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ABSTRACT: Infection with human papillomavirus (HPV) is a critical factor in the development of cervical cancer. Smoking is an additional risk factor. Tobacco smoke carcinogens, such as benzo[a]pyrene (B[a]P), and their cytochrome P450-related metabolites are present in significantly higher levels in the cervical mucus of women smokers than in nonsmokers. We determined the metabolism and P450 expression of B[a]P-treated human keratinocytes infected with HPV-16 or -18.
Monolayer cultures of uninfected primary human foreskin keratinocytes, human vaginal and cervical keratinocytes carrying episomal genomes of HPV-16 and -18, respectively, and invasive cervical carcinoma cell lines carrying either HPV-16 or -18 genomes integrated into the host DNA, were incubated with 0.1 μM [(3)H]B[a]P. The resulting oxidative metabolites were analyzed and quantified by radioflow high-performance liquid chromatography. Additionally, all cell lines were incubated with unlabeled 0.1 μM B[a]P for Western blot analysis of cytochrome P450 1A1 and 1B1.
Significant enhancement in levels of both detoxification and activation metabolites was found in incubations with all types of HPV-infected cells compared with control incubations (P < 0.05). The highest capacity to metabolize B[a]P was observed with cells containing integrated HPV-18 genomes. Induction of cytochrome 1B1 was observed in HPV-16 and -18 integrated, and in HPV-16 episomal cell types.
Both viral genotype and genomic status in the host cell affect B[a]P metabolism and cytochrome P450 1B1 expression. An increase of DNA-damaging metabolites might result from exposure of HPV-infected women to cigarette smoke carcinogens.
Journal of Carcinogenesis 01/2012; 11:1.
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Andrea Manni,
John P Richie,
Haifang Xu,
Sharlene Washington,
Cesar Aliaga,
Timothy K Cooper,
Richard Bruggeman,
Arunangshu Das, Bogdan Prokopczyk,
Ana Calcagnotto,
Neil Trushin,
Rebecca Dickinson,
Jason Liao,
Michael F Verderame,
Karam El-Bayoumy
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ABSTRACT: Epidemiologic studies on the protective role of omega-3 fatty acids (n:3) on breast cancer prevention remain inconclusive but studies in preclinical models provide more positive outcome. However, the mechanisms accounting for the protective effect of n:3 are not defined. In the present study, conducted in the N-methyl-N-nitrosourea-induced rat mammary carcinogenesis model, we examined the effects of n:3 individually and in combination with the anti-estrogen Tamoxifen (Tam) on a comprehensive panel of systemic and preneoplastic mammary gland restricted biomarkers which may be critical in the progression to invasive cancer. We observed that fish oil (FO) rich diets significantly reduced Ki67 expression in hyperplastic lesions, while cleaved caspase-3 expression was not affected. Dietary FO and/or Tam did not have major effects on systemic oxidative stress biomarkers, based on oxidative damage to DNA measured as 8-hydroxy-2-deoxyguanosine (8-OH-dG) and lipid peroxidation assessed as thiobarbituric acid reactive substances (TBARS). Tissue levels of 8-isoprostane, on the other hand, were markedly reduced (p<0.0001) in FO-fed rats, possibly as a result of FO-induced depletion of arachidonic acid in the mammary gland. These results suggest that the protective effect of n:3 in this experimental system is not mediated by changes in the levels of oxidative stress but may result from suppression of arachidonic acid-specific pathways.
International Journal of Oncology 11/2011; 39(5):1153-64. · 2.40 Impact Factor
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Andrea Manni,
Haifang Xu,
Sharlene Washington,
Cesar Aliaga,
Arunangshu Das,
Timothy Cooper,
John P Richie, Bogdan Prokopczyk,
Ana Calcagnotto,
Neil Trushin,
John P Van den Heuvel,
Christopher Hamilton,
Laurence M Demers,
Jason Liao,
Michael F Verderame,
Karam El-Bayoumy
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ABSTRACT: In these experiments, we tested the hypothesis that inhibition of the estrogen receptor (ER) with Tamoxifen and activation of PPARγ with fish oil (FO) rich in omega-3 (n-3; known PPAR agonists) inhibit the development of hormone-independent breast cancer in view of the known crosstalk between the ER and PPARγ pathways. We selected the polyoma middle T transgenic mouse model, since in this system the development of ER- tumors is preceded by ER positive preneoplastic lesions. Tamoxifen admixed with a 20% corn oil (CO) modified AIN-76A diet delayed mammary carcinogenesis and inhibited tumor multiplicity, volume, and weight in a dose-dependent (1, 10, and 100 ppm) fashion. Administration of increasing concentrations of FO in the diet (5%, 10%, and 17%) did not affect any of the tumor parameters. Combined administration of different doses of Tamoxifen and FO delayed carcinogenesis and suppressed tumor multiplicity and volume to the same extent as Tamoxifen alone. Mice fed 10% FO exhibited the expected increase in n-3/n-6 ratio in plasma and tumor based on diet analysis. Further increase in the n-3/n-6 ratio was not observed in mice fed the 17% FO diet. FO reduced tissue levels of arachidonic acid and its metabolite PGF-2α. Our results support the role of ER expression by preneoplastic lesions in the development of hormone-independent tumors and consequently the importance of including ER targeting in combination with mechanistically based novel chemopreventive agents.
Hormones and Cancer 08/2011; 2(4):249-59.
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Andrea Manni,
Haifang Xu,
Sharlene Washington,
Cesar Aliaga,
Timothy Cooper,
John P Richie,
Richard Bruggeman, Bogdan Prokopczyk,
Ana Calcagnotto,
Neil Trushin,
David Mauger,
Michael F Verderame,
Karam El-Bayoumy
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ABSTRACT: The antiestrogen tamoxifen reduces breast cancer incidence in high-risk women but is unable to inhibit the development of hormone-independent tumors. Omega-3 polyunsaturated fatty acids (n-3 PUFA), known ligands of the peroxisome proliferator activated receptor-gamma (PPARgamma), generally exert tumor-suppressive effects. Based on the known crosstalk between the estrogen and the PPARgamma receptors, we tested the hypothesis that the combination of tamoxifen with n-3 PUFA results in a superior antitumor action over the individual interventions. In this study, we report for the first time that the combination of a fish oil diet rich in n-3 PUFA and tamoxifen seemed to inhibit N-methyl-N-nitrosourea-induced mammary carcinogenesis, tumor multiplicity, and volume to a greater extent than the individual interventions. The potential superiority of the combination was particularly evident at a suboptimal dose of tamoxifen, which, by itself, was unable to significantly decrease tumor development. Because activation of PPARgamma is known to inhibit oxidative stress, we examined the effects of our interventions on circulating and tumor levels of glutathione, a major intracellular antioxidant. Our results indicate that reduction in the level of oxidative stress may be a potential mechanism by which the n-3 PUFA-rich diet potentiated the tumor-suppressive effect of tamoxifen. Our interventions were well tolerated without evidence of toxicity. Combined administration of tamoxifen and n-3 PUFA is a promising new approach to breast cancer prevention. Because of its safety, this combination can quickly be translated to the clinic if its superiority can be supported by future studies.
Cancer Prevention Research 02/2010; 3(3):322-30. · 4.91 Impact Factor
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ABSTRACT: Human papillomavirus (HPV) infection is an established etiological factor for cervical cancer. Epidemiological studies suggest that smoking in combination with HPV infection plays a significant role in the etiology of this disease. We have previously shown that the tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is present in human cervical mucus. Here, we hypothesized that treatment of HPV-16-immortalized human ectocervical cells (Ecto1/E6E7) with NNK would alter the expression of genes involved in cellular transformation. Ecto1/E6E7 cells were treated with water (vehicle control) alone or with 1 microM, 10 microM, and 100 microM of NNK in water for 12 weeks. The colony-forming efficiency increased following NNK treatment; the maximum effect was observed after 12 weeks with 100 microM NNK. Microarray analysis revealed that, independent of the dose of NNK, expression of 30 genes was significantly altered; 22 of these genes showed a dose-response pattern. Genes identified are categorized as immune response (LTB4R), RNA surveillance pathway (SMG1), metabolism (ALDH7A1), genes frequently expressed in later stages of neoplastic development (MT1F), DNA binding (HIST3H3 and CHD1L), and protein biosynthesis (UBA52). Selected genes were confirmed by qRT-PCR. Western blot analysis indicates that phosphorylation of histone 3 at serine 10, a marker of cellular transformation, was up-regulated in cells treated with NNK. This is the first study showing that NNK can alter gene expression that may, in part, account for transformation of HPV-immortalized human cervical cells. The results support previous epidemiological observations that, in addition to HPV, tobacco smoking also plays an important role in the development of cervical cancer.
Chemico-biological interactions 12/2008; 177(3):173-80. · 2.46 Impact Factor
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ABSTRACT: Cigarette smoking increases the risk of cancer of the pancreas. The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the only known environmental compound that induces pancreatic cancer in laboratory animals. Concentrations of NNK are significantly higher in the pancreatic juice of smokers than in that of nonsmokers. The chiral NNK metabolite, (R,S)-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is itself a potent pancreatic carcinogen in rats. The carcinogenicity of NNAL is related to its stereochemistry; (S)-NNAL is a more potent lung tumorigen in the A/J mouse than is (R)-NNAL. In this study, we determined the potential of the human pancreas to convert NNK into NNAL.
Human pancreatic microsomes and cytosols were incubated with [5-(3)H]NNK, and the metabolic products were determined by high-performance liquid chromatography (HPLC).
(S)-NNAL was the predominant isomer formed in all cytosolic incubations. In ten microsomal samples, NNAL was formed at an average rate of 3.8 +/- 1.6 pmol/mg/min; (R)-NNAL was the predominant isomer in this group. The average rate of NNAL formation in 18 other microsomal samples was significantly lower, 0.13 +/- 0.12 pmol/mg/min (p < 0.001); (S)-NNAL was the predominant isomer formed in this group.
In human pancreatic tissues, there is intraindividual variability regarding the capacity for, and stereoselectivity of, carbonyl reduction of NNK.
Langenbeck s Archives of Surgery 07/2008; 393(4):571-9. · 1.81 Impact Factor
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ABSTRACT: The nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent lung carcinogens in rodents. Several epidemiologic studies indicated that the development of lung cancer in smokers is influenced by the type and amount of dietary polyunsaturated fatty acids. A high corn oil diet has been shown to increase lung tumor volume and to decrease tumor latency in rats treated with NNK. In this study, we investigated the effects of dietary polyunsaturated fatty acids in the form of corn oil or fish oil on lung proteomes in F344 rats treated with or without NNK. The fish oil diet contained 17% fish oil and 3% corn oil, and the corn oil diet contained 20% corn oil. Rats were sacrificed after 3 months, and lungs were excised. Whole lung tissue proteins were separated by two-dimensional liquid chromatography, and differentially expressed proteins were identified by trypsin digestion and tandem mass spectrometry. Apolipoprotein A-I and Clara cell 17-kDa protein were overexpressed in the lungs of rats fed corn oil diet, compared with fish oil diet. NNK further enhanced their expression in rats fed corn oil diet; this effect was not observed in animals fed fish oil diet. The results suggest that the elevated levels of apolipoprotein A-I and Clara cell 17-kDa protein may be involved in the development of NNK-induced lung cancer in rats fed a high corn oil diet. Therefore, we propose that both proteins may serve as potential biomarkers in future molecular epidemiologic and clinical chemoprevention intervention studies.
Cancer Epidemiology Biomarkers & Prevention 03/2007; 16(2):228-35. · 4.12 Impact Factor
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ABSTRACT: We previously developed a historical reconstruction model to estimate exposure to airborne polycyclic aromatic hydrocarbons (PAHs) from traffic back to 1960 for use in case-control studies of breast cancer risk. Here we report the results of four exercises to validate and calibrate the model.
Model predictions of benzo[a]pyrene (BaP) concentration in soil and carpet dust were tested against measurements collected at subjects' homes at interview. In addition, predictions of air intake of BaP were compared with blood PAH-DNA adducts. These same soil, carpet, and blood measurements were used for model optimization. In a separate test of the meteorological dispersion part of the model, predictions of hourly concentrations of carbon monoxide from traffic were compared with data collected at a U.S. Environmental Protection Agency monitoring station.
The data for soil, PAH-DNA adducts, and carbon monoxide concentrations were all consistent with model predictions. The carpet dust data were inconsistent, suggesting possible spatial confounding with PAH-containing contamination tracked in from outdoors or unmodeled cooking sources. BaP was found proportional to other PAHs in our soil and dust data, making it reasonable to use BaP historical data as a surrogate for other PAHs. Road intersections contributed 40-80% of both total emissions and average exposures, suggesting that the repertoire of simple markers of exposure, such as traffic counts and/or distance to nearest road, needs to be expanded to include distance to nearest intersection.
Environmental Health Perspectives 08/2006; 114(7):1053-8. · 7.04 Impact Factor
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Sumitra Shantakumar,
Marilie D Gammon,
Sybil M Eng,
Sharon K Sagiv,
Mia M Gaudet,
Susan L Teitelbaum,
Julie A Britton,
Mary Beth Terry,
Andrea Paykin,
Tie Lan Young, [......],
Qiao Wang,
Steven D Stellman,
Jan Beyea,
Maureen Hatch,
David Camann, Bogdan Prokopczyk,
Geoffrey C Kabat,
Bruce Levin,
Alfred I Neugut,
Regina M Santella
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ABSTRACT: The detection of polycyclic aromatic hydrocarbon (PAH)-DNA adducts in human lymphocytes may be useful as a surrogate end point for individual cancer risk prediction. In this study, we examined the relationship between environmental sources of residential PAH, as well as other potential factors that may confound their association with cancer risk, and the detection of PAH-DNA adducts in a large population-based sample of adult women. Adult female residents of Long Island, New York, aged at least 20 years were identified from the general population between August 1996 and July 1997. Among 1556 women who completed a structured questionnaire, 941 donated sufficient blood (25+ ml) to allow use of a competitive ELISA for measurement of PAH-DNA adducts in peripheral blood mononuclear cells. Ambient PAH exposure at the current residence was estimated using geographic modeling (n=796). Environmental home samples of dust (n=356) and soil (n=360) were collected on a random subset of long-term residents (15+ years). Multivariable regression was conducted to obtain the best-fitting predictive models. Three separate models were constructed based on data from : (A) the questionnaire, including a dietary history; (B) environmental home samples; and (C) geographic modeling. Women who donated blood in summer and fall had increased odds of detectable PAH-DNA adducts (OR=2.65, 95% confidence interval (CI)=1.69, 4.17; OR=1.59, 95% CI=1.08, 2.32, respectively), as did current and past smokers (OR=1.50, 95% CI=1.00, 2.24; OR=1.46, 95% CI=1.05, 2.02, respectively). There were inconsistent associations between detectable PAH-DNA adducts and other known sources of residential PAH, such as grilled and smoked foods, or a summary measure of total dietary benzo-[a]-pyrene (BaP) intake during the year prior to the interview. Detectable PAH-DNA adducts were inversely associated with increased BaP levels in dust in the home, but positively associated with BaP levels in soil outside of the home, although CIs were wide. Ambient BaP estimates from the geographic model were not associated with detectable PAH-DNA adducts. These data suggest that PAH-DNA adducts detected in a population-based sample of adult women with ambient exposure levels reflect some key residential PAH exposure sources assessed in this study, such as cigarette smoking.
Journal of Exposure Analysis and Environmental Epidemiology 12/2005; 15(6):482-90. · 2.72 Impact Factor
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Bogdan Prokopczyk,
Gerhard Leder,
Neil Trushin,
A John Cunningham,
Shobha Akerkar,
Brian Pittman,
Marco Ramadani,
Joern Straeter,
Hans G Beger,
Doris Henne-Bruns,
Karam El-Bayoumy
Cancer Epidemiology Biomarkers & Prevention 03/2005; 14(2):540-1. · 4.12 Impact Factor
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ABSTRACT: The mechanisms responsible for the protective role of selenium against the development of prostate cancer remain to be determined (L. C. Clark et al., J. Am. Med. Assoc., 276: 1957-1963, 1996). In the present study, we tested the hypothesis that selenium supplementation reduces oxidative stress. A secondary aim was to determine whether selenium-induced changes in testosterone (T) metabolism may also be involved. To this end, we conducted a double-blind, randomized, placebo-controlled trial of 247 micro g selenium/day administered p.o. in the form of Se-enriched yeast. Study subjects were 36 healthy adult males, 11 blacks and 25 whites, 19-43 years of age. Supplementation occurred over the first 9 months, after which all subjects were placed on placebo for an additional 3 months. Blood and urine were collected at baseline and after 3, 9, and 12 months. In the selenium group, plasma selenium levels were 2-fold higher than baseline values after 3 and 9 months and returned to 136% of baseline after 12 months (P < 0.0001), whereas in the placebo group, levels were unchanged. A 32% increase in blood glutathione (GSH) levels was observed after 9 months in the selenium group only (P < 0.05). This change coincided with a 26% decrease in protein-bound GSH (bGSH) and a 44% decrease in bGSH:GSH ratios (P < 0.05). The changes in GSH and bGSH were highly correlated with changes in plasma selenium concentrations and may reflect a decrease in oxidative stress. No changes were observed in either group for plasma T, dihydrotestosterone (DHT) or DHT:T ratios, suggesting that selenium had no effect on the alpha-reductase involved in the conversion of T to DHT. A small but significant decrease in prostate-specific antigen levels was observed after 3 and 9 months (P < 0.001), and this difference disappeared after 12 months. Future trials will test the above hypothesis in prostate cancer patients and in subjects at high risk for prostate cancer.
Cancer Epidemiology Biomarkers & Prevention 12/2002; 11(11):1459-65. · 4.12 Impact Factor
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Bogdan Prokopczyk,
Dietrich Hoffmann,
Matthew Bologna,
A John Cunningham,
Neil Trushin,
Shobha Akerkar,
Telih Boyiri,
Shantu Amin,
Dhimant Desai,
Stephen Colosimo,
Brian Pittman,
Gerhard Leder,
Marco Ramadani,
Doris Henne-Bruns,
Hans G Beger,
Karam El-Bayoumy
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ABSTRACT: Cancer of the pancreas is the fourth leading cause of cancer mortality in the USA with an estimated 28 900 deaths in 2001. Several factors have been implicated in the etiology of this disease. However, at present, only cigarette smoking has been positively associated with pancreatic cancer. It is our working hypothesis that tobacco-derived compounds can be delivered to the pancreas where, upon metabolic activation, they can initiate carcinogenesis. Our current investigation was conducted to determine whether cotinine and tobacco-specific nitrosamines (TSNA) are present in human pancreatic juice. Smoking status was assessed by the determination of levels of urinary cotinine and was further supported by quantifying nicotine in hair. The TSNA were extracted from the pancreatic juice of 18 smokers and 9 nonsmokers by supercritical carbon dioxide that contained 10% methanol. The extracts were analyzed for TSNA, namely, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), by gas chromatography with mass spectrometric detection using a selected ion monitoring technique (GC-SIM-MS). Twenty-three extracts of human pancreatic juice were also analyzed for the presence of the NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by GC-SIM-MS and by gas chromatography interfaced wit a thermal energy analyzer (GC-TEA; TEA, a nitrosamine-specific detector). Cotinine was detected in all analyzed samples of pancreatic juice from smokers (129 +/- 150 ng/mL juice; mean +/- standard deviation) and was present in only two of the nine samples of pancreatic juice from nonsmokers. Its levels in these two samples were 7 and 9 ng/mL juice. NNK was detected in 15 of 18 samples (83%) from smokers at levels from 1.37 to 604 ng/mL pancreatic juice. In nine samples of pancreatic juice from nonsmokers, NNK ranged from not detected (in three samples) to 96.8 ng/mL juice. In pancreatic juice from smokers the mean level of NNK (88.7 +/- 161 ng/mL juice) was significantly higher (p < 0.04) than in that from nonsmokers (12.4 +/- 31.7 ng/mL juice). In addition to NNK, NNN was found in two samples of pancreatic juice of smokers at levels of 68.1 and 242 ng/mL juice; NNN was not detected in any other sample. NNAL was present in 8 of 14 pancreatic juice samples (57%) from smokers and in three of nine samples (33%) from nonsmokers. This research presents preliminary data that supports the hypothesis that pancreatic tissue is exposed to TSNA and that they may be important contributors to pancreatic carcinogenesis in humans.
Chemical Research in Toxicology 05/2002; 15(5):677-85. · 3.78 Impact Factor
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04/2002;
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ABSTRACT: In assays of Areca -specific N -nitrosamines, 3-(methylnitrosamino)propionaldehyde (MNPA) exhibits higher cytotoxicity than nitrosoguvacine (NGC), nitrosoguvacoline (NG) and 3-(methylnitrosamino)propionitrile (MNPN). NGC is not mutagenic. However, NG is a weak carcinogen in F344 rats while MNPN is a potent carcinogen; MNPA had thus far not been tested. In this study MMPA was injected s.c. at a dose of 6.57 mg three times weekly for 15 weeks (total dose 2.6 mmol/rat). During the 100 weeks of the bioassay, the treated K344 rats, and especially the females, showed significantly less weight gain than the control animals, indicating high toxicity for MNPA at the tested dose. Upon termination of the bioassay, the MNPA-treated animals were found to have tumors of the lung, liver, nasal cavity, forestomach and kidneys. The control animals showed no tumors in these organs. The incidence of lung tumors in the MNPA group was statistically significant ( P < 0.025). The results of this study show that MNPA is a carcinogen in K344 rats.
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ABSTRACT: A precise and highly reproducible analytical method was developed for the assessment of organochlorinated pesticide and polychlorinated biphenyl residues in adipose tissue (≥ 50 mg). The method can be utilized for epidemlologlcal studies on the significance of these environmental pollutants in the etiology of breast cancer. Supercritical fluid extrac tion (SFE) with CO 2 and modified CO 2 (addition of 5% dichloromethane) Is employed to remove incurred pesticide residues from adipose tissues that have been surgically removed from breast cancer patients and controls. An alumina sorbent, placed in the extracting vessel together with a specimen, removes the bulk of co-extracted lipids; a subsequent purification of the SFE extracts by column chromatography on alumina removes the remaining traces of lipids that would interfere with the gas chromatographlc analysis with electron capture detection. The method was tested by analyzing a Certified Reference MaterIal 430 pork fat with known amounts of pesticide residues that are commonly found in fat or in foods with a high fat content. The recoveries of analytes ranged from 73.4% for endrin to 115% for α-, β- and γ-hexachlorocydohexane, hexachlorobenzene and dietdrin, with standard deviations of 4–12% for individual analytes. The analysis of adipose tissue for organochlorinated compounds on the basis of this new method suggested that the pesticide levels were higher in breast cancer patients than in controls. However, the small number of samples analyzed In this study ( n = 5, both groups) precludes definitive conclusions. The most abundant compounds in both cases and controls were p , p -DDE (379 ± 286 and 160 ± 149 p.p.b.) and PCB (223 ± 145 and 124 ± 65.7 p.p.b.), followed by the termiticlde chlordane residues oxychlordane and tmnsnonachlor.
