Cancer is the second leading cause of death in the United States and involves multiple stages including, initiation, promotion, progression, and metastasis. This Program will dissect the discrete molecular events associated with early components of this multistage disease by using complete carcinogens as chemical tweezers [polycyclic aromatic hydrocarbons (PAH)]. The hypothesis to be tested is that reactive and redox active PAH o-quinones generated by constitutively expressed aldo-keto reductase (AKR?s)contribute to PAHmultistage carcinogenesis. We propose that the electrophilic PAH-o-quinones plus the reactive oxygen species (ROS) they generate lead to covalent modifications of DNA in PAH target tissues and this may have mutational consequences leading to initiation. We also propose that the PAH o-quinones and ROS have direct effects on protein kinase C and its downstream signals. These epigenetic effects may have consequences for cell proliferation leading to promotion. These events could explain how PAH act as complete carcinogens. The Program consists of three interactive Projects and two Cores. Each project will use common human cell lines which are either capable of PAH activation (MCF-7 cells) or are PAH targets (bronchoalveolar cells). Project # 1 (Dr. Penning) will compare the roles of human aldehyde reductase (AKR1A1), CYP1A1/CYP1B1, and CYP-peroxidase in the metabolic activation of PAH using a stable expression strategy. Project #2 (Dr. Blair) will develop quantitative LC/MS methods to measure covalent modifications to DNA by reactive PAH-metabolites (o-quinones, anti-diol epoxides and radical cations), ROS and decomposition products of lipid hydroperoxides. The relative abundance of these DNA-adducts will be measured in bronchoalveolar cells (Project #1) and in sites of PAH carcinogenesis i.e, SENCAR mouse skin (Project #2). This will identify the metabolic pathway most responsible for adduct formation. Project #3 (Drs. Kazanietz and Assoian) will determine whether PAH o-quinones and ROS activate or inhibit individual PKC isoforms in vitro and in vivo and measure the phenotypic outcome on PMA-induced cell proliferation or growth inhibition. Changes in growth properties will be correlated to effects on cell cycle signaling pathways. The Bioanalytical Core (Core B) will provide LC/MS support to monitor the purity of PAH metabolites used in all projects, and will provide authentic PAH-DNA adduct reference compounds for Projects 1 and 2. The administrative core (Core A) will provide oversight to the program, a share Program Database, and biostatistical support to tract trends within and between projects. By studying the discrete molecular events responsible for the causation of cancer this Program may lead to the early prevention and intervention of this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA092537-03
Application #
6791186
Study Section
Subcommittee G - Education (NCI)
Program Officer
Poland, Alan P
Project Start
2002-08-30
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$1,458,702
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Shultz, Carol A; Quinn, Amy M; Park, Jong-Heum et al. (2011) Specificity of human aldo-keto reductases, NAD(P)H:quinone oxidoreductase, and carbonyl reductases to redox-cycle polycyclic aromatic hydrocarbon diones and 4-hydroxyequilenin-o-quinone. Chem Res Toxicol 24:2153-66
Xu, Daiwang; Penning, Trevor M; Blair, Ian A et al. (2009) Synthesis of phenol and quinone metabolites of benzo[a]pyrene, a carcinogenic component of tobacco smoke implicated in lung cancer. J Org Chem 74:597-604
Ran, Chongzhao; Dai, Qing; Ruan, Qian et al. (2008) Strategies for synthesis of adducts of omicron-quinone metabolites of carcinogenic polycyclic aromatic hydrocarbons with 2'-deoxyribonucleosides. J Org Chem 73:992-1003
Oliva, Jose L; Caino, M Cecilia; Senderowicz, Adrian M et al. (2008) S-Phase-specific activation of PKC alpha induces senescence in non-small cell lung cancer cells. J Biol Chem 283:5466-76
Xu, Daiwang; Duan, Yazhen; Blair, Ian A et al. (2008) Synthesis of dibenzo[def,p]chrysene, its active metabolites, and their 13C-labeled analogues. Org Lett 10:1059-62
Park, Jong-Heum; Gelhaus, Stacy; Vedantam, Srilakshmi et al. (2008) The pattern of p53 mutations caused by PAH o-quinones is driven by 8-oxo-dGuo formation while the spectrum of mutations is determined by biological selection for dominance. Chem Res Toxicol 21:1039-49
Quinn, Amy M; Penning, Trevor M (2008) Comparisons of (+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol activation by human cytochrome P450 and aldo-keto reductase enzymes: effect of redox state and expression levels. Chem Res Toxicol 21:1086-94
Shultz, Carol A; Palackal, Nisha T; Mangal, Dipti et al. (2008) Fjord-region benzo[g]chrysene-11,12-dihydrodiol and benzo[c]phenanthrene-3,4-dihydrodiol as substrates for rat liver dihydrodiol dehydrogenase (AKR1C9): structural basis for stereochemical preference. Chem Res Toxicol 21:668-77
Jiang, Hao; Gelhaus, Stacy L; Mangal, Dipti et al. (2007) Metabolism of benzo[a]pyrene in human bronchoalveolar H358 cells using liquid chromatography-mass spectrometry. Chem Res Toxicol 20:1331-41
Dai, Qing; Xu, Daiwang; Lim, Keunpoong et al. (2007) Efficient syntheses of C(8)-aryl adducts of adenine and guanine formed by reaction of radical cation metabolites of carcinogenic polycyclic aromatic hydrocarbons with DNA. J Org Chem 72:4856-63

Showing the most recent 10 out of 29 publications