamster cheek pouch. However, DMBA is not present in the environment and the hamster cheek pouch model may not be applicable to humans. We have shown that the tobacco carcinogen, dibenzo[a,l]pyrene (DB[a,l]P) can induce SCC in oral tissues. Its metabolite, ()-anti- DB[a,l]PDE is a potent and specific carcinogen in oral tissues in mice and the mutational profiles induced by DB[a,l]P and its diol epoxide are very similar, consistent with the formation of stable covalent DNA adducts (Preliminary Results). Mutations in both lacI and p53 genes in oral tissues of mice treated with DB[a,l]P are similar to those observed in OSCC in humans. In addition, DNA lesions induced by DB[a,l]P and ()-anti- DB[a,l]PDE in the oral tissues of mice were detected by LC-MS/MS. Preliminary Results showed 5% BRB powder or 0.025% kaempferol (KF) in diets significantly inhibited DB[a,l]P-DNA adduct formation in the oral cavity of mice treated with DB[a,l]P. We hypothesize that BRB and its active components including BRB powder and its anthocyanins enriched extract, protocatechuic acid (a major metabolite of anthocyanins), KF, and ferulic acid (components of raspberries) will inhibit oral tumorigenesis and do so by multiple mechanisms including: inhibition of DNA damage and cell proliferation, modulation of genes critical to cancer progression, and induction of apoptosis (Aim 1), and will also exhibit the same mechanistic effects in human oral cell cultures representing different stages of the disease (Aim 2).
Aim 2 will extend and translate our findings to future clinical studies. Innovation: This application is he first to examine the chemopreventive effects of BRB and related agents on the induction of OSCC in a highly relevant animal model. The mechanisms of chemoprevention by BRB will also be investigated. Relevance/Impact: The results of this study using a relevant animal model for OSCC will provide mechanistic insights that are urgently needed to formulate the most effective strategies for future clinical chemoprevention trials by BRB and its active compounds.

Public Health Relevance

The poor diagnosis of OSCC has not significantly improved and existing strategies to prevent the disease remain imperfect. The results of this study will provide urgently needed mechanistic insights that can account for chemoprevention of OSCC by raspberries and active components in a highly relevant animal model of OSCC recently developed by us. Such information is requisite in the design of future clinical chemoprevention trials in subjects at high risk of developing OSCC (smokers and ex-smokers).

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Chemo/Dietary Prevention Study Section (CDP)
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Riscuta, Gabriela
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Pennsylvania State University
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Chen, Kun-Ming; Guttenplan, Joseph B; Sun, Yuan-Wan et al. (2018) Effects of Black Raspberry on Dibenzo[a,l]Pyrene Diol Epoxide Induced DNA Adducts, Mutagenesis, and Tumorigenesis in the Mouse Oral Cavity. Cancer Prev Res (Phila) 11:157-164
Sun, Yuan-Wan; Chen, Kun-Ming; Imamura Kawasawa, Yuka et al. (2017) Hypomethylated Fgf3 is a potential biomarker for early detection of oral cancer in mice treated with the tobacco carcinogen dibenzo[def,p]chrysene. PLoS One 12:e0186873
Chen, Kun-Ming; Schell, Todd D; Richie Jr, John P et al. (2017) Effects of chronic alcohol consumption on DNA damage and immune regulation induced by the environmental pollutant dibenzo[a,l]pyrene in oral tissues of mice. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 35:213-222
El-Bayoumy, Karam; Chen, Kun-Ming; Zhang, Shang-Min et al. (2017) Carcinogenesis of the Oral Cavity: Environmental Causes and Potential Prevention by Black Raspberry. Chem Res Toxicol 30:126-144
Guttenplan, Joseph B; Chen, Kun-Ming; Sun, Yuan-Wan et al. (2016) Effects of Black Raspberry Extract and Protocatechuic Acid on Carcinogen-DNA Adducts and Mutagenesis, and Oxidative Stress in Rat and Human Oral Cells. Cancer Prev Res (Phila) 9:704-12
Sun, Yuan-Wan; El-Bayoumy, Karam; Aliaga, Cesar et al. (2015) Tissue Distribution, Excretion and Pharmacokinetics of the Environmental Pollutant Dibenzo[def,p]chrysene in Mice. Chem Res Toxicol 28:1427-33
Zhang, Shang-Min; Chen, Kun-Ming; Sun, Yuan-Wan et al. (2014) Simultaneous detection of deoxyadenosine and deoxyguanosine adducts in the tongue and other oral tissues of mice treated with Dibenzo[a,l]pyrene. Chem Res Toxicol 27:1199-206
Chen, Kun-Ming; Guttenplan, Joseph B; Zhang, Shang-Min et al. (2013) Mechanisms of oral carcinogenesis induced by dibenzo[a,l]pyrene: an environmental pollutant and a tobacco smoke constituent. Int J Cancer 133:1300-9