A model of progression of head and neck sqiamous cell carcinoma (HNSCC) in humans has been described which includes up-regulation of cyclin D1, activation of Stat-3, and expression of high levels of cyclooxygenase-2 (COX-2). Mutations and inactivation of p53 and other tumor suppressor genes (e.g. Rb, p16) have also been observed. Primary prevention, e.g., cessation of tobacco use, moderation of alcohol consumption, and increased intake of fruits and vegetables appears unattainable for a significant fraction of the population. Thus, other approaches such as chemoprevention are being explored. We have reported that selenium, as 1,4-phenylenebis(methylene)selenocyanate (p-XSC), inhibited tongue tumors of rats treated with 4-nitroquinoline-N-oxide (NQO). p-XSC also leads to growth inhibition and/or apoptosis in cultured human oral carcinoma cells, inhibits the formation of benzo[a]pyrene (B[a]P)-DNA adducts in the mouse tongue, and therefore has the potential of inhibiting B[a]P-induced tongue tumorigenesis. Based on these previous studies we hypothesize thatp-XSC inhibits tumorigenesis by multiple mechanisms including inhibition of DNA damage and cell proliferation, as well as induction of apoptosis in premalignant and transformed cells. To test our hypothesis we propose the following specific aims, Aim 1: To elucidate the mechanism of inhibition of NQO-induced tongue tumorigenesis by p-XSC. During tumor induction we will determine the effect of-XSC on: a) NQO-induced DNA damage; b) NQO-induced mutagenesis in vivo (in the lacI rat); c) NQO-induced (i) cell proliferation, (ii) apoptosis and (iii) proteins involved in cell cycle, cell proliferation, and apoptosis that have been implicated in the development of HNSCC (cyclin D1, Stat-3, COX-2, p16, pRb and p53). Changes in global gene expression will also be examined using eDNA microarray analysis;
Aim 2 : To determine the effect of p-XSC on tongue tumor induction by B[a]P in mice and on endpoints described in Aim 1;
and Aim 3 : To determine the effect of NQO or B[a]P, and p-XSC individually and in combination on certain of the biochemical, molecular and cellular events described in Aim 1 using cultures of normal cells, leukoplakia, and squamous cell carcinoma. To our knowledge, this application is the first to determine whether a tobacco smoke carcinogen (B[a]P) which induces tongue tumors in the mouse, alters those genes that are known to be involved in HNSCC and thus provides important leads toward the etiology of oral cancer. The long-term applications of this project may lead to strategies for the prevention and control of HNSCC. By identifying critical intervention targets in tongue tumorigenesis, it should be possible to minimize the gap between basic research and clinical application, and lead to translational clinical interventions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100924-04
Application #
6879212
Study Section
Special Emphasis Panel (ZRG1-PTHB (02))
Program Officer
Crowell, James A
Project Start
2003-05-01
Project End
2008-02-29
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
4
Fiscal Year
2006
Total Cost
$285,609
Indirect Cost
Name
Pennsylvania State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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Zhang, Shang-Min; Chen, Kun-Ming; Aliaga, Cesar et al. (2011) Identification and quantification of DNA adducts in the oral tissues of mice treated with the environmental carcinogen dibenzo[a,l]pyrene by HPLC-MS/MS. Chem Res Toxicol 24:1297-303
Chen, Kun-Ming; Sacks, Peter G; Spratt, Thomas E et al. (2009) Modulations of benzo[a]pyrene-induced DNA adduct, cyclin D1 and PCNA in oral tissue by 1,4-phenylenebis(methylene)selenocyanate. Biochem Biophys Res Commun 383:151-5
Guttenplan, Joseph; Chen, Kun-Ming; Khmelnitsky, Michael et al. (2007) Effects of 1,4-phenylenebis(methylene)selenocyanate on mutagenesis and p53 protein expression in the tongue of lacI rats treated with 4-nitroquinoline-N-oxide. Mutat Res 634:146-55
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El-Bayoumy, Karam; Sinha, Raghu (2005) Molecular chemoprevention by selenium: a genomic approach. Mutat Res 591:224-36
Guttenplan, Joseph B; Spratt, Thomas E; Khmelnitsky, Michael et al. (2004) Effects of 3H-1,2-dithiole-3-thione, 1,4-phenylenebis(methylene)selenocyanate, and selenium-enriched yeast individually and in combination on benzo[a]pyrene-induced mutagenesis in oral tissue and esophagus in lacZ mice. Mutat Res 559:199-210
Sinha, R; El-Bayoumy, K (2004) Apoptosis is a critical cellular event in cancer chemoprevention and chemotherapy by selenium compounds. Curr Cancer Drug Targets 4:13-28