Henry P Ciolino

University of Texas at Austin, Austin, Texas, United States

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Publications (31)146.67 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Obesity is associated with an increased risk of infectious diseases. It has been shown to have deleterious effects on cell-mediated immunity, including reducing thymocyte numbers and altering responses of thymocytes to pathogens. In the current study, we examined the efficacy of the antiobesity phytochemical resveratrol in preventing the deleterious effects of a high-fat diet on thymic anatomy and function. Compared to C57Bl/6 male mice fed a low-fat diet, mice on a high-fat diet had a significant increase in thymic weight and lipid content, and a disrupted anatomy, including a reduction of the medullary compartment and absence of a corticomedullary junction. There were a decrease in thymic cellularity and mature T-cell output, and a disrupted T-cell maturation, as evidenced by increased double-negative and decreased single- and double-positive thymocytes. Mice that had been fed resveratrol along with a high-fat diet had a dose-dependent reversal in all these parameters. Western blots from thymi showed that obese mice had lower levels of the key stimulators of lipid metabolism, phospho-5' adenosine monophosphate-activated protein kinase and its downstream target, carnitine palmitoyl transferase-1; this was restored to normal levels in resveratrol-fed mice. Resveratrol also reversed an increase in glycerol-3-phosphate acyltransferase-1, the enzyme that catalyzes the first step in triglycerol synthesis. Taken together, these results indicate that resveratrol is a potent inhibitor of the deleterious effects of diet-induced obesity on thymic anatomy and function, and this may hold promise in preventing obesity-related deficits in cell-mediated immunity.
    The Journal of nutritional biochemistry 04/2013; · 4.29 Impact Factor
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    ABSTRACT: Glycerol 3-phosphate acyltransferase-1 (GPAT-1) catalyzes the initial and rate-limiting step in de novo glycerophospholipid and triacylglycerol (TAG) biosynthesis. We have previously shown that peripheral T cell proliferation and cytokine production is altered in GPAT-1 gene-ablated (KO) mice. This finding is important in light of the reduction in GPAT-1 activity associated with aged T cells. To determine if the mechanism for altered peripheral T cell function is linked to altered T cell development, we assessed thymic function in 3, 6 and 16-week old GPAT-1 KO compared to wild type (WT) mice. At 16 weeks of age, there was a significant reduction in thymic T cell production in KO compared to WT mice but not at 6 weeks of age. The reduced thymic T cell production was associated with altered thymic development as confirmed by increased numbers of double-negative (DN) thymocytes and a significant reduction in the double positive (DP) thymocytes suggesting a developmental block at the DN stage. This change was accompanied by an increase in the single positive CD4 subset. These changes were associated with reduced glycerophospholipid mass while thymic cortex and medulla architecture was not altered by GPAT-1 KO. Taken together, these data suggest that GPAT-1 deletion is capable of reducing the number of new T cells produced via alterations in membrane receptor function rather than by causing deleterious changes within the thymic microenvironment explaining in part the observed alterations in peripheral T cell function.
    Lipids 11/2012; · 2.56 Impact Factor
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    Vidhya Nair, Zhaoli Dai, Maruf Khan, Henry P Ciolino
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    ABSTRACT: Pomegranate extract (PE) is a standardized whole-fruit extract of pomegranate, a fruit with known anticancer properties. PANC-1 and AsPC-1 human pancreatic cancer cells were used as in vitro models to test the effects of PE. PE treatment induced cell cycle arrest and inhibited cell proliferation in PANC-1 cells. PE treatment increased the proportion of cells lacking CD44 and CD24 expression, which are associated with increased tumor-initiating ability, demonstrating that PE altered cell phenotype. PE was more effective in inhibiting the proliferation of PANC-1 cells than the clinically used dose of paclitaxel. Similar results were obtained in the AsPC-1 cell line. Individual pomegranate phytochemicals were only modestly effective in inhibiting cell proliferation, suggesting that unidentified phytochemicals are responsible for the inhibitory effect of PE. These data suggest that PE is a promising candidate for further preclinical testing for treatment of human pancreatic cancer.
    Anticancer research 09/2011; 31(9):2699-704. · 1.71 Impact Factor
  • Henry P Ciolino, Zhaoli Dai, Vidhya Nair
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    ABSTRACT: Aromatase converts androgens into estrogens and is thought to supply a local source of estrogen that facilitates the growth of hormone-responsive tumor cells. Inhibition of aromatase is therefore an important chemopreventive strategy. We investigated the effect of retinol and selected retinoids on the activity and expression of aromatase in two human carcinoma cell lines in vitro. Retinol (ROH) and all-trans retinoic acid (ATRA) significantly inhibited aromatase activity in a concentration-dependent manner in microsomes isolated from JEG-3 human placental carcinoma cells, whereas 9-cis and 13-cis retinoic acid had significant inhibitory activity only at the highest concentrations tested. Similar results were observed in an assay of cellular aromatase activity in MCF-7 human breast cancer cells. Enzyme kinetic studies by double-reciprocal plot demonstrated that ROH inhibited microsomal aromatase activity in a mixed manner. In addition, ROH suppressed both the basal and cAMP-induced expression of aromatase mRNA in MCF-7 cells and inhibited transcription controlled by a cAMP-responsive element. These results suggest that aromatase activity and expression are a molecular target of ROH and chemopreventive retinoids, an activity that may underlie, in part, their inhibitory effects on hormone-dependent cancer.
    The Journal of nutritional biochemistry 06/2011; 22(6):522-6. · 4.29 Impact Factor
  • Zhaoli Dai, Vidhya Nair, Maruf Khan, Henry P Ciolino
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    ABSTRACT: Pomegranate (Punica granatum L.) is known to possess anticancer activities. The effects of a standardized extract of pomegranate (PE) on a mouse mammary cancer cell line (designated WA4) derived from mouse MMTV-Wnt-1 mammary tumors were examined in this study. The WA4 cell line has been previously characterized as containing a majority of cells possessing stem cell characteristics. PE inhibited the proliferation of WA4 cells in a time- and concentration-dependent manner. This was due to an arrest of cell cycle progression in the G0/G1 phase. PE was also cytotoxic to quiescent WA4 cells in a concentration-dependent manner at concentrations >10 microg/ml. PE treatment of WA4 cells resulted in an increase in caspase-3 enzyme activity in a time- and concentration-dependent manner, indicating that the cytotoxic effect of PE was due to the induction of apoptosis. We tested the effect of several individual phytochemicals derived from PE on WA4 cells. Ellagic acid, ursolic acid and luteolin caused a time- and concentration-dependent reduction of cell proliferation and viability, suggesting that they contribute to the inhibitory effect of PE, while caffeic acid had no effect. Cancer stem cells, which are highly resistant to conventional chemotherapeutic agents, are thought to be the origin of both primary and secondary breast tumors, and thus are a critical target in both breast cancer therapy and prevention. These data suggest that PE, which is a proven and safe dietary supplement, has promise as an treatment against breast cancer by preventing proliferation of cancer stem cells.
    Oncology Reports 10/2010; 24(4):1087-91. · 2.30 Impact Factor
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    ABSTRACT: Sulindac is a nonsteroidal antiinflammatory drug that has been demonstrated to be a potent chemopreventive agent against colorectal cancer in both human and animal models. In vivo, sulindac may be reversibly reduced to the active antiinflammatory compound, sulindac sulfide, or irreversibly oxidized to sulindac sulfone. Sulindac has also been shown to inhibit polycyclic aromatic hydrocarbon (PAH)-induced cancer, but the molecular mechanisms of its antitumor effect remain unclear. In this study, we investigated the effects of sulindac and its metabolites on the expression of enzymes that metabolize and detoxify PAHs in 2 human colon cancer cell lines, LS180 and Caco-2. Sulindac and sulindac sulfide induced a sustained, concentration-dependent increase in CYP enzyme activity as well as an increase in the mRNA levels of CYP1A1, CYP1A2 and CYP1B1. Sulindac and sulindac sulfide induced the transcription of the CYP1A1 gene, as measured by the level of heterogeneous nuclear CYP1A1 RNA and verified by the use of actinomycin D as a transcription inhibitor. Chromatin immunoprecipitation assays demonstrated that sulindac and sulindac sulfide also increased the nuclear level of activated aryl hydrocarbon receptor, the transcription factor which mediates CYP expression. Additionally, sulindac and both metabolites increased the activity and mRNA expression of the carcinogen detoxification enzyme NAD(P)H:quinone oxidoreductase, as well as the expression of UDP-glucuronosyltransferase mRNA. These results show an overall upregulation of carcinogen metabolizing enzymes in colon cancer cells treated with sulindac, sulindac sulfide and sulindac sulfone that may contribute to the established chemoprotective effects of these compounds.
    International Journal of Cancer 04/2008; 122(5):990-8. · 6.20 Impact Factor
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    ABSTRACT: We investigated the effect of a novel synthetic analogue of a constituent from the Chinese medicinal herb Isodon excisus, 3-(3-methoxy-phenyl)-N-(3, 4, 5-trimethoxy-phenyl)-acrylamide (compound 343), on the carcinogen activation pathway mediated by the aryl hydrocarbon receptor (AhR) in human hepatoma HepG2 cells. We found that compound 343 inhibited the upregulation of cytochrome P-450 (CYP) enzyme activity in cells treated with the AhR ligands and potent carcinogens, dimethylbenz[a]anthracene (DMBA) or 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). Compound 343 also inhibited the DMBA- or TCDD-induced increase in CYP1A1, -1A2 and -1B1 mRNA levels. Carcinogen-induced transcription of CYP genes was also suppressed by compound 343, as measured by a reporter gene controlled by the xenobiotic-responsive element (XRE). This was confirmed by measuring the amount of carcinogen-induced CYP1A1 heterogeneous nuclear RNA. Compound 343 blocked the DMBA- or TCDD-induced activation of the AhR DNA-binding capacity for the XRE, as measured by a chromatin immunoprecipitation assay. Compound 343 also inhibited CYP enzyme activity in microsomes isolated from DMBA- or TCDD-treated cells, as well as the activity of recombinant CYP1A1, -1A2 and -1B1, indicating that compound 343 directly inhibits CYP enzymes. These results indicate that compound 343 is both a potent inhibitor of carcinogen-induced CYP enzyme expression, as well as a direct inhibitor of CYP enzymes.
    Carcinogenesis 06/2007; 28(5):1052-7. · 5.64 Impact Factor
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    ABSTRACT: Sulindac, a widely used non-steroidal anti-inflammatory drug (NSAID), has been shown to inhibit chemically induced carcinogenesis in animal models. In the present study, we have investigated the molecular mechanism by which sulindac affects the activity and expression of the enzymes that mediate the initial detoxification steps of many environmental carcinogens, the cytochromes P450 1A1, 1A2 and 1B1. Sulindac treatment of Sprague-Dawley rats resulted in a dose-dependent increase in hepatic cytochrome P450 (CYP) enzyme activity and in the expression of hepatic CYPs 1A1 and 1B1 mRNA. In the HepG2 human liver cancer cell line, sulindac caused a sustained, dose-dependent increase in CYP enzyme activity. Sulindac treatment resulted in a profound, dose-dependent increase in CYP 1A1 mRNA and a modest increase in 1A2 mRNA. The increase in CYP 1A1 mRNA induced by sulindac was, like enzyme activity, sustained for several days after the initial treatment. Sulindac induced the transcription of the CYP1A1 gene, as measured by the level of heterogeneous nuclear 1A1 RNA and by actinomycin D chase experiment. Since the transcription of CYP1A1 is under the control of the aryl hydrocarbon receptor (AhR), we examined the ability of sulindac to activate the receptor. Sulindac bound to the AhR, as measured by ligand-binding assay, and induced the binding of the AhR with the xenobiotic-responsive element present in the promoter region of the CYP1A1 gene. These results are the first demonstration that NSAIDs modulate carcinogen metabolic enzymes and provide a novel mechanism to explain the established chemopreventive activity of sulindac.
    Carcinogenesis 09/2006; 27(8):1586-92. · 5.64 Impact Factor
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    ABSTRACT: 2-(4-Amino-3-methylphenyl)-5-fluoro-benzothiazole (5F 203) potently inhibits MCF-7 breast cancer cell growth in part by activating the aryl hydrocarbon receptor (AhR) signaling pathway. Ligands for the AhR (i.e. dioxin) have also been shown to modulate the NF-kappaB signaling cascade, affecting physiological processes such as cellular immunity, inflammation, proliferation and survival. The objective of this study was to investigate the effect of 5F 203 treatment on the NF-kappaB signaling pathway in breast cancer cells. Exposure of MCF-7 cells to 5F 203 increased protein-DNA complex formation on the NF-kappaB-responsive element as determined by electrophoretic mobility shift assay, but this effect was eliminated in MDA-MB-435 cells, which are resistant to the antiproliferative effects of 5F 203. An increase in NF-kappaB-dependent transcriptional activity was confirmed by a significant increase in NF-kappaB-dependent reporter activity in sensitive MCF-7 cells, which was absent in resistant MDA-MB-435 cells and AhR-deficient subclones of MCF-7 cells. Inhibition of NF-kappaB activation enhanced the increase in xenobiotic response element-dependent reporter activity in MCF-7 cells when treated with 5F 203. The drug candidate 5F 203 also induced mRNA levels of IL-6, an NF-kappaB-responsive gene, in MCF-7 cells, but not in MDA-MB-435 cells, as determined by quantitative RT-PCR. These findings suggest that 5F 203 activation of the NF-kappaB signaling cascade may contribute to 5F 203-mediated anticancer activity in human breast cancer MCF-7 cells.
    Anti-Cancer Drugs 03/2005; 16(2):137-43. · 2.23 Impact Factor
  • Anti-cancer Drugs - ANTI-CANCER DRUG. 01/2005; 16(2):137-143.
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    ABSTRACT: Aminoflavone (4H-1-benzopyran-4-one, 5-amino-2-(4-amino-3-fluorophenyl)-6,8-difluoro-7-methyl; NSC 686288) demonstrates differential antiproliferative activity in the National Cancer Institute's anticancer drug screen. We demonstrate here that MCF-7 human breast cancer cells are sensitive to aminoflavone both in vitro and when grown in vivo as xenografts in athymic mice. As previous work has indicated that aminoflavone requires metabolic activation by cytochrome P450 1A1 (CYP1A1), we investigated the effect of aminoflavone on CYP1A1 expression and on the aryl hydrocarbon receptor (AhR), a transcriptional regulator of CYP1A1. In aminoflavone-sensitive but not aminoflavone-resistant cells, the drug caused a 100-fold induction of CYP1A1 mRNA and a corresponding increase in ethoxyresorufin-O-deethylase activity. An AhR-deficient variant of the MCF-7 breast carcinoma, AH(R100), with diminished CYP1A1 inducibility, exhibits cellular resistance to aminoflavone and is refractory to CYP1A1 mRNA induction by the drug. The increase in CYP1A1 mRNA in the aminoflavone-sensitive MCF-7 breast tumor cell results from transcriptional activation of xenobiotic-responsive element (XRE)-controlled transcription. Aminoflavone treatment causes a translocation of the AhR from the cytoplasm to the nucleus with subsequent formation of AhR-XRE protein DNA complexes. In contrast to the aminoflavone-sensitive MCF-7 cells, the resistant cell lines (MDA-MB-435, PC-3, and AH(R100)) demonstrated constitutive nuclear localization of AhR. Additionally, aminoflavone failed to induce ethoxyresorufin-O-deethylase activity, CYP1A1 transcription, AhR-XRE complex formation, and apoptosis in aminoflavone-resistant cells. These results suggest that the cytotoxicity of aminoflavone in a sensitive breast tumor cell line is the result of the engagement of AhR-mediated signal transduction.
    Molecular Cancer Therapeutics 07/2004; 3(6):715-25. · 5.60 Impact Factor
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    ABSTRACT: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant, that has been linked with a variety of deleterious effects on human health, including increased cancer rates and reproductive anomalies. The detrimental effects of TCDD are mediated via the aryl hydrocarbon receptor (AhR), a transcription factor that regulates the expression of the carcinogen-activating enzymes cytochromes P-450 (CYP) 1A1, 1A2, and 1B1. In the present study, we examined the ability of synthetic derivatives of salicylic acid to affect TCDD-stimulated AhR-mediated signal transduction in human hepatoma HepG2 cells. Salicylamide (SAL), an analgesic drug, caused a potent and long-lasting inhibition of TCDD-induced CYP enzyme activity. Acetylsalicylic acid (aspirin) and the naturally occurring phytochemical salicylic acid had no effect on CYP activity. SAL inhibited the increase in CYP1A1, -1A2, and -1B1 mRNA levels that occurs on exposure to TCDD. TCDD-induced transcription of these genes was also inhibited by SAL, but not by aspirin or salicylic acid, as demonstrated by luciferase reporter assays. The transcription of the CYP1 family of genes is regulated by the interaction of TCDD-activated AhR with the xenobiotic-responsive element present in the promoter regions of these genes. As shown by electrophoretic mobility shift assay, SAL completely blocked the binding of TCDD-activated AhR to the xenobiotic responsive element. Also, SAL substantially blocked the binding of TCDD to the cytosolic AhR. These results demonstrate that SAL, a commonly used analgesic, is a potent inhibitor of AhR-mediated signal transduction, and may be an effective agent in the prevention of TCDD-associated disease.
    Cancer Research 02/2004; 64(1):429-34. · 8.65 Impact Factor
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    ABSTRACT: We investigated the effect of the steroid hormone dehydroepiandrosterone (DHEA) on the hepatic expression and activity of carcinogen-activating enzymes, the cytochromes P450 (CYP) 1A1, 1A2 and 1B1, in Sprague-Dawley rats. In animals fed DHEA at 200 or 400 mg/kg body weight every other day for 2 weeks prior to exposure to the aryl hydrocarbon dimethylbenz[a]anthracene (DMBA, 5 mg/kg), there was a dose-dependent decrease in hepatic CYP activity, as measured by ethoxyresorufin-O (EROD) assay, from 37.1 to 22.9 and 14.7 pmoles/min/10 microg microsomes, respectively. DHEA did not directly inhibit microsomal EROD activity, however, leading us to investigate its effects on enzyme expression. To test this, we examined protein and mRNA levels of the enzymes. Western blot for CYP1A1 and CYP1A2 showed that DHEA inhibited the increase in hepatic CYP1A1 and CYP1A2 enzyme levels that are normally induced by DMBA. DMBA-induced increase in expression of CYP1A1, CYP1A2 and CYP1B1 mRNA was similarly blunted in DHEA-treated animals. DHEA was also able to significantly reduce the basal expression of CYP1A1 and CYP1A2 but not of CYP1B1. These results indicate that DHEA regulates the expression and, hence, the activity of hepatic carcinogen-activating enzymes in vivo, and this may be an important mechanism of its chemopreventive activity.
    International Journal of Cancer 07/2003; 105(3):321-5. · 6.20 Impact Factor
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    ABSTRACT: The fluorinated benzothiazole analogue 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is a novel agent with potent and selective antitumour properties and, in the form of its L-lysylamide prodrug Phortress (NSC 710305), is a current candidate for early phase clinical studies. Previous findings have indicated that cytochrome P450 1A1 (CYP1A1) may play a role in the antitumour activity of molecules in the benzothiazole series including the nonfluorinated parent compound 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495) (Kashiyama et al, 1999; Chua et al, 2000; Loaiza-Pérez et al, 2002). In this study, we assessed and verified that a fully functional aryl hydrocarbon receptor (AhR) signalling pathway is a necessary requisite for the induction of efficient cytotoxicity by 5F 203 in MCF-7 wild-type sensitive cells. Drug exposure caused MCF-7 sensitive cells to arrest in G(1) and S phase, and induced DNA adduct formation, in contrast to AhR-deficient AH(R100) variant MCF-7 cells. In sensitive MCF-7 cells, induction of CYP1A1 and CYP1B1 transcription (measured by luciferase reporter assay and real-time reverse transcriptase-polymerase chain reaction (RT-PCR)), and 7-ethoxyresorufin-O-deethylase (EROD) activity was demonstrated, following treatment with 5F 203. In contrast, in resistant AH(R100) cells, drug treatment did not affect CYP1A1 and CYP1B1 transcription and EROD activity. Furthermore, AH(R100) cells failed to produce either protein/DNA complexes on the xenobiotic responsive element (XRE) sequence of CYP1A1 promoter (measured by electrophoretic mobility shift assay) or DNA adducts. The data confirm that activation of the AhR signalling pathway is an important feature of the antitumour activity of 5F 203.
    British Journal of Cancer 03/2003; 88(4):599-605. · 5.08 Impact Factor
  • Henry P Ciolino, Maame Dankwah, Grace Chao Yeh
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    ABSTRACT: We have developed a series of aryl hydrocarbon (AH)-resistant cell lines derived from MCF-7 human breast epithelial cancer cells by continuous exposure to the AH benzo[a]pyrene. These cell lines display cross-resistance to the mammary carcinogen dimethylbenz[a]anthracene (DMBA). Apoptosis induced by exposure to DMBA is greatly decreased in the resistant cell lines compared to the wild-type, in proportion to the level of resistance. Apoptosis induced by DMBA could be blocked by inhibitors of DMBA metabolism such as alpha-naphthoflavone and diosmetin. We therefore examined the resistant cell lines for their ability to metabolize DMBA and for the formation of DMBA-DNA adducts, and found that both parameters were decreased compared to wild-type cells in proportion to the level of resistance. When exposed to DMBA or 2,3,7,8-tetrachlorodibenzo-p-dioxin, the resistant cell lines have a diminished capacity to carry out ethoxyresorufin-O-deethylation, indicating that the induction of cytochrome P450 1A1 (CYP1A1) enzyme is impaired. We therefore examined the expression of the CYP1A1 gene, and found reduced levels of both CYP1A1 mRNA and CYP1A1-promoter controlled transcription in resistant cells compared to the wild-type. The deleterious effects of AHs are believed to be mediated by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor which regulates CYP1A1 expression. Resistant cell lines had a reduced expression of the AhR, as measured at the mRNA and protein levels. These data demonstrate that AH resistance in these cells is mediated by changes in the signal transduction pathway which regulates CYP1A1 expression.
    International Journal of Oncology 09/2002; 21(2):385-91. · 2.66 Impact Factor
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    ABSTRACT: In the present study, we examined the effect of a synthetic analogue of the chemopreventive hormone dehydroepiandrosterone, 16alpha-fluoro-5-androsten-17-one, also known as fluasterone, on the activity and expression of carcinogen-activating enzymes in MCF-7 cells. The increase in cytochrome P450 (CYP) 1A1 and 1B1 activity, as measured by ethoxyresorufin-O-deethylase activity, in cells treated with the carcinogens dimethylbenzanthracene (DMBA) or 2,3,5,7-tetrachlorodibenzo-p-dioxin (TCDD), was inhibited by cotreatment with fluasterone. However, treatment of the cells with fluasterone after induction with DMBA or TCDD failed to decrease enzyme activity, indicating that inhibition was not the result of direct enzyme inhibition. Therefore, we examined the effect of fluasterone on gene expression at the mRNA level. Both DMBA and TCDD caused a dramatic increase in the amount of CYP1A1 and CYP1B1 mRNA, the two major isoforms involved in carcinogen activation in these cells. In cells cotreated with fluasterone, however, there was a dose-dependent decrease in CYP1A1 and CYP1B1 mRNA. Fluasterone also inhibited the basal level of CYP1A1 mRNA but not CYP1B1. Fluasterone inhibited the rate of CYP1A1 promoter-controlled transcription, indicating that it affects the transcriptional regulation of the gene. Actinomycin D chase experiments showed that fluasterone also caused an increase in the degradation of CYP1A1 mRNA, while leaving CYP1B1 mRNA unaffected. These results indicate that fluasterone inhibits the increase in the expression of CYP1A1 normally caused by exposure to carcinogens by both transcriptional and post-transcriptional mechanisms and that CYP1B1 expression is not susceptible to the same post-transcriptional mechanism.
    Cancer Research 08/2002; 62(13):3685-90. · 8.65 Impact Factor
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    ABSTRACT: The mutagenic effect of environmental carcinogens has been well documented in animal models and in human studies but the mechanisms involved in preventing carcinogen insult have not been fully elucidated. In this study we examined the molecular and biochemical changes associated with carcinogen resistance in a series of aryl hydrocarbon-resistant MCF-7 cell lines developed by exposure to benzo[a]pyrene (BP). The cell lines were designated as AH(R40), AH(R100), and AH(R200) to denote their increasing fold resistance to BP compared with wild type cells. These cell lines were also resistant to another aryl hydrocarbon (AH), dimethylbenz[a]anthracene, but not to pleiotropic drugs (doxorubicin, vinblastine, and taxol). The resistant cell lines showed an increase in the level of the primary intracellular antioxidant, reduced glutathione, corresponding to increasing AH resistance. However, there was no change in glutathione reductase activity. The generation of reduced glutathione requires NADPH, and we therefore examined the activity and expression of the rate-limiting enzyme in NADPH production, glucose-6-phosphate dehydrogenase (G6PD). An increase in G6PD specific activity was associated with increasing aryl hydrocarbon resistance. This was due to an increased expression of G6PD in resistant cells, which was demonstrated by increases in both protein and mRNA levels. However, there was no increase in the transcription rate of G6PD in the resistant cell lines, indicating that the increase G6PD expression is due to a post-transcriptional modulation, which was confirmed by actinomycin D chase experiments. These results demonstrate that modulation of G6PD expression and activity is an important mechanism in AH resistance.
    Journal of Biological Chemistry 10/2001; 276(37):34708-13. · 4.65 Impact Factor
  • C J MacDonald, H P Ciolino, G C Yeh
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    ABSTRACT: The phytochemical dibenzoylmethane (DBM) has been shown to prevent polycyclic aromatic hydrocarbon (PAH)-induced tumorigenesis in rodents. However, the biochemical basis of this activity is unclear. We have therefore investigated the effects of DBM on the activity and expression of carcinogen-activating enzymes, the cytochromes P450 (CYP) 1A1, 1A2, and 1B1. Oral administration of DBM to female Sprague Dawley rats inhibited the increase in hepatic enzyme activity and mRNA levels of CYP1A1, 1A2, and 1B1 caused by the PAH 7,12-dimethylbenz[a]anthracene (DMBA). However, DBM administration alone caused an increase in both activity and expression in the liver, albeit to levels much lower than that induced by DMBA. To characterize the molecular mechanisms involved in this dual action of DBM, we examined the effects of DBM in vitro. In HepG2 human hepatoma cells, DBM inhibited DMBA- and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced enzyme activity and CYP1A1, 1A2, and 1B1 mRNA levels, whereas DBM itself induced activity and mRNA expression. Modulation of CYP1A1 expression by DBM occurred at the transcriptional level, as transient transfection assays demonstrated. Because the transcription of CYP1A1 is regulated by the aryl hydrocarbon receptor (AhR), we investigated the effect of DBM on AhR activation. DBM inhibited TCCD-induced DNA-binding of the AhR to the xenobiotic-responsive element (XRE) of CYP1A1 as measured by electrophoretic mobility shift assay. These data suggest that the chemopreventive activity of DBM results from its ability to affect Phase 1 enzyme expression by modulation of AhR function.
    Cancer Research 06/2001; 61(10):3919-24. · 8.65 Impact Factor
  • H P Ciolino, G C Yeh
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    ABSTRACT: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor of the basic helix-loop-helix family) It binds and is activated by a number of compounds, including polycyclic aromatic hydrocarbons (PAH) such as benzo[a]pyrene (B[a]P), which are generated during the combustion of fossil fuels and are present in tobacco smoke and smoked meats. The AHR also binds halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), which is a contaminant formed during the manufacture of chlorophenols (for chemical structures see Fig. 1). Both these classes of AHR ligands are persistent environmental pollutants and cause a variety of toxic and carcinogenic effects that are mediated by the AHR.
    Advances in experimental medicine and biology 02/2001; 492:183-93. · 1.83 Impact Factor
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    H P Ciolino, T T Y Wang, N Sathyamoorthy
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    ABSTRACT: The effect of the chemopreventive synthetic retinoid N-(4-hydroxyphenyl)-retinamide (4-HPR) on aromatase activity and expression was examined. 4-HPR caused a dose-dependent inhibition of aromatase activity in microsomes isolated from JEG-3 human placental carcinoma cells. The kinetics of inhibition were analysed by double-reciprocal plot. The Km of the substrate increased and the Vmax of the reaction decreased in the presence of 4-HPR, indicating that enzyme inhibition involved both competition for the substrate-binding site and non-competitive mechanisms. To determine whether 4-HPR would also inhibit aromatase activity in intact cells, MCF-7 human breast cancer cells were incubated with or without cAMP in the presence of 4-HPR. 4-HPR inhibited both basal and cAMP-induced aromatase activity in intact MCF-7 cells. The induction of aromatase mRNA expression in MCF-7 cells by cAMP was inhibited in cells treated with 4-HPR. These results indicate that 4-HPR inhibits both the enzymatic activity and expression of aromatase. These activities may play an important role in the known chemopreventive effect of 4-HPR towards breast cancer.
    British Journal of Cancer 09/2000; 83(3):333-7. · 5.08 Impact Factor

Publication Stats

921 Citations
146.67 Total Impact Points

Institutions

  • 2008–2013
    • University of Texas at Austin
      • Division of Nutritional Sciences
      Austin, Texas, United States
  • 1999–2012
    • National Cancer Institute (USA)
      • Basic Research Laboratory
      Maryland, United States
    • SAIC
      Maryland, United States
  • 1998–2007
    • National Institutes of Health
      • • Center for Cancer Research
      • • Basic Research Laboratory
      Bethesda, MD, United States
  • 1998–2003
    • Leidos Biomedical Research
      Maryland, United States