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1
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Singhabahu R, Kodagoda Gamage SM, Gopalan V. Pathological significance of heme oxygenase-1 as a potential tumor promoter in heme-induced colorectal carcinogenesis. CANCER PATHOGENESIS AND THERAPY 2024; 2:65-73. [PMID: 38601482 PMCID: PMC11002664 DOI: 10.1016/j.cpt.2023.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/01/2023] [Accepted: 04/06/2023] [Indexed: 04/12/2024]
Abstract
The significance of the heme-metabolizing enzyme heme oxygenase-1 (HMOX1) in the pathogenesis of colorectal cancer (CRC) has not been fully explored. HMOX1 cytoprotection is imperative to limit oxidative stress. However, its roles in preventing carcinogenesis in response to high levels of heme are not thoroughly understood. This study reviews various mechanisms associated with the paradoxical role of HMOX1, which is advantageous for tumor growth, refractoriness, and survival of cancer cells amid oxidative stress in heme-induced CRC. The alternate role of HMOX1 promotes cell proliferation and metastasis through immune modulation and angiogenesis. Inhibiting HMOX1 has been found to reverse tumor promotion. Thus, HMOX1 acts as a conditional tumor promoter in CRC pathogenesis.
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Affiliation(s)
- Rachitha Singhabahu
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland 4222, Australia
| | - Sujani M. Kodagoda Gamage
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland 4222, Australia
- Faculty of Health Sciences and Medicine, Bond University, Robina 4226, Australia
| | - Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland 4222, Australia
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2
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Salminen A. Aryl hydrocarbon receptor (AhR) reveals evidence of antagonistic pleiotropy in the regulation of the aging process. Cell Mol Life Sci 2022; 79:489. [PMID: 35987825 PMCID: PMC9392714 DOI: 10.1007/s00018-022-04520-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/14/2022] [Accepted: 08/08/2022] [Indexed: 11/24/2022]
Abstract
The antagonistic pleiotropy hypothesis is a well-known evolutionary theory to explain the aging process. It proposes that while a particular gene may possess beneficial effects during development, it can exert deleterious properties in the aging process. The aryl hydrocarbon receptor (AhR) has a significant role during embryogenesis, but later in life, it promotes several age-related degenerative processes. For instance, AhR factor (i) controls the pluripotency of stem cells and the stemness of cancer stem cells, (ii) it enhances the differentiation of embryonal stem cells, especially AhR signaling modulates the differentiation of hematopoietic stem cells and progenitor cells, (iii) it also stimulates the differentiation of immunosuppressive Tregs, Bregs, and M2 macrophages, and finally, (iv) AhR signaling participates in the differentiation of many peripheral tissues. On the other hand, AhR signaling is involved in many processes promoting cellular senescence and pathological processes, e.g., osteoporosis, vascular dysfunction, and the age-related remodeling of the immune system. Moreover, it inhibits autophagy and aggravates extracellular matrix degeneration. AhR signaling also stimulates oxidative stress, promotes excessive sphingolipid synthesis, and disturbs energy metabolism by catabolizing NAD+ degradation. The antagonistic pleiotropy of AhR signaling is based on the complex and diverse connections with major signaling pathways in a context-dependent manner. The major regulatory steps include, (i) a specific ligand-dependent activation, (ii) modulation of both genetic and non-genetic responses, (iii) a competition and crosstalk with several transcription factors, such as ARNT, HIF-1α, E2F1, and NF-κB, and (iv) the epigenetic regulation of target genes with binding partners. Thus, not only mTOR signaling but also the AhR factor demonstrates antagonistic pleiotropy in the regulation of the aging process.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
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3
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Gährs M, Schrenk D. Suppression of apoptotic signaling in rat hepatocytes by non-dioxin-like polychlorinated biphenyls depends on the receptors CAR and PXR. Toxicology 2021; 464:153023. [PMID: 34743025 DOI: 10.1016/j.tox.2021.153023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 10/19/2021] [Accepted: 11/02/2021] [Indexed: 10/19/2022]
Abstract
Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) represent a sub-group of persistent organic pollutants found in food, environmental samples and human and animal tissues. Promotion of pre-neoplastic lesions in rodent liver has been suggested as an indicator for a possible increased risk of liver cancer in humans exposed to NDL-PCBs. In rodent hepatocytes, suppression of DNA damage-triggered apoptosis is a typical mode of action of liver tumor promoters. Here, we report that NDL-PCBs suppress apoptosis in rat hepatocytes treated in culture with an apoptogenic dose of UV light. Suppression became less pronounced when the constitutive androstane receptor (CAR) and/or the pregnane-X-receptor (PXR) where knocked-out using siRNAs, while knocking-out both receptors led to a full reconstitution of apoptosis. In contrast, suppression of apoptosis by the CAR or PXR activators phenobarbital or dexamethasone were CAR- or PXR-specific. Induction and suppression of apoptosis were paralleled by changes in caspase 3/7, 8 and 9 activities. Our findings indicate that NDL-PCBs can suppress UV-induced apoptosis in rat hepatocytes by activating CAR and PXR. It needs further investigation if these mechanisms of action are also of relevance for human liver.
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Affiliation(s)
- Maike Gährs
- Food Chemistry and Toxicology, University of Kaiserslautern, Kaiserslautern, Germany
| | - Dieter Schrenk
- Food Chemistry and Toxicology, University of Kaiserslautern, Kaiserslautern, Germany.
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Becker RA, Patlewicz G, Simon TW, Rowlands JC, Budinsky RA. The adverse outcome pathway for rodent liver tumor promotion by sustained activation of the aryl hydrocarbon receptor. Regul Toxicol Pharmacol 2015; 73:172-90. [PMID: 26145830 DOI: 10.1016/j.yrtph.2015.06.015] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 06/19/2015] [Accepted: 06/22/2015] [Indexed: 12/29/2022]
Abstract
An Adverse Outcome Pathway (AOP) represents the existing knowledge of a biological pathway leading from initial molecular interactions of a toxicant and progressing through a series of key events (KEs), culminating with an apical adverse outcome (AO) that has to be of regulatory relevance. An AOP based on the mode of action (MOA) of rodent liver tumor promotion by dioxin-like compounds (DLCs) has been developed and the weight of evidence (WoE) of key event relationships (KERs) evaluated using evolved Bradford Hill considerations. Dioxins and DLCs are potent aryl hydrocarbon receptor (AHR) ligands that cause a range of species-specific adverse outcomes. The occurrence of KEs is necessary for inducing downstream biological responses and KEs may occur at the molecular, cellular, tissue and organ levels. The common convention is that an AOP begins with the toxicant interaction with a biological response element; for this AOP, this initial event is binding of a DLC ligand to the AHR. Data from mechanistic studies, lifetime bioassays and approximately thirty initiation-promotion studies have established dioxin and DLCs as rat liver tumor promoters. Such studies clearly show that sustained AHR activation, weeks or months in duration, is necessary to induce rodent liver tumor promotion--hence, sustained AHR activation is deemed the molecular initiating event (MIE). After this MIE, subsequent KEs are 1) changes in cellular growth homeostasis likely associated with expression changes in a number of genes and observed as development of hepatic foci and decreases in apoptosis within foci; 2) extensive liver toxicity observed as the constellation of effects called toxic hepatopathy; 3) cellular proliferation and hyperplasia in several hepatic cell types. This progression of KEs culminates in the AO, the development of hepatocellular adenomas and carcinomas and cholangiolar carcinomas. A rich data set provides both qualitative and quantitative knowledge of the progression of this AOP through KEs and the KERs. Thus, the WoE for this AOP is judged to be strong. Species-specific effects of dioxins and DLCs are well known--humans are less responsive than rodents and rodent species differ in sensitivity between strains. Consequently, application of this AOP to evaluate potential human health risks must take these differences into account.
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Affiliation(s)
- Richard A Becker
- Regulatory and Technical Affairs Department, American Chemistry Council (ACC), Washington, DC 20002, USA.
| | - Grace Patlewicz
- DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, DE 19711, USA
| | - Ted W Simon
- Ted Simon LLC, 4184 Johnston Road, Winston, GA 30187, USA
| | - J Craig Rowlands
- The Dow Chemical Company, Toxicology & Environmental Research & Consulting, 1803 Building Washington Street, Midland, MI 48674, USA
| | - Robert A Budinsky
- The Dow Chemical Company, Toxicology & Environmental Research & Consulting, 1803 Building Washington Street, Midland, MI 48674, USA
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Rhein Elicits In Vitro Cytotoxicity in Primary Human Liver HL-7702 Cells by Inducing Apoptosis through Mitochondria-Mediated Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015. [PMID: 26221172 PMCID: PMC4484835 DOI: 10.1155/2015/329831] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Objective. To study rhein-induced apoptosis signaling pathway and to investigate its molecular mechanisms in primary human hepatic cells. Results. Cell viability of HL-7702 cells treated with rhein showed significant decrease in dose-dependent manner. Following rhein treatment (25 μM, 50 μM, and 100 μM) for 12 h, the detection of apoptotic cells was significantly analyzed by flow cytometry and nuclear morphological changes by Hoechst 33258, respectively. Fatty degeneration studies showed upregulation level of the relevant hepatic markers (P < 0.01). Caspase activities expressed significant upregulation of caspase-3, caspase-9, and caspase-8. Moreover, apoptotic cells by rhein were significantly inhibited by Z-LEHD-FMK and Z-DEVD-FMK, caspase-9 inhibitor, and caspase-3 inhibitor, respectively. Overproduction of reactive oxygen species, lipid peroxidation, and loss of mitochondrial membrane potential were detected by fluorometry. Additionally, NAC, a ROS scavenger, significantly attenuated rhein-induced oxidative damage in HL-7702 cells. Furthermore, real-time qPCR results showed significant upregulation of p53, PUMA, Apaf-1, and Casp-9 and Casp-3 mRNA, with no significant changes of Fas and Cytochrome-c. Immunoblotting revealed significant Cytochrome-c release from mitochondria into cytosol and no change in Fas expression. Conclusion. Taken together, these observations suggested that rhein could induce apoptosis in HL-7702 cells via mitochondria-mediated signal pathway with involvement of oxidative stress mechanism.
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Song L, Zhao M, Liu J, Li Z, Xiao H, Liu W. p,p′-Dichlorodiphenyltrichloroethane inhibits the apoptosis of colorectal adenocarcinoma DLD1 cells through PI3K/AKT and Hedgehog/Gli1 signaling pathways. Toxicol Res (Camb) 2015. [DOI: 10.1039/c5tx00006h] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
p,p′-Dichlorodiphenyltrichloroethane is able to inhibit the apoptosis of human colorectal adenocarcinoma cells, which may be an important mechanism to contribute to colorectal cancer development.
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Affiliation(s)
- Li Song
- Institute of Biotechnology
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education
- Shanxi University
- Taiyuan 030006
- China
| | - Meirong Zhao
- Research Center of Environmental Science
- Zhejiang University of Technology
- Hangzhou 310032
- China
| | - Jianxin Liu
- Institute of Biotechnology
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education
- Shanxi University
- Taiyuan 030006
- China
| | - Zhuoyu Li
- Institute of Biotechnology
- Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education
- Shanxi University
- Taiyuan 030006
- China
| | - Hong Xiao
- Department of Pathology
- The First Affiliated Hospital
- Shanxi Medical University
- Taiyuan
- China
| | - Weiping Liu
- MOE Key Lab of Environmental Remediation and Ecosystem Health
- College of Environmental and Resource Sciences
- Zhejiang University
- Hangzhou 310058
- China
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Budinsky RA, Schrenk D, Simon T, Van den Berg M, Reichard JF, Silkworth JB, Aylward LL, Brix A, Gasiewicz T, Kaminski N, Perdew G, Starr TB, Walker NJ, Rowlands JC. Mode of action and dose–response framework analysis for receptor-mediated toxicity: The aryl hydrocarbon receptor as a case study. Crit Rev Toxicol 2013; 44:83-119. [DOI: 10.3109/10408444.2013.835787] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Wei M, Yamada T, Yamano S, Kato M, Kakehashi A, Fujioka M, Tago Y, Kitano M, Wanibuchi H. Diphenylarsinic acid, a chemical warfare-related neurotoxicant, promotes liver carcinogenesis via activation of aryl hydrocarbon receptor signaling and consequent induction of oxidative DAN damage in rats. Toxicol Appl Pharmacol 2013; 273:1-9. [DOI: 10.1016/j.taap.2013.08.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Revised: 08/20/2013] [Accepted: 08/20/2013] [Indexed: 02/05/2023]
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9
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Primary hepatocytes and their cultures in liver apoptosis research. Arch Toxicol 2013; 88:199-212. [PMID: 24013573 DOI: 10.1007/s00204-013-1123-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Accepted: 08/29/2013] [Indexed: 01/18/2023]
Abstract
Apoptosis not only plays a key role in physiological demise of defunct hepatocytes, but is also associated with a plethora of acute and chronic liver diseases as well as with hepatotoxicity. The present paper focuses on the modelling of this mode of programmed cell death in primary hepatocyte cultures. Particular attention is paid to the activation of spontaneous apoptosis during the isolation of hepatocytes from the liver, its progressive manifestation upon the subsequent establishment of cell cultures and simultaneously to strategies to counteract this deleterious process. In addition, currently applied approaches to experimentally induce controlled apoptosis in this in vitro setting for mechanistic research purposes and thereby its detection using relevant biomarkers are reviewed.
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Schoener CA, Hutson HN, Peppas NA. pH-responsive hydrogels with dispersed hydrophobic nanoparticles for the oral delivery of chemotherapeutics. J Biomed Mater Res A 2012; 101:2229-36. [PMID: 23281185 DOI: 10.1002/jbm.a.34532] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2012] [Revised: 10/16/2012] [Accepted: 10/18/2012] [Indexed: 01/13/2023]
Abstract
Amphiphilic polymer carriers were formed by polymerizing a hydrophilic, pH-responsive hydrogel composed of poly(methacrylic-grafted-ethylene glycol) (P(MAA-g-EG)) in the presence of hydrophobic PMMA nanoparticles. These polymer carriers were varied in PMMA nanoparticle content to elicit a variety of physiochemical properties which would preferentially load doxorubicin, a hydrophobic chemotherapeutic, and release doxorubicin locally in the colon for the treatment of colon cancers. Loading levels ranged from 49% to 64% and increased with increasing nanoparticle content. Doxorubicin loaded polymers were released in a physiological model where low pH was used to simulate the stomach and then stepped to more neutral conditions to simulate the upper small intestine. P(MAA-g-EG) containing nanoparticles were less mucoadhesive as determined using a tensile tester, polymer samples, and fresh porcine small intestine. The cytocompatibility of the polymer materials were assessed using cell lines representing the GI tract and colon cancer and were noncytotoxic at varying concentrations and exposure times.
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Affiliation(s)
- Cody A Schoener
- Department of Chemical Engineering, The University of Texas at Austin, Austin, Texas 78712, USA
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11
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Schoener CA, Hutson HN, Peppas NA. pH-Responsive Hydrogels with Dispersed Hydrophobic Nanoparticles for the Delivery of Hydrophobic Therapeutic Agents. POLYM INT 2012; 61:874-879. [PMID: 23087546 DOI: 10.1002/pi.4219] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
To investigate the delivery of hydrophobic therapeutic agents, a new class of polymer carriers was synthesized. These carriers are composed of two components: (i) a pH-responsive hydrogel composed of methacrylic acid grafted with poly(ethylene glycol) tethers, P(MAA-g-EG), and (ii) hydrophobic poly(methyl methacrylate) (PMMA) nanoparticles. Before the P(MAA-g-EG) hydrogel was crosslinked, PMMA nanoparticles were added to the solution and upon exposure to UV light they were photoencapsulated throughout the P(MAA-g-EG) hydrogel structure. The pH-responsive behavior of P(MAA-g-EG) is capable of triggered release of a loaded therapeutic agent, such as a low molecular weight drug or protein, when it passes from the stomach (low pH) to upper small intestine (neutral pH). The introduction of PMMA nanoparticles into the hydrogel structure affected the swelling behavior, therapeutic agent loading efficiency, and solute release profiles. In equilibrium swelling conditions the swelling ratio of nanoparticle-containing hydrogels decreased with increasing nanoparticle content. Loading efficiencies of the model therapeutic agent fluorescein ranged from 38 - 51 % and increased with increasing hydrophobic content. Release studies from neat P(MAA-g-EG) and the ensuing P(MAA-g-EG) hydrogels containing nanoparticles indicated that the transition from low pH (2.0) to neutral pH (7.0) triggered fluorescein release. Maximum fluorescein release depended on the structure and hydrophobicity of the carriers used in these studies.
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Affiliation(s)
- Cody A Schoener
- Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
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12
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Volkov MS, Bolotina NA, Evteev VA, Koblyakov VA. Ah-receptor-independent stimulation of hepatoma 27 culture cell proliferation by polycyclic aromatic hydrocarbons. BIOCHEMISTRY (MOSCOW) 2012; 77:201-7. [DOI: 10.1134/s0006297912020125] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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13
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Schoener CA, Hutson HN, Fletcher GK, Peppas NA. Amphiphilic Interpenetrating Networks for the Delivery of Hydrophobic, Low Molecular Weight Therapeutic Agents. Ind Eng Chem Res 2011; 50:12556-12561. [PMID: 22247592 DOI: 10.1021/ie201593h] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
To investigate the delivery of hydrophobic therapeutic agents, a novel class of interpenetrating networks (IPNs) were synthesized and composed of two networks: methacrylic acid grafted with poly(ethylene glycol) tethers, P(MAA-g-EG), and poly(n-butyl acrylate) (PBA). The hydrophilic P(MAA-g-EG) networks are pH-responsive hydrogels capable of triggered release of an encapsulated therapeutic agent, such as a low molecular weight drug or a protein, when it passes from the stomach (low pH) to upper small intestine (neutral pH). PBA is a hydrophobic homopolymer that can affect the IPN swelling behavior, the therapeutic agent loading efficiencies in IPNs, and solute release profiles from IPNs. In dynamic swelling conditions, IPNs had greater swelling ratios than P(MAA-g-EG), but in equilibrium swelling conditions the IPN swelling ratio decreased with increasing PBA content. Loading efficiencies of the model therapeutic agent fluorescein ranged from 21 - 44%. Release studies from neat P(MAA-g-EG) and the ensuing IPNs indicated that the transition from low pH (2.0) to neutral pH (7.0) triggered fluorescein release. Maximum fluorescein release depended on the structure and hydrophilicity of the carriers used in these studies.
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Affiliation(s)
- Cody A Schoener
- Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
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Gaitanis G, Velegraki A, Magiatis P, Pappas P, Bassukas ID. Could Malassezia yeasts be implicated in skin carcinogenesis through the production of aryl-hydrocarbon receptor ligands? Med Hypotheses 2011; 77:47-51. [PMID: 21444158 DOI: 10.1016/j.mehy.2011.03.020] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2010] [Accepted: 03/07/2011] [Indexed: 01/09/2023]
Abstract
UNLABELLED Malassezia yeasts are found on the skin of all humans and many warm-blooded animals. In vitro they have the ability to synthesize potent ligands (indolo[3,2-b]carbazole, malassezin and indirubin) of the aryl-hydrocarbon receptor (AhR; synonym: dioxin receptor) when the sweat contained L-tryptophan is used as the single nitrogen source. The production of these AhR-ligands has been associated with pathogenic strains of a certain Malassezia species (Malassezia furfur) but recent evidence shows that this property is widely distributed in almost all currently known Malassezia species. AhR is associated with carcinogenesis and the potential connection of these ubiquitous skin symbionts, and putative pathogens, with skin neoplasia should be evaluated mainly focusing on mechanisms related to the distinctive ability of the yeast to produce potent AhR ligands. HYPOTHESIS Synthesis of available pertinent data show a possible link between Malassezia produced AhR ligands and skin carcinogenesis, particularly of basal cell carcinoma (BCC). BCCs are almost exclusively observed in animal species colonized by Malassezia. In humans and animals there is overlapping in the skin regions colonized by this yeast and affected by BCC. The potent AhR ligands synthesized by pathogenic Malassezia strains could contribute to tumor promotion by: modification of the UV radiation carcinogenesis, alterations in the salvage/survival of initiated tumor cells, inhibition of cell senescence, interaction with vitamin D metabolism, promotion of immune tolerance and finally pro-carcinogenic modulation of cell cycle progression and apoptosis.
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Affiliation(s)
- G Gaitanis
- Department of Skin and Venereal Diseases, Medical School, University of Ioannina, S. Niarchou Av., University Campus, 45110 Ioannina, Greece.
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Yang X, Zhang B, Molony C, Chudin E, Hao K, Zhu J, Gaedigk A, Suver C, Zhong H, Leeder JS, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich RG, Slatter JG, Schadt EE, Kasarskis A, Lum PY. Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver. Genome Res 2010; 20:1020-36. [PMID: 20538623 DOI: 10.1101/gr.103341.109] [Citation(s) in RCA: 211] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s.
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Affiliation(s)
- Xia Yang
- Rosetta Inpharmatics, LLC, Merck & Co., Inc., Seattle, Washington 98109, USA.
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Jin MH, Hong CH, Lee HY, Kang HJ, Han SW. Toxic effects of lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on development of male reproductive system: involvement of antioxidants, oxidants, and p53 protein. ENVIRONMENTAL TOXICOLOGY 2010; 25:1-8. [PMID: 19085997 DOI: 10.1002/tox.20466] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent endocrine disruptor compound and induces multiple organ dysfunctions. The effect of TCDD exposure both in adults and in utero has been well established. However, little is known about the effects of TCDD acquired through mother's milk on the development of the male reproductive system. The aim of this study was to investigate the effects and mechanisms of TCDD from lactational exposure. TCDD (1 microg/kg) was administered to C57BL/6 mouse mothers for 4 days from the day of delivery. On postnatal day 30 (PND 30) and postnatal day 60 (PND 60), body weight, body length, and anogenital distance (AGD) of male offspring were measured. The weights of the testes and epididymides were also measured. Epididymides were used for sperm counts, and testes were used to measure the activity of antioxidant enzymes (SOD, CAT, GPX, GR), the parameters of oxidative stress (hydrogen peroxide, MDA), and testosterone. In addition, expression of p53 and the proapoptotic protein, Bax, were analyzed by Western blot. TCDD exposure decreased body weight, body length, and AGD in both PND 30 and PND 60 groups compared with the control group. The activity of all antioxidant enzymes at PND 60 was decreased after TCDD treatment. TCDD treatment decreased testicular testosterone levels in both the PND 30 and PND 60 groups. The expression of p53 and Bax were also upregulated by TCDD and did not return to normal levels by PND 60. These data suggest that TCDD affects development of male offspring when the mother is exposed to TCDD during lactation. In addition, oxidative stress is a major mediator of TCDD-induced adverse effects, and p53 may play an important role in this mechanism.
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Affiliation(s)
- Mei Hua Jin
- Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
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Simon T, Aylward LL, Kirman CR, Rowlands JC, Budinsky RA. Estimates of Cancer Potency of 2,3,7,8-Tetrachlorodibenzo(p)dioxin Using Linear and Nonlinear Dose-Response Modeling and Toxicokinetics. Toxicol Sci 2009; 112:490-506. [DOI: 10.1093/toxsci/kfp232] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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18
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Schreck I, Chudziak D, Schneider S, Seidel A, Platt KL, Oesch F, Weiss C. Influence of aryl hydrocarbon- (Ah) receptor and genotoxins on DNA repair gene expression and cell survival of mouse hepatoma cells. Toxicology 2009; 259:91-6. [DOI: 10.1016/j.tox.2009.02.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2009] [Revised: 02/13/2009] [Accepted: 02/13/2009] [Indexed: 01/15/2023]
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Puga A, Ma C, Marlowe JL. The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways. Biochem Pharmacol 2008; 77:713-22. [PMID: 18817753 DOI: 10.1016/j.bcp.2008.08.031] [Citation(s) in RCA: 288] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2008] [Revised: 08/20/2008] [Accepted: 08/21/2008] [Indexed: 12/13/2022]
Abstract
Exposure to toxic polycyclic aromatic hydrocarbons raises a number of toxic and carcinogenic responses in experimental animals and humans mediated for the most part by the aryl hydrocarbon -- or dioxin -- receptor (AHR). The AHR is a ligand-activated transcription factor whose central role in the induction of drug-metabolizing enzymes has long been recognized. For quite some time now, it has become clear that the AHR also functions in pathways outside of its role in detoxification and that perturbation of these pathways by xenobiotic ligands may be an important part of the toxicity of these compounds. AHR activation by some of its ligands participates among others in pathways critical to cell cycle regulation, mitogen-activated protein kinase cascades, immediate-early gene induction, cross-talk within the RB/E2F axis and mobilization of crucial calcium stores. Ultimately, the effect of a particular AHR ligand may depend as much on the adaptive interactions that it established with pathways and proteins expressed in a specific cell or tissue as on the toxic responses that it raises.
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Affiliation(s)
- Alvaro Puga
- Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA.
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20
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Marlowe JL, Fan Y, Chang X, Peng L, Knudsen ES, Xia Y, Puga A. The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis. Mol Biol Cell 2008; 19:3263-71. [PMID: 18524851 DOI: 10.1091/mbc.e08-04-0359] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Cellular stress by DNA damage induces checkpoint kinase-2 (CHK2)-mediated phosphorylation and stabilization of the E2F1 transcription factor, leading to induction of apoptosis by activation of a subset of proapoptotic E2F1 target genes, including Apaf1 and p73. This report characterizes an interaction between the aryl hydrocarbon (Ah) receptor (AHR), a ligand-activated transcription factor, and E2F1 that results in the attenuation of E2F1-mediated apoptosis. In Ahr(-/-) fibroblasts stably transfected with a doxycycline-regulated AHR expression vector, inhibition of AHR expression causes a significant elevation of oxidative stress, gammaH2A.X histone phosphorylation, and E2F1-dependent apoptosis, which can be blocked by small interfering RNA-mediated knockdown of E2F1 expression. In contrast, ligand-dependent AHR activation protects these cells from etoposide-induced cell death. In cells expressing both proteins, AHR and E2F1 interact independently of the retinoblastoma protein (RB), because AHR and E2F1 coimmunoprecipitate from extracts of RB-negative cells. Additionally, chromatin immunoprecipitation assays indicate that AHR and E2F1 bind to the Apaf1 promoter at a region containing a consensus E2F1 binding site but no AHR binding sites. AHR activation represses Apaf1 and TAp73 mRNA induction by a constitutively active CHK2 expression vector. Furthermore, AHR overexpression blocks the transcriptional induction of Apaf1 and p73 and the accumulation of sub-G(0)/G(1) cells resulting from ectopic overexpression of E2F1. These results point to a proproliferative, antiapoptotic function of the Ah receptor that likely plays a role in tumor progression.
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Affiliation(s)
- Jennifer L Marlowe
- Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0056, USA
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21
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Schlezinger JJ, Liu D, Farago M, Seldin DC, Belguise K, Sonenshein GE, Sherr DH. A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis. Biol Chem 2008; 387:1175-87. [PMID: 16972784 DOI: 10.1515/bc.2006.145] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The aryl hydrocarbon receptor (AhR) is an evolutionarily conserved transcription factor bound and activated by ubiquitous environmental pollutants. Historically, the AhR has been studied for its transcriptional regulation of genes encoding cytochrome P450 enzymes, which metabolize many of these chemicals into mutagenic and toxic intermediates. However, recent studies demonstrate that the AhR plays an important role in the biology of several cell types in the absence of environmental chemicals. Here, this paradigm shift is discussed in the context of a putative role for the AhR in mammary gland tumorigenesis. Data demonstrating high levels of constitutively active AhR in mammary tumors are summarized. Particular focus is placed on the likelihood that the AhR contributes to ongoing mammary tumor cell growth and on the possibility that the AhR inhibits apoptosis while promoting transition to an invasive, metastatic phenotype. A working model is proposed that may help explain the sometimes contradictory outcomes observed after AhR manipulation and that serves as a blueprint for the design of therapeutics which target the AhR in breast cancer. The theme that malignant cells reveal the functions for which the AhR has been evolutionarily conserved is presented throughout this discussion.
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Affiliation(s)
- Jennifer J Schlezinger
- Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA
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22
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Vogel CFA, Li W, Sciullo E, Newman J, Hammock B, Reader JR, Tuscano J, Matsumura F. Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygenase-2 expression. THE AMERICAN JOURNAL OF PATHOLOGY 2007; 171:1538-48. [PMID: 17823287 PMCID: PMC2043515 DOI: 10.2353/ajpath.2007.070406] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Epidemiological studies indicate that exposure to environmental pollutants such as pesticides and dioxins leads to the pathogenesis of lymphoma and leukemia. Here, we show that activation of the aryl hydrocarbon receptor (AhR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in loss of the programmed cell death (apoptosis) response in three different lymphoma cell lines, which plays a key role in the development of cancer, especially lymphoma and leukemia. The AhR-mediated inhibition of apoptosis in vitro was associated with a clear increase of cyclooxygenase-2 (COX-2) and deregulation of genes of the B-cell lymphoma-2 (Bcl-2) family involved in apoptosis including Bcl-xl and Mcl-1 in several lymphoma cell lines. Treatment with the COX-2 inhibitor NS-398 and the AhR antagonist 3'-methoxy-4'-nitroflavone abolished the TCDD-induced resistance of apoptosis in vitro. Furthermore, using micropositron emission tomography imaging, in vivo findings demonstrated that exposure to TCDD promotes the development of lymphoma in superficial lymph nodes of C57BL/10J mice, which was associated with a marked increase of COX-2 expression in the affected lymph nodes. The results indicate that AhR activation and COX-2 overexpression likely represent a mechanism of resistance to apoptosis in lymphoma cell lines that might be relevant for the development of lymphoma in vivo.
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Affiliation(s)
- Christoph F A Vogel
- Department of Environmental Toxicology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
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23
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McCullough CT, Tura BJ, Harrison DJ. c-Myc partially mediates IFNgamma-induced apoptosis in the primary hepatocyte. Int J Exp Pathol 2007; 88:129-36. [PMID: 17504442 PMCID: PMC2517301 DOI: 10.1111/j.1365-2613.2006.00521.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Interferon-gamma (IFNgamma) is a central component of the complex cytokine and inflammatory response that contributes to liver cell injury in hepatitis. We report that in the primary hepatocyte IFNgamma synergizes with the mechanistically distinct apoptotic stimuli CD95, tumour necrosis factor-alpha (TNFalpha) and UV-irradiation. For the first time in primary hepatocytes, we show that IFNgamma-mediated apoptotic signalling requires the cell surface interaction of CD95 and its ligand, and we demonstrate that IFNgamma induces soluble CD95 ligand release from hepatocyte monolayers. Utilizing c-myc phosphorothioate antisense fragments, we suppresses hepatocyte apoptosis induced by IFNgamma. In summary, we identify apoptotic pathways that contribute to IFNgamma-mediated cell death. The hepatocellular response to IFNgamma signalling can be modulated by cytokines and by the interruption of CD95 interaction with its ligand. We present evidence to suggest that c-myc contributes to IFNgamma signalling.
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Affiliation(s)
- C T McCullough
- Edinburgh Cancer Research Centre, University of Edinburgh, Crewe Road South, Edinburgh, UK
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24
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Lim J, DeWitt JC, Sanders RA, Watkins JB, Henshel DS. Suppression of endogenous antioxidant enzymes by 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced oxidative stress in chicken liver during development. ARCHIVES OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY 2007; 52:590-5. [PMID: 17285237 DOI: 10.1007/s00244-006-0168-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2006] [Accepted: 10/15/2006] [Indexed: 05/13/2023]
Abstract
Domestic chickens (Gallus gallus) are an excellent model in which to evaluate developmental toxicity and oxidative stress because of their high sensitivity to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The goal of this study was to measure the effects of environmentally relevant doses of TCDD on endogenous hepatic antioxidant enzyme activity in hatchling chickens. The vehicle (sunflower oil) or 2, 20, or 200 pg/g TCDD was injected into chicken eggs before incubation. On hatching, livers were harvested and quickly frozen. The changes in activity of antioxidant enzymes, including glutathione peroxidase (GPx), glutathione reductase (GRx), copper zinc superoxide dismutase (SOD), and catalase (CAT) were determined as indicators of oxidative stress. TCDD exposure was associated with a significant suppression of the activities of the protective endogenous enzymes GPx, GRx, and SOD in the liver, even at the lowest dose. CAT activity was also suppressed, but not significantly. The measured decreases were 37% to 63% for GPx, 50% to 58% for GRx, 30% to 40% for SOD, and 16% to 24% for CAT. Noncomplex dose-response relationships were evident in GPx and GRx, whereas SOD and CAT curves were U-shaped. These results demonstrate that a decreased ability to scavenge reactive oxygen species may result from developmental TCDD exposure at very low doses, contributing to oxidative stress and thus to the embryotoxicity of TCDD.
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Affiliation(s)
- J Lim
- School of Public and Environmental Affairs, Indiana University, Bloomington, IN 47405, USA.
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25
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Wu R, Zhang L, Hoagland MS, Swanson HI. Lack of the aryl hydrocarbon receptor leads to impaired activation of AKT/protein kinase B and enhanced sensitivity to apoptosis induced via the intrinsic pathway. J Pharmacol Exp Ther 2007; 320:448-57. [PMID: 17018692 DOI: 10.1124/jpet.106.111773] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that is best known for its role in mediating the toxicity of many environmental contaminants such as 2,3,7,8 tetrachlorodibenzo-p-dioxin. However, the endogenous role of AHR, especially with respect to the apoptotic process, is largely unknown and contradictory. In this report, we have used a mouse hepatoma cell line (Hepa1c1c7) and its AHR-deficient derivative (LA1) to examine the effect of differing AHR levels on apoptosis susceptibility, in particular, apoptosis regulated by the intrinsic pathway. Toward this end, the cells were subjected to UV irradiation, hydrogen peroxide, and serum starvation. Analyses of a number of different endpoints of apoptosis revealed that the LA1 cells were more sensitive to these stresses than the wild-type cells, indicating that the AHR plays a cytoprotective role in the face of stimuli that initiate the intrinsic apoptotic pathway. A direct role of the AHR in mediating this effect was confirmed using both pharmacological and molecular approaches. Further analyses imply that lack of the AHR leads to an impaired survival response mediated by phosphatidylinositol 3'-OH kinase-Akt/protein kinase B and, to a lesser degree, epidermal growth factor receptor activation. These findings indicate that exploring the use of the AHR antagonist as agents that enhance the proapoptotic actions of cancer therapies may be a valid approach.
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Affiliation(s)
- Ran Wu
- Department of Molecular and Biomedical Pharmacology, MS305, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536, USA
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26
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Silva HTH, Hartmann AA. [Potentially pre-neoplasics areas in rat's liver associated to chronic use of phenobarbital]. ARQUIVOS DE GASTROENTEROLOGIA 2006; 43:121-4. [PMID: 17119667 DOI: 10.1590/s0004-28032006000200012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2004] [Accepted: 08/23/2005] [Indexed: 11/22/2022]
Abstract
BACKGROUND Phenobarbital has been used in experimental models because it is an important agent of carcinogenesis promotion in the liver of rats, and it is also non-genotoxic, organ-specific and dose-dependent. AIM To evaluate the effects of the daily administration of phenobarbital in old rats treated with phenobarbital since their birth up to 24 months of age, in the absence of concomitant administration of chemical agents, which initiate carcinogenesis. PATIENTS AND METHODS A control group of male Wistar rats was fed with a basic diet and a second group was fed with the same basic diet added of 0.05% of phenobarbital, for a period of 24 months. Medium and right liver fragments were submitted to the histological processing and they were stained by hematoxiciline and eosin and were immunohystochemically colored to glutathione S-transferase placentary form. RESULTS Glutathione S-transferase placentary positive zones were detected in both groups and the images were analyzed concerning their number and surface extension through the technique of histometry analyses. CONCLUSION Chronic use of phenobarbital did not modify the number of glutathione S-transferase placentary form positive areas. Although, data indicates that glutathione S-transferase placentary form positive areas media size are increased, probably because there are an increase in their evolution capacity and irreversibility.
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27
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Kokel D, Li Y, Qin J, Xue D. The nongenotoxic carcinogens naphthalene and para-dichlorobenzene suppress apoptosis in Caenorhabditis elegans. Nat Chem Biol 2006; 2:338-45. [PMID: 16699520 DOI: 10.1038/nchembio791] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2006] [Accepted: 04/13/2006] [Indexed: 11/09/2022]
Abstract
Naphthalene (1) and para-dichlorobenzene (PDCB, 2), which are widely used as moth repellents and air fresheners, cause cancer in rodents and are potential human carcinogens. However, their mechanisms of action remain unclear. Here we describe a novel method for delivering and screening hydrophobic chemicals in C. elegans and apply this technique to investigate the ways in which naphthalene and PDCB may promote tumorigenesis in mammals. We show that naphthalene and PDCB inhibit apoptosis in C. elegans, a result that suggests a cellular mechanism by which these chemicals may promote the survival and proliferation of latent tumor cells. In addition, we find that a naphthalene metabolite directly inactivates caspases by oxidizing the active site cysteine residue; this suggests a molecular mechanism by which these chemicals suppress apoptosis. Naphthalene and PDCB are the first small-molecule apoptosis inhibitors identified in C. elegans. The power of C. elegans molecular genetics, in combination with the possibility of carrying out large-scale chemical screens in this organism, makes C. elegans an attractive and economic animal model for both toxicological studies and drug screens.
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Affiliation(s)
- David Kokel
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309-0347, USA
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28
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Ahn NS, Hu H, Park JS, Park JS, Kim JS, An S, Kong G, Aruoma OI, Lee YS, Kang KS. Molecular mechanisms of the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced inverted U-shaped dose responsiveness in anchorage independent growth and cell proliferation of human breast epithelial cells with stem cell characteristics. Mutat Res 2005; 579:189-99. [PMID: 16051281 DOI: 10.1016/j.mrfmmm.2005.03.026] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2005] [Revised: 03/02/2005] [Accepted: 03/07/2005] [Indexed: 05/03/2023]
Abstract
Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has a variety of carcinogenic and noncarcinogenic effects in experimental animals, its role in human carcinogenicity remain controversial. A simian virus 40-immortalized cell line from normal human breast epithelial cells with stem cells and luminal characteristics (M13SV1) was used to study whether TCDD can induce AIG positive colony formation and cause increased cell numbers in a inverted U-shaped dose-response manner. TCDD activated Akt, ERK2, and increased the expression of CYP1A1, PAI-2, IL-lb mRNA, and ERK2 protein levels. TCDD was able to increased phosphorylation and expression of ERK2 in same dose-response manner as AIG positive colony formation. Thus, TCDD induced tumorigenicity in M13SV1, possibly through the phosphorylation of ERK2 and/or Akt. Further, cDNA microarray with 7448 sequence-verified clones was used to profile various gene expression patterns after treatment of TCDD. Three clear patterns could be delineated: genes that were dose-dependently up-regulated, genes expressed in either U-shape and/or inverted U-shape. The fact that these genes are intrinsically related to breast epithelial cell proliferation and survival clearly suggests that they may be involved in the TCDD-induced breast tumorigenesis.
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Affiliation(s)
- Nam-Shik Ahn
- Laboratory of Stem Cell and Tumor Biology, Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, San 56-1 Sillim-Dong, Kwanak-Gu, Seoul 151-742, Republic of Korea
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29
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Hoagland MS, Hoagland EM, Swanson HI. The p53 inhibitor pifithrin-alpha is a potent agonist of the aryl hydrocarbon receptor. J Pharmacol Exp Ther 2005; 314:603-10. [PMID: 15843497 DOI: 10.1124/jpet.105.084186] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
The tumor suppressor protein p53 is currently a target of emerging drug therapies directed toward neurodegenerative diseases, such as Alzheimer's and Parkinson's, and side effects associated with cancer treatments. Of this group of drugs, the best characterized is pifithrin-alpha, a small molecule that inhibits p53-dependent apoptosis through an undetermined mechanism. In this study, we have used a number of molecular approaches to test the hypothesis that pifithrin-alpha acts as an aryl hydrocarbon receptor (AhR) agonist and, in this manner, inhibits the actions of p53. Toward this end, we have found that pifithrin-alpha is a potent AhR agonist as determined by its ability to bind the AhR, induce formation of its DNA binding complex, activate reporter activity, and up-regulate the classic AhR target gene CYP1A1. However, examination of its ability to inhibit p53-mediated gene activation and apoptosis revealed that these actions occurred via an AhR-independent manner. The significance of this study is based on the fact that activation of the AhR is typically associated with an increase in phase I and phase II metabolizing enzymes and adverse biological events such as tumor promotion that may contribute to untoward effects of pifithrin-alpha. Hence, this work will aid in the future design of more specific members of this important class of p53 inhibitors for use in a clinical setting.
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Affiliation(s)
- Martin S Hoagland
- University of Kentucky Medical Center S-305, 800 Rose Street, Lexington, KY 40536-0084, USA
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30
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Abstract
The development of carriers to deliver a variety of cancer therapeutics orally would represent a significant advance in the treatment of this disease. This system is based on hydrophilic polymer carriers to deliver therapeutic agents to the upper region of the small intestine in response to the pH increase when passing from the stomach. Methacrylic acid (MAA) and ethylene glycol (EG) combined in a 1:1 molar ratio were reacted to form P(MAA-g-EG) nanospheres by UV-initiated free radical polymerization. Bleomycin was added prior to polymerization to allow in situ polymerization loading. Release studies were carried out in conditions to model the environment of the stomach and small intestine. Results showed that bleomycin is preferentially released at a higher pH due to the increased mesh size of the swollen hydrogel carrier. The potential cytotoxicity of bleomycin on the small intestine was investigated with the use of Caco-2 cells (human colon adenocarcinoma). Cytotoxicity studies showed maintenance of both viability and proliferation. The presence of the nanospheres decreases the transepithelial electrical resistance across Caco-2 cell monolayers. Complexation hydrogels are promising carriers to expand the number of chemotherapeutics capable of being administered orally.
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Affiliation(s)
- James Blanchette
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712-0231, USA
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31
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Marlowe JL, Puga A. Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. J Cell Biochem 2005; 96:1174-84. [PMID: 16211578 DOI: 10.1002/jcb.20656] [Citation(s) in RCA: 237] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Most effects of exposure to halogenated and polycyclic aromatic hydrocarbons are mediated by the aryl hydrocarbon receptor (AHR). It has long been recognized that the AHR is a ligand-activated transcription factor that plays a central role in the induction of drug-metabolizing enzymes and hence in xenobiotic detoxification. Of late, it has become evident that outside this well-characterized role, the AHR also functions as a modulator of cellular signaling pathways. In this Prospect, we discuss the involvement of the AHR in pathways critical to cell cycle regulation, mitogen-activated protein kinase cascades, immediate-early gene induction, and the functions of the RB protein. Ultimately, the toxicity of AHR xenobiotic ligands may be intrinsically connected with the perturbation of these pathways and depend on the many critical signaling pathways and effectors with which the AHR itself interacts.
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Affiliation(s)
- Jennifer L Marlowe
- Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, USA
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32
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Lin WL, Li DG, Chen Q, Lu HM. Clinical and experimental study of oxaliplatin in treating human gastric carcinoma. World J Gastroenterol 2004; 10:2911-5. [PMID: 15334700 PMCID: PMC4572132 DOI: 10.3748/wjg.v10.i19.2911] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To evaluate the therapeutic effectiveness of oxaliplatin on human gastric carcinoma and to explore its mechanisms.
METHODS: Twenty-two cases of stage IV gastric carcinoma received 4-6 (mean 4.6) cycles of first line combined chemotherapy with oxaliplatin (oxaliplatin 85 mg/m2, iv, gtt, 1 h, d 1; leukovorin 200 mg/m2, iv, gtt, 1 h, d 1 and d 2; 5-FU 300 mg/m2,iv, d 1 and d 2, 5-FU, continuous iv, gtt, 48 h; 1 cycle/2 wk). Response rate, progression-free survival (PFS), total survival time, toxic side effects were evaluated. The inhibitory effect of oxaliplatin on human gastric cell line SGC-7901 was detected and IC50 was calculated by MTT. Transmission electron microscopy, flow cytometry and TUNEL were performed to evaluate the apoptosis of cell line induced by the drug. The expression of Caspase-3 m-RNA was detected by RT-PCR. AC-DEVD-CHO, a Caspase-3 specific inhibitor, was used to elucidate the role of activated Caspase-3 in the process of apoptosis induced by oxaliplatin.
RESULTS: Total response (complete and partial) occurred in 9 (40.9%) patients. Mean PFS was 4.2 mo and mean total survival time was 7.2 mo. Cumulative neurotoxicity (all grade I-II), vomiting and diarrhea, myelosuppression appeared in 93.5%, 20%, 32.9% patients, respectively. IC50 was calculated to be 0.71 mg/L by MTT assay. A maximal inhibitory rate reached 85.3%. Apoptosis index was elevated after incubated with 1 mmol/L oxaliplatin for 30 min, but without statistic significance (P > 0.05). However it could be detected at a much higher degree both by flowcytometry and by TUNEL with a statistical significance (68.47% ± 7.92% and 8.23% ± 2.67%, respectively, P < 0.05) after incubated with 1 mmol/L oxaliplatin for 2 d. By means of RT-PCR, we detected an enhancement of Caspase-3 m-RNA expression induced by oxaliplatin which was also in positive correlation with the apoptotic level. AC-DEVD-CHO, a Caspase-3 specific inhibitor, could significantly inhibit and delay apoptosis induced by oxaliplatin.
CONCLUSION: Oxaliplatin is effective and well-tolerated in patients with advanced gastric carcinoma. Oxaliplatin could significantly inhibit the growth of human gastric cell line SGC-7901. The induction of Caspase-3 m-RNA expression, activation of Caspase-3 and promotion of apoptosis may be some of the therapeutic mechanisms of oxaliplatin on gastric carcinoma. Annexin-V-fluorescein labeling flow cytometry is much more sensitive than TUNEL in detecting early stage apoptosis.
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Affiliation(s)
- Wan-Long Lin
- Department of Gastroenterology, Affiliated Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China.
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33
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Pääjärvi G, Viluksela M, Pohjanvirta R, Stenius U, Högberg J. TCDD activates Mdm2 and attenuates the p53 response to DNA damaging agents. Carcinogenesis 2004; 26:201-8. [PMID: 15459018 DOI: 10.1093/carcin/bgh289] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
In this study we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the p53 response to DNA damaging agents. Pre-treatment of rats with TCDD attenuated the p53 liver response to diethylnitrosamine (DEN) and reduced levels of p53 and Ser15 phosphorylated p53. In addition, there were more slowly migrating p53 species, forming a ladder, which suggests an increased ubiquination of p53 in TCDD-pre-treated rats. Terminal deoxynucleotidyl transferase-mediated X-dUTP nick-end labelling analysis indicated decreased apoptosis rates in the livers of these rats. Studies on aryl hydrocarbon receptor (AhR) knockout mice and their wild-type littermates confirmed this effect in AhR +/+ but not in AhR -/- mice, indicating that this effect may be AhR-mediated. Quantitative RT-PCR analysis revealed no increased mRNA levels in TCDD-treated rats, but immunohistological studies indicated that TCDD modulated Mdm2 protein levels, and in particular, increased nuclear levels in rat hepatocytes in situ. In vitro studies employing HepG2 cells confirmed the in vivo data. Thus, TCDD increased basal levels of Mdm2 protein, but not mRNA, and attenuated the p53 response to a variety of genotoxic and cytotoxic agents. The increase in Mdm2 protein levels was accompanied by rapid and highly sensitive phosphorylation of Mdm2 at Ser166, which has been associated to active Mdm2. In summary, TCDD is a potent inhibitor of p53 that may influence the liver's ability to handle genotoxic agents in a safe way, and may play a role in TCDD-induced carcinogenesis.
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Affiliation(s)
- Gerd Pääjärvi
- Institute of Environmental Medicine, Karolinska Institutet, Box 210, 17177 Stockholm, Sweden
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