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Kirsch-Volders M, Mišík M, de Gerlache J. Tetraploidy as a metastable state towards malignant cell transformation within a systemic approach of cancer development. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2024; 896:503764. [PMID: 38821671 DOI: 10.1016/j.mrgentox.2024.503764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 04/08/2024] [Accepted: 05/06/2024] [Indexed: 06/02/2024]
Abstract
Tetraploidy, a condition in which a cell has four homologous sets of chromosomes, may be a natural physiological condition or pathophysiological such as in cancer cells or stress induced tetraploidisation. Its contribution to cancer development is well known. However, among the many models proposed to explain the causes, mechanisms and steps of malignant cell transformation, only few integrate tetraploidization into a systemic multistep approach of carcinogenesis. Therefore, we will i) describe the molecular and cellular characteristics of tetraploidy; ii) assess the contribution of stress-induced tetraploidy in cancer development; iii) situate tetraploidy as a metastable state leading to cancer development in a systemic cell-centered approach; iiii) consider knowledge gaps and future perspectives. The available data shows that stress-induced tetraploidisation/polyploidisation leads to p53 stabilisation, cell cycle arrest, followed by cellular senescence or apoptosis, suppressing the proliferation of tetraploid cells. However, if tetraploid cells escape the G1-tetraploidy checkpoint, it may lead to uncontrolled proliferation of tetraploid cells, micronuclei induction, aneuploidy and deploidisation. In addition, tetraploidization favors 3D-chromatin changes and epigenetic effects. The combined effects of genetic and epigenetic changes allow the expression of oncogenic gene expression and cancer progression. Moreover, since micronuclei are inducing inflammation, which in turn may induce additional tetraploidization, tetraploidy-derived genetic instability leads to a carcinogenic vicious cycle. The concept that polyploid cells are metastable intermediates between diploidy and aneuploidy is not new. Metastability denotes an intermediate energetic state within a dynamic system other than the system's state at least energy. Considering in parallel the genetic/epigenetic changes and the probable entropy levels induced by stress-induced tetraploidisation provides a new systemic approach to describe cancer development.
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Affiliation(s)
- Micheline Kirsch-Volders
- Laboratory for Cell Genetics, Department Biology, Faculty of Sciences and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, Brussels 1050, Belgium
| | - Miroslav Mišík
- Center for Cancer Research, Medical University of Vienna, Borschkegasse 8a, Vienna 1090, Austria.
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Hussain Y, Singh J, Meena A, Sinha RA, Luqman S. Escin-sorafenib synergy up-regulates LC3-II and p62 to induce apoptosis in hepatocellular carcinoma cells. ENVIRONMENTAL TOXICOLOGY 2024; 39:840-856. [PMID: 37853854 DOI: 10.1002/tox.23988] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 09/19/2023] [Accepted: 09/21/2023] [Indexed: 10/20/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a common solid cancer and the leading cause of cancer deaths worldwide. Sorafenib is the first drug used to treat HCC but its effectiveness needs to be improved, and it is important to find ways to treat cancer that combine sorafenib with other drugs. Synergistic therapies lower effective drug doses and side effects while enhancing the anticancer effect. PURPOSE In the present study, the therapeutic potential of sorafenib in combination with escin and its underlying mechanism in targeting liver cancer has been established. STUDY DESIGN/METHODS The IC50 of sorafenib and escin against HepG2, PLC/PRF5 and Huh7 cell lines were determined using MTT assay. The combination index, dose reduction index, isobologram and concentrations producing synergy were evaluated using the Chou-Talaly algorithm. The sub-effective concentration of sorafenib and escin was selected to analyze cytotoxic synergistic potential. Cellular ROS, mitochondrial membrane potential, annexin V and cell cycle were evaluated using a flow-cytometer, and autophagy biomarkers were determined using western blotting. Moreover, autophagy was knocked down using ATG5 siRNA to confirm its role. A DEN-induced liver cancer rat model was developed to check the synergy of sorafenib and escin. RESULTS Different concentrations of escin reduced the IC50 of sorafenib in HepG2, PLC/PRF5 and Huh7 cell lines. Chou-Talaly algorithm determined cytotoxic synergistic concentrations of sorafenib and escin in these cell lines. Mechanistically, this combination over-expressed p62 and LC-II, reflecting autophagy block and induced late apoptosis, further reconfirmed by ATG5 knockdown. Sorafenib and escin combination reduced HCC serum biomarker α-feto protein (α-FP) by 1.5 folds. This combination restricted liver weight, tumor number and size, also, conserved morphological features of liver cells. The combination selectively targeted the G0 /G1 phase of cancer cells. CONCLUSION Escin and sorafenib combination potentially up-regulates p62 to block autophagy to induce late apoptosis in liver cancer cells.
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Affiliation(s)
- Yusuf Hussain
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Jyoti Singh
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Jawaharlal Nehru University, New Delhi, India
| | - Abha Meena
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Rohit Anthony Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Suaib Luqman
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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Khan AA, Alanazi AM, Jabeen M, Chauhan A, Ansari MA. Therapeutic potential of functionalized siRNA nanoparticles on regression of liver cancer in experimental mice. Sci Rep 2019; 9:15825. [PMID: 31676815 PMCID: PMC6825139 DOI: 10.1038/s41598-019-52142-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 10/14/2019] [Indexed: 12/14/2022] Open
Abstract
Short interfering RNA (siRNA) possesses special ability of silencing specific gene. To increase siRNA stability, transportation and its uptake by tumor cells, effective delivery to the appropriate target cells is a major challenge of siRNA-based therapy. In the present study, an effective, safe and biocompatible survivin siRNA encapsulated, GalNAc decorated PEGylated PLGA nanoconjugates (NCs) viz., GalNAc@PEG@siRNA-PLGA were engineered and their synergistic antitumor efficacy was evaluated for targeted delivery in HCC bearing experimental mice. GalNAc@PEG@siRNA-PLGA NCs were characterized for size, bioavailability, toxicity and biocompatibility. Their antitumor potential was evaluated considering gene silencing, apoptosis, histopathology and survival of treated mice. Exceptional accumulation of hepatocytes, reduction in survivin expression and prominent regression in tumor size confirmed the ASGPR-mediated uptake of ligand-anchored NCs and silencing of survivin gene in a targeted manner. Increased DNA fragmentation and potential modulation of caspase-3, Bax and Bcl-2 factors specified the induction of apoptosis that helped in significant inhibition of HCC progression. The potential synchronous and tumor selective delivery of versatile NCs indicated the effective payloads towards the target site, increased apoptosis in cancer cells and improved survival of treated animals.
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Affiliation(s)
- Azmat Ali Khan
- 0000 0004 1773 5396grid.56302.32Pharmaceutical Biotechnology Laboratory, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451 Saudi Arabia
| | - Amer M. Alanazi
- 0000 0004 1773 5396grid.56302.32Pharmaceutical Biotechnology Laboratory, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451 Saudi Arabia
| | - Mumtaz Jabeen
- 0000 0004 1937 0765grid.411340.3Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, India
| | - Arun Chauhan
- 0000 0004 1936 8163grid.266862.eDepartment of Neuroimmunology, School of Health and Medicine, University of North Dakota, Grand Forks, ND USA
| | - Mohammad Azam Ansari
- 0000 0004 0607 035Xgrid.411975.fDepartment of Epidemic Disease Research, Institutes of Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, 31441 Dammam, Saudi Arabia
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Review of the evidence for thresholds for DNA-Reactive and epigenetic experimental chemical carcinogens. Chem Biol Interact 2019; 301:88-111. [DOI: 10.1016/j.cbi.2018.11.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 11/06/2018] [Accepted: 11/22/2018] [Indexed: 01/01/2023]
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Abdel-Hamid NM, Abdullah AH. Serum histamine and acetylcholine variations as new noninvasive biochemical markers in staging of experimental hepatocellular carcinoma. Clin Exp Med 2019; 19:115-120. [PMID: 30460419 DOI: 10.1007/s10238-018-0537-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 11/15/2018] [Indexed: 12/25/2022]
Abstract
Angiogenesis is a major prerequisite for hepatocellular carcinoma (HCC) development and progression. The present study aims to assess the potential role of two endogenous regulators of angiogenesis histamine (His) and acetylcholine (Ach), as possible biochemical markers for staging of HCC. Five groups of rats were used in this study: a control healthy group (I), another 4 intoxicated groups used for the induction of HCC with a high dose of diethyl nitrosamine (DENA, 200 mg/kg, single I.P. dose), (II, III, IV, and V). Groups II, III, IV, and V were killed following 8, 16, 24, and 32 weeks after DENA injection, respectively. Serum level of His and Ach was estimated using high-performance liquid chromatography technique coupled with diode array detector (HPLC-DAD), and alpha-fetoprotein (AFP) was measured using ELISA technique along with liver histological examination for all groups. Progression of HCC was estimated by histopathological examination. The results exhibited prominent increase in serum His and Ach levels during the early stages of HCC in group II, III in comparison with the control, and then His serum level declined to the normal level during the last stage of HCC development (group V).However, Ach elevation continued. AFP serum level showed marked increase, till 32 weeks after hepatocarcinogenesis. The decreased histamine level, combined to elevated AFP, indicates an early stage, while continued elevation of Ach with decreased His levels indicates a later stage of HCC. The combination of these two neurotransmitters to AFP may contribute to a noninvasive biochemical staging for HCC.
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Affiliation(s)
- Nabil M Abdel-Hamid
- Department of Biochemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El Sheikh, Egypt.
- Department of Biochemistry, Faculty of Pharmacy, Al-Farahidi University, Baghdad, Iraq.
| | - Amer Hasan Abdullah
- Department of Chemistry, Faculty of Science, Al-Mustansiryah University, Baghdad, Iraq
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Khan H, Khan MS, Ahmad S. The in vivo and in vitro approaches for establishing a link between advanced glycation end products and lung cancer. J Cell Biochem 2018; 119:9099-9109. [PMID: 30076739 DOI: 10.1002/jcb.27170] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 05/18/2018] [Indexed: 01/12/2023]
Abstract
Advanced glycation end products (AGEs) are directly related to third aging-associated diseases, such as cardiovascular diseases, arteriosclerosis, and neurodegeneration. Likewise, these irreversible and nonenzymatic products have been reported to be involved in the progression of malignant cancers. In general, aging-associated diseases and the initiation of cancer have been subjects of interest for several years. Few studies on the role of AGEs in cancer have been performed on cell lines. Moreover, past investigations in the field of glycation biology still lack the knowledge of in vivo and in vitro approaches for cancer cells. Accordingly, we aimed to focus on and establish a link between cancer and glycation with respect to all the possible AGEs. In our study, the levels of carboxymethyllysine (CML) increased by 50.94% in an animal model of glycation, whereas in an animal model of cancer, the contents of CML increased by 45.94% compared with their negative controls. Similarly, fluorescent AGEs were also examined and were found to be increased by 65.3% and 58.63% in the animal models of glycation and cancer, respectively, compared with the control subjects. The protein carbonyl contents were also found to be enhanced in the animal models of glycation and cancer. In our study, the levels of reactive oxygen species were also found to be significantly increased in the in vitro model of cancer cells as compared with the controls. Such an initial breakthrough indicated that AGEs were present in the serum of the animal models of cancer and glycation.
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Affiliation(s)
- Hamda Khan
- Department of Biosciences, Integral University, Lucknow, India.,IIRC-1, Laboratory of Glycation Biology and Metabolic Disorders, Integral University, Lucknow, India
| | - Mohd Sajid Khan
- Department of Biosciences, Integral University, Lucknow, India
| | - Saheem Ahmad
- Department of Biosciences, Integral University, Lucknow, India.,IIRC-1, Laboratory of Glycation Biology and Metabolic Disorders, Integral University, Lucknow, India
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Affiliation(s)
- Thomas J. Slaga
- AMC Cancer Research Center, 1600 Pierce Street, Lakewood,
CO 80214, USA
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Dixon D, Sleight S, Aust S, Rezabek M. Tumor-Promoting, Initiating, and Hepatotoxic Effects of 3,4,3',4'-Tetrabromobiphenyl (34-TBB) in Rats. ACTA ACUST UNITED AC 2016. [DOI: 10.3109/10915818809019543] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Female, 180–200 g Sprague-Dawley rats were used to determine if 3,4,3',4'-tetrabromobi-phenyl (34-TBB) is a promoter or initiator in a two-stage hepatocarcinogenesis assay. To test for promotion, rats were partially hepatectomized (PH) 24 hr before initiation (day 1) with 10 mg of diethylnitrosamine (DEN)/kg body weight given intraperitoneally (IP). Thirty days later, promotion was with 34-TBB (0.1,1 or 5 mg/kg) or phenobarbital (PB) (500 mg/kg) in diets for 180 days. To test for initiation, rats were PH and were initiated on day 1 with 34-TBB (1, 5, or 10 mg/kg) orally or DEN (10 mg/kg) IP. On day 31, promotion was with 500 mg of PB/kg of diet for 180 days. Noninitiated and non-PH rats were used to assess the histological and ultrastructural tissue changes associated with administration of 34-TBB in the diet for 180 days. Tumor promotion-initiation were assessed by counting and measuring hepatic enzyme-altered foci (EAF) with gamma-glutamyl transpeptidase (GGT) activity. Congener 34-TBB acts as a promoter in experimental hepatocarcinogenesis in rats, as evidenced by increased numbers of GGT-positive EAF. Also, 34-TBB may have initiation potential, as suggested by increased numbers of EAF in rats initiated with 34-TBB and promoted by PB. Dietary administration of 34-TBB for 180 days is not severely toxic in rats, as evidenced by mild histological and ultrastructural changes and minimal alterations in organ and body weights. Congener 34-TBB does not accumulate in liver and adipose tissue of rats.
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Affiliation(s)
- D. Dixon
- Department of Pathology Michigan State University East Lansing, MI 48824
| | - S.D. Sleight
- The Rockefeller University, Laboratory Animal Research Center, New York, New York
| | - S.D. Aust
- Department of Biochemistry, Michigan State University, East Lansing, Michigan
| | - M.S. Rezabek
- The Rockefeller University, Laboratory Animal Research Center, New York, New York
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Evans MG, Sleight SD. Effects of Simultaneous Dietary Exposure to 2,2′,4,4′,5,5′-Hexabromobiphenyl and 3,3′,4,4′,5,5′-Hexachlorobiphenyl on Hepatic Tumor Promotion in Rats. ACTA ACUST UNITED AC 2016. [DOI: 10.3109/10915818909018078] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Female Sprague-Dawley rats were partially hepatectomized, initiated with diethylnitrosamine (DEN), and fed diets containing 2,2′,4,4′,5,5′-hexabromobiphenyl (245-HBB), 3,3′,4,4′,5,5′-hexachlorobiphenyl (345-HCB), or combinations of 245-HBB and 345-HCB to determine the tumor-promoting ability of these compounds in a two-stage (initiation/promotion) hepatocar-cinogenesis system. Tumor-promoting ability was assessed by measuring hepatic foci positive for gamma glutamyl transpeptidase (GGT) activity. Concentrations of 10 or 100 mg 245-HBB/kg of diet caused significantly increased numbers of GGT-positive hepatic foci. When 245-HBB and 345-HCB were fed simultaneously, an additive effect on tumor-promoting ability was observed at dietary concentrations of 10 mg/kg 245-HBB and 0.1 mg/kg 345-HCB. However, an inhibitory effect on tumor promotion occurred when dietary concentrations of 100 mg/kg 245-HBB and 1.0 mg/kg 345-HCB were fed simultaneously. These results suggest that the tumor-promoting ability of simultaneous exposure to 245-HBB and 345-HCB can be additive or inhibitory depending upon the concentration of each congener in the diet.
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Affiliation(s)
- M. G. Evans
- Harvard Medical School New England Regional Primate Research Center One Pine Hill Drive Southborough, Massachusetts 01772
| | - S. D. Sleight
- Harvard Medical School New England Regional Primate Research Center One Pine Hill Drive Southborough, Massachusetts 01772
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Trosko JE, Chang CC. Potential Role of Intercellular Communication in the Rate-Limiting Step in Carcinogenesis. ACTA ACUST UNITED AC 2016. [DOI: 10.3109/10915818309140689] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
In order to ascertain whether there might be a scientific basis for determining practical “thresholds” for “carcinogens,” the concepts of thresholds and carcinogens were examined in the context of some current ideas on cardnogenesis. The observation that cardnogenesis seems to involve the donal expansion of a pre-malignant cell through a series of pheno-typic changes was explained by the initiation/promotion model of cardnogenesis. Unrepaired DNA lesions, acting as substrates for mutations in dividing cells, were speculated to play a role in the initiation phase of cardnogenesis (and indirectly to the promotion phase if the lesions lead to significant cell killing, forcing “compensatory hyperplasia”). Inhibition of intercellular communication, either by cell removal, cell death, growth factors or chemical promoters, was speculated to allow the donal expansion of initiated cells to reach a “critical mass.” During that donal expansion of initiated cells, additional phenotypic changes were speculated to occur during cell replication by mutational and/or epigenetic events. Therefore, it was concluded, on the basis of this model, that conditions which prevented the inhibition of intercellular communication between normal cells and the initiated cell(s) contributed to the rate limiting step of cardnogenesis.Assuming the initiation and promotion model of cardnogenesis, the classical concepts of “thresholds” and “carcinogens” were viewed as grossly inadequate because they did not symbolically represent the known determinants of the complex carcinogenic process. Unless genetic, developmental stage, tissue, nutritional, stress, life style, as well as concurrent antagonists and/or synergists, factors are known, extrapolation about the potential carcinogenicity of a given chemical from molecular, in vitro or even in vivo experiments or epidemiological data would be extremely risky. It was concluded that, at this stage of our understanding of the mech-anism(s) of carcinogenesis, attempts to determine “thresholds” for “carcinogens” naively assume “carcinogens” are the single determinants for carcinogenesis, and that all chemicals which might influence the appearance of tumors act the same way.
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Affiliation(s)
- James E. Trosko
- Department of Pediatrics and Human Development Division of Human Genetics, Genetic Toxicology, Endocrinology and Oncology. Michigan State University
| | - Chia-cheng Chang
- Department of Pediatrics and Human Development Division of Human Genetics, Genetic Toxicology, Endocrinology and Oncology. Michigan State University
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Goldfarb S, Pugh TD. The Origin and Significance of Hyperplastic Hepatocellular Islands and Nodules in Hepatic Carcinogenesis. ACTA ACUST UNITED AC 2016. [DOI: 10.3109/10915818209013137] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Results of many studies, summarized in this review, support the hypothesis that carcinogen-induced hepatocellular carcinomas develop from phenotypically-altered hyperplastic hepatocellular nodules; these in turn apparently arise from smaller focal collections of hyperplastic cells referred to as hepatocellular islands. The very recent recognition that phenobarbital, when administered after carcinogens, fosters the outgrowth of hepatocellular islands and carcinomas, now provides the means for studying stages of initiation and promotion in hep-atocarcinogenesis. In addition, the recognition that enzymatic alterations, particularly the acquisition of canalicular gamma glutamyl transpeptidase activity, loss of ATP'ase activity, and loss of glucose-6-phosphatase activity that characterize many islands, have been particularly useful for measuring and evaluating the growth kinetics and heterogeneity of the islands. Evidence is presented that periportal gamma glutamyl transpeptidase positive hepatocytes are considerably more abundant after four weeks of feeding .02% 2-acetyl-aminofluorene to young rats than in control animals, and that the outgrowth of these cells is fostered by a distinctive type of periportal reparative hyperplasia. The cells appear to arise from a pool of cells that are normally abundant in periportal location in young growing rats. The studies suggest that it may now be possible to develop short term in vivo bioassays for initiators, promoters, and complete carcinogens in the rodent liver.
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Affiliation(s)
- Stanley Goldfarb
- Department of Pathology, University of Wisconsin School of Medicine, Madison, Wl 53706
| | - Thomas D. Pugh
- Department of Pathology, University of Wisconsin School of Medicine, Madison, Wl 53706
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Giampaolo C, Brady K, Kowalski B, Rogers AE. Cytologic Characteristics of Neoplastic and of Regenerating Hepatocytes in Fine, Needle ASPirates of Rat Liver. Toxicol Pathol 2016. [DOI: 10.1177/0192623389017004202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Popp JA, Leonard TB. The Use of In vivo Hepatic Initiation-Promotion Systems in Understanding the Hepatocarcinogenesis of Technical Grade Dinitrotoluene. Toxicol Pathol 2016. [DOI: 10.1177/019262338201000232] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
A 2 year bioassay sponsored by the Chemical Industry Institute of Toxicology demonstrated the potent hepatocarcinogenicity of technical grade dinitrotoluene (DNT) which contains 76% 2,4-DNT, 18% 2,6-DNT and less than 3% of each 2,3; 2,5; 3,4 and 3,5-DNT isomers. In contrast, a 2 year bioassay of 2,4-DNT sponsored by the National Cancer Institute did not result in the appearance of hepatic neoplasms above the spontaneous incidence. Using previously described in vivo hepatic initiation-promotion systems, an evaluation of the initiating and promoting activity of individual DNT isomers was undertaken to provide an understanding for the differences between the two bioassays. Weak hepatocyte initiating activity was identified in technical grade DNT and purified 2,6-DNT. In contrast, 2,3; 2,4; 2,5; 3,4 and 3,5 isomers had no detectable initiating activity. When fed following a diethylnitrosamine initiating regimen, technical grade DNT, purified 2,4 and 2,6-DNT isomers had demonstrable promoting activity. Therefore, the hepatic neoplasms resulting from technical grade DNT feeding apparently resulted from the initiating activity of 2,6-DNT followed by the promoting effect of both the 2,4 and 2,6-DNT isomers. The lack of hepatic neoplasms following chronic feeding of 2,4-DNT was apparently due to the lack of hepatic initiating activity.
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Affiliation(s)
- James A. Popp
- Department of Pathology Chemical Industry Institute of Toxicology P. O. Box 12137 Research Triangle Park, NC 27709
| | - Thomas B. Leonard
- Department of Pathology Chemical Industry Institute of Toxicology P. O. Box 12137 Research Triangle Park, NC 27709
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Williams GM. Phenotypic Properties of Preneoplastic Rat Liver Lesions and Applications to Detection of Carcinogens and Tumor Promoters. Toxicol Pathol 2016; 10:3-10. [DOI: 10.1177/019262338201000204] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
A variety of cellular lesions arise during liver carcinogenesis by chemicals in rats. The altered focus is a lesion of hepatocytes that occurs early in hepatocarcinogenesis and appears to give rise to both neoplastic nodules and carcinomas. Foci display numerous phenotypic abnormalities which together with nuclear abnormalities indicate that they are truly a new altered population. Using histochemical markers, the induction of foci can be measured as a quantitative index of hepatocarcinogenicity of genotoxic carcinogens. In addition, determination of the effect of agents on foci previously induced by genotoxic carcinogens can be used to assess the capacity of chemicals to act as liver tumor promoters.
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Popp JA, Leonard TB. The Use of In vivo Hepatic Initiation-Promotion Systems in Understanding the Hepatocarcinogenesis of Technical Grade Dinitrotoluene. Toxicol Pathol 2016; 10:190-194. [DOI: 10.1177/019262338201000220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A 2 year bioassay sponsored by the Chemical Industry Institute of Toxicology demonstrated the potent hepatocarcinogenicity of technical grade dinitrotoluene (DNT) which contains 76% 2,4-DNT, 18% 2,6-DNT and less than 3% of each 2,3; 2,5; 3,4 and 3,5-DNT isomers. In contrast, a 2 year bioassay of 2,4-DNT sponsored by the National Cancer Institute did not result in the appearance of hepatic neoplasms above the spontaneous incidence. Using previously described in vivo hepatic initiation-promotion systems, an evaluation of the initiating and promoting activity of individual DNT isomers was undertaken to provide an understanding for the differences between the two bioassays. Weak hepatocyte initiating activity was identified in technical grade DNT and purified 2,6-DNT. In contrast, 2,3; 2,4; 2,5; 3,4 and 3,5 isomers had no detectable initiating activity. When fed following a diethylnitrosamine initiating regimen, technical grade DNT, purified 2,4 and 2,6-DNT isomers had demonstrable promoting activity. Therefore, the hepatic neoplasms resulting from technical grade DNT feeding apparently resulted from the initiating activity of 2,6-DNT followed by the promoting effect of both the 2,4 and 2,6-DNT isomers. The lack of hepatic neoplasms following chronic feeding of 2,4-DNT was apparently due to the lack of hepatic initiating activity.
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Affiliation(s)
- James A. Popp
- Department of Pathology Chemical Industry Institute of Toxicology P. O. Box 12137 Research Triangle Park, NC 27709
| | - Thomas B. Leonard
- Department of Pathology Chemical Industry Institute of Toxicology P. O. Box 12137 Research Triangle Park, NC 27709
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Bannasch P, Moore MA, Klimek F, Zerban H. Biological markers of preneoplastic foci and neoplastic nodules in rodent liver. Toxicol Pathol 2016; 10:19-34. [DOI: 10.1177/019262338201000206] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Foci of altered hepatocytes are regularly observed early during hepatocarcinogenesis in rodents. The abnormal hepatocytes may show a number of different phenotypes as characterized by various cytomorphological and cytochemical markers. The first appearance and the further development of the abnormal cell populations depend on the dose of the carcinogen given and on the duration of the carcinogenic treatment. According to cytochemical, morphometric and autoradiographic findings in rats receiving low doses (2–10% of the LD 50/kg bw/day) of hepatocarcinogens for limited periods (“stop” experiments), glycogenotic (clear or acidophilic) hepatocytes indicate the first step of the neoplastic cell transformation which can be detected by these methods at present. The glycogenotic cells undergo a characteristic metamorphosis and give rise to basophilic tumor cells poor in glycogen, but rich in ribosomes. Under extreme experimental conditions, such as a single or repeated application of higher doses of one or several chemical carcinogens a puzzling picture emerges which is “reversible” to a large extent after withdrawal of the respective compounds. This observation points to a phenotypic instability of the cellular changes induced in certain experimental systems. Foci of altered hepatocytes persisting after withdrawal of the carcinogenic compounds are considered preneoplastic lesions. They may transform into neoplastic nodules which are also persistent and share a number of cytomorphological and cytochemical markers with the focal lesions. The persistent nodules progress to hepatocarcinomas after lag periods of weeks or months. However, the foci may also progress to hepatocarcinomas without passing a nodular intermediate stage. The development of both neoplastic nodules and carcinomas from the preneoplastic glycogen storage foci can proceed independent of further administration of carcinogen. The sequence of cellular changes during hepatocarcinogenesis derived from the experimental results in rodents is strongly supported by observations in humans, especially by the increasing reports on the appearance of hepatic tumors in patients who suffer from inborn hepatic glycogenosis.
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Affiliation(s)
- Peter Bannasch
- Division of Cytopathology, Institute of Experimental Pathology, German Cancer Research Center, Heidelberg, F.R.G
| | - Malcolm A. Moore
- Division of Cytopathology, Institute of Experimental Pathology, German Cancer Research Center, Heidelberg, F.R.G
| | - Fritz Klimek
- Division of Cytopathology, Institute of Experimental Pathology, German Cancer Research Center, Heidelberg, F.R.G
| | - Heide Zerban
- Division of Cytopathology, Institute of Experimental Pathology, German Cancer Research Center, Heidelberg, F.R.G
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Khan AA, Alanazi AM, Jabeen M, Hassan I, Bhat MA. Targeted nano-delivery of novel omega-3 conjugate against hepatocellular carcinoma: Regulating COX-2/bcl-2 expression in an animal model. Biomed Pharmacother 2016; 81:394-401. [PMID: 27261618 DOI: 10.1016/j.biopha.2016.04.033] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Revised: 04/14/2016] [Accepted: 04/17/2016] [Indexed: 12/30/2022] Open
Abstract
The present approach enumerates the effectiveness of tuftsin tagged nano-liposome for the cytosolic transport of 2,6-di-isopropylphenol-linolenic acid conjugate against liver cancer in mice. Initially, the conjugate in its free form was examined for anticancer potential on HepG2 liver cancer cells. Induction of apoptosis and suppression of migration and adhesion of HepG2 cells confirmed the effectiveness of conjugate as an anticancer agent. After this, role of the conjugate entrapped in a nano-carrier was evaluated in animal model. The nano-formulation comprising of conjugate bearing tuftsin tagged liposome was firsly characterized and then its therapeutic effect was determined. The nano-formulation had 100-130nm size nanoparticles and showed sustained release of the conjugate in the surrounding milieu. The nano-formulation distinctly reduced the expression of COX-2, an important molecule that is vastly expressed in hepatocellular carcinoma. The utilization of in-house engineered nano-formulation was also successful in significantly up-regulating Bax and down-regulating bcl-2 gene expression eventually helping in better survival of treated mice. Histopathological analysis also revealed positive recovery of the general architecture and the violent death of cancer cells by apoptosis at tumor specific site. The site specific delivery of conjugate entrapped in tuftsin tagged liposomes was highly safe as well as efficaceous. Nano-formulation based approach showed a visible chemotherapeutic effect on liver cancer progression in experimental mice thereby making it a potential candidate for treatment of liver cancer in clinical settings.
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Affiliation(s)
- Azmat Ali Khan
- Pharmaceutical Biotechnology Laboratory, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
| | - Amer M Alanazi
- Pharmaceutical Biotechnology Laboratory, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mumtaz Jabeen
- Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
| | - Iftekhar Hassan
- Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mashooq Ahmad Bhat
- Pharmaceutical Biotechnology Laboratory, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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Hirane M, Ishii S, Tomimatsu A, Fukushima K, Takahashi K, Fukushima N, Honoki K, Tsujiuchi T. Different induction of LPA receptors by chemical liver carcinogens regulates cellular functions of liver epithelial WB-F344 cells. Mol Carcinog 2015; 55:1573-1583. [DOI: 10.1002/mc.22410] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 08/17/2015] [Accepted: 08/31/2015] [Indexed: 01/22/2023]
Affiliation(s)
- Miku Hirane
- Division of Molecular Oncology; Department of Life Science; Faculty of Science and Engineering, Kinki University; Kowakae, Higashiosaka Osaka Japan
| | - Shuhei Ishii
- Division of Molecular Oncology; Department of Life Science; Faculty of Science and Engineering, Kinki University; Kowakae, Higashiosaka Osaka Japan
| | - Ayaka Tomimatsu
- Division of Molecular Oncology; Department of Life Science; Faculty of Science and Engineering, Kinki University; Kowakae, Higashiosaka Osaka Japan
| | - Kaori Fukushima
- Division of Molecular Oncology; Department of Life Science; Faculty of Science and Engineering, Kinki University; Kowakae, Higashiosaka Osaka Japan
| | - Kaede Takahashi
- Division of Molecular Oncology; Department of Life Science; Faculty of Science and Engineering, Kinki University; Kowakae, Higashiosaka Osaka Japan
| | - Nobuyuki Fukushima
- Division of Molecular Neurobiology; Department of Life Science; Faculty of Science and Engineering, Kinki University; Kowakae, Higashiosaka Osaka Japan
| | - Kanya Honoki
- Department of Orthopedic Surgery; Nara Medical University; Kashihara Nara Japan
| | - Toshifumi Tsujiuchi
- Division of Molecular Oncology; Department of Life Science; Faculty of Science and Engineering, Kinki University; Kowakae, Higashiosaka Osaka Japan
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Chen Q, Zhang N, Xie R, Wang W, Cai J, Choi KS, David KK, Huang B, Yabuta N, Nojima H, Anders RA, Pan D. Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP. Genes Dev 2015; 29:1285-97. [PMID: 26109051 PMCID: PMC4495399 DOI: 10.1101/gad.264234.115] [Citation(s) in RCA: 121] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In this study, Chen et al. investigate the physiological importance of YAP phosphorylation in regulating endogenous YAP activity. Using mutant YapS112A knock-in mice, they found that the mice show a compensatory decrease in YAP protein levels due to increased phosphorylation at a mammalian-specific phosphodegron site on YAP. The results provide novel insight into a homeostatic mechanism that maintains physiological levels of YAP activity, which could work to prevent oncogenic activation of YAP. The Hippo signaling pathway converges on YAP to regulate growth, differentiation, and regeneration. Previous studies with overexpressed proteins have shown that YAP is phosphorylated by its upstream kinase, Lats1/2, on multiple sites, including an evolutionarily conserved 14-3-3-binding site whose phosphorylation is believed to inhibit YAP by excluding it from the nucleus. Indeed, nuclear localization of YAP or decreased YAP phosphorylation at this site (S168 in Drosophila, S127 in humans, and S112 in mice) is widely used in current literature as a surrogate of YAP activation even though the physiological importance of this phosphorylation event in regulating endogenous YAP activity has not been defined. Here we address this question by introducing a YapS112A knock-in mutation in the endogenous Yap locus. The YapS112A mice are surprisingly normal despite nuclear localization of the mutant YAP protein in vivo and profound defects in cytoplasmic translocation in vitro. Interestingly, the mutant YapS112A mice show a compensatory decrease in YAP protein levels due to increased phosphorylation at a mammalian-specific phosphodegron site on YAP. These findings reveal a robust homeostatic mechanism that maintains physiological levels of YAP activity and caution against the assumptive use of YAP localization alone as a surrogate of YAP activity.
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Affiliation(s)
- Qian Chen
- Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Nailing Zhang
- Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Rui Xie
- Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Wei Wang
- Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Jing Cai
- Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Kyung-Suk Choi
- Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Karen Kate David
- Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Bo Huang
- Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Norikazu Yabuta
- Department of Molecular Genetics, Osaka University, Suita City, Osaka 565-0871, Japan
| | - Hiroshi Nojima
- Department of Molecular Genetics, Osaka University, Suita City, Osaka 565-0871, Japan
| | - Robert A Anders
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Duojia Pan
- Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
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Chauhan A, Zubair S, Nadeem A, Ansari SA, Ansari MY, Mohammad O. Escheriosome-mediated cytosolic delivery of PLK1-specific siRNA: potential in treatment of liver cancer in BALB/c mice. Nanomedicine (Lond) 2014; 9:407-20. [PMID: 24910873 DOI: 10.2217/nnm.13.21] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM In the present study, the anticancer efficacy of a novel escheriosome-based formulation of PLK1-specific siRNA was evaluated against liver cancer in BALB/c mice. MATERIALS & METHODS The escheriosome-based siRNA nanoparticles were prepared using lipids isolated from Escherichia coli. The escheriosomes were characterized for size, surface charge and stability. The anticancer potential of PLK1-specific siRNA formulation was ascertained on the basis of expression of pro-/anti-apoptotic factors and histopathological studies. RESULTS The escheriosome-entrapped siRNA was found to be released in surrounding milieu in a sustained manner. The nanoformulation was successful in modulating proapoptotic factors and eventually helped in better survival of the treated animals. CONCLUSION Our data demonstrate the efficacy of systemically administered siRNA in the treatment of experimental liver cancer. This novel therapeutic strategy may be applicable to a broad range of cancers in patients with the obstinate form of the disease.
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Farazuddin M, Dua B, Zia Q, Khan AA, Joshi B, Owais M. Chemotherapeutic potential of curcumin-bearing microcells against hepatocellular carcinoma in model animals. Int J Nanomedicine 2014; 9:1139-52. [PMID: 24627632 PMCID: PMC3945993 DOI: 10.2147/ijn.s34668] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Curcumin (diferuloylmethane) is found in large quantities in the roots of Curcuma longa. It possesses strong antioxidant and anti-inflammatory properties, and inhibits chemically-induced carcinogenesis in the skin, forestomach, colon, and liver. Unfortunately, the poor bioavailability and hydrophobicity of curcumin pose a major hurdle to its use as a potent anticancer agent. To circumvent some of these problems, we developed a novel, dual-core microcell formulation of curcumin. The encapsulation of curcumin in microcells increases its solubility and bioavailability, and facilitates slow release kinetics over extended periods. Besides being safe, these formulations do not bear any toxicity constraints, as revealed by in vitro and in vivo studies. Histopathological analysis revealed that curcumin-bearing microcells helped in regression of hepatocellular carcinoma and the maintenance of cellular architecture in liver tissue. Free curcumin had a very mild effect on cancer suppression. Empty (sham) microcells and microparticles failed to inhibit cancer cells. The novel curcumin formulation was found to suppress hepatocellular carcinoma efficiently in Swiss albino mice.
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Affiliation(s)
- Mohammad Farazuddin
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
| | - Bhavyata Dua
- Immunology Division, National JALMA Institute for Leprosy and Other Mycobacterial Diseases (NJIL), Agra, India
| | - Qamar Zia
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
| | - Aijaz Ahmad Khan
- Department of Anatomy, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, India
| | - Beenu Joshi
- Immunology Division, National JALMA Institute for Leprosy and Other Mycobacterial Diseases (NJIL), Agra, India
| | - Mohammad Owais
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
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22
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Chauhan A, Zubair S, Tufail S, Sherwani A, Sajid M, Raman SC, Azam A, Owais M. Fungus-mediated biological synthesis of gold nanoparticles: potential in detection of liver cancer. Int J Nanomedicine 2011; 6:2305-19. [PMID: 22072868 PMCID: PMC3205127 DOI: 10.2147/ijn.s23195] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Nanomaterials are considered to be the pre-eminent component of the rapidly advancing field of nanotechnology. However, developments in the biologically inspired synthesis of nanoparticles are still in their infancy and consequently attracting the attention of material scientists throughout the world. Keeping in mind the fact that microorganism-assisted synthesis of nanoparticles is a safe and economically viable prospect, in the current study we report Candida albicans-mediated biological synthesis of gold nanoparticles. METHODS AND RESULTS Transmission electron microscopy, atomic force microscopy, and various spectrophotometric analyses were performed to characterize the gold nanoparticles. The morphology of the synthesized gold particles depended on the abundance of C. albicans cytosolic extract. Transmission electron microscopy, nanophox particle analysis, and atomic force microscopy revealed the size of spherical gold nanoparticles to be in the range of 20-40 nm and nonspherical gold particles were found to be 60-80 nm. We also evaluated the potential of biogenic gold nanoparticles to probe liver cancer cells by conjugating them with liver cancer cell surface-specific antibodies. The antibody-conjugated gold particles were found to bind specifically to the surface antigens of the cancer cells. CONCLUSION The antibody-conjugated gold particles synthesized in this study could successfully differentiate normal cell populations from cancerous cells.
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Affiliation(s)
- Arun Chauhan
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
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23
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Xu J, Sagawa Y, Futakuchi M, Fukamachi K, Alexander DB, Furukawa F, Ikarashi Y, Uchino T, Nishimura T, Morita A, Suzui M, Tsuda H. Lack of promoting effect of titanium dioxide particles on ultraviolet B-initiated skin carcinogenesis in rats. Food Chem Toxicol 2011; 49:1298-302. [DOI: 10.1016/j.fct.2011.03.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Revised: 02/25/2011] [Accepted: 03/09/2011] [Indexed: 10/18/2022]
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Glauert HP, Calfee-Mason K, Stemm DN, Tharappel JC, Spear BT. Dietary antioxidants in the prevention of hepatocarcinogenesis: a review. Mol Nutr Food Res 2010; 54:875-96. [PMID: 20512789 DOI: 10.1002/mnfr.200900482] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In this review, the role of dietary antioxidants in the prevention of hepatocarcinogenesis is examined. Both human and animal models are discussed. Vitamin C, vitamin E, and selenium are antioxidants that are essential in the human diet. A number of non-essential chemicals also contain antioxidant activity and are consumed in the human diet, mainly as plants or as supplements, including beta-carotene, ellagic acid, curcumin, lycopene, coenzyme Q(10), epigallocatechin gallate, N-acetyl cysteine, and resveratrol. Although some human and animal studies show protection against carcinogenesis with the consumption of higher amounts of antioxidants, many studies show no effect or an enhancement of carcinogenesis. Because of the conflicting results from these studies, it is difficult to make dietary recommendations as to whether consuming higher amounts of specific antioxidants will decrease the risk of developing hepatocellular carcinoma.
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Affiliation(s)
- Howard P Glauert
- Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40506-0054, USA.
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25
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Yamamoto Y, Moore R, Flavell RA, Lu B, Negishi M. Nuclear receptor CAR represses TNFalpha-induced cell death by interacting with the anti-apoptotic GADD45B. PLoS One 2010; 5:e10121. [PMID: 20404936 PMCID: PMC2853562 DOI: 10.1371/journal.pone.0010121] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2010] [Accepted: 03/15/2010] [Indexed: 01/01/2023] Open
Abstract
Background Phenobarbital (PB) is the most well-known among numerous non-genotoxic carcinogens that cause the development of hepatocellular carcinoma (HCC). PB activates nuclear xenobiotic receptor Constitutive Active/Androstane Receptor (CAR; NR1I3) and this activation is shown to determine PB promotion of HCC in mice. The molecular mechanism of CAR-mediated tumor promotion, however, remains elusive at the present time. Here we have identified Growth Arrest and DNA Damage-inducible 45β (GADD45B) as a novel CAR target, through which CAR represses cell death. Methodology/Principal Findings PB activation of nuclear xenobiotic receptor CAR is found to induce the Gadd45b gene in mouse liver throughout the development of HCC as well as in liver tumors. Given the known function of GADD45B as a factor that represses Mitogen-activated protein Kinase Kinase 7 - c-Jun N-terminal Kinase (MKK7-JNK) pathway-mediated apoptosis, we have now demonstrated that CAR interacts with GADD45B to repress Tumor Necrosis Factor α ( TNFα)-induced JNK1 phosphorylation as well as cell death. Primary hepatocytes, prepared from Car+/+, Car−/−, Gadd45b+/+ and Gadd45b−/− mice, were treated with TNFα and Actinomycin D to induce phosphorylation of JNK1 and cell death. Co-treatment with the CAR activating ligand TCPOBOP (1,4 bis[2-(3,5-dichloropyridyloxy)]benzene) has resulted in repression of both phosphorylation and cell death in the primary hepatocytes from Car+/+ but not Car−/−mice. Repression by TCPOBOP was not observed in those prepared from Gadd45b−/− mice. In vitro protein-protein interaction and phosphorylation assays have revealed that CAR interacts with MKK7 and represses the MKK7-mediated phosphorylation of JNK1. Conclusions/Significance CAR can form a protein complex with GADD45B, through which CAR represses MKK7-mediated phosphorylation of JNK1. In addition to activating the Gadd45b gene, CAR may repress death of mouse primary hepatocytes by forming a GADD45B complex and repressing MKK7-mediated phosphorylation of JNK1. The present finding that CAR can repress cell death via its interaction with GADD45B provides an insight for further investigations into the CAR-regulated molecular mechanism by which PB promotes development of HCC.
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Affiliation(s)
- Yukio Yamamoto
- Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
| | - Rick Moore
- Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
| | - Richard A. Flavell
- Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Binfeng Lu
- Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Masahiko Negishi
- Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
- * E-mail:
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Xu J, Futakuchi M, Iigo M, Fukamachi K, Alexander DB, Shimizu H, Sakai Y, Tamano S, Furukawa F, Uchino T, Tokunaga H, Nishimura T, Hirose A, Kanno J, Tsuda H. Involvement of macrophage inflammatory protein 1α (MIP1α) in promotion of rat lung and mammary carcinogenic activity of nanoscale titanium dioxide particles administered by intra-pulmonary spraying. Carcinogenesis 2010; 31:927-35. [DOI: 10.1093/carcin/bgq029] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Cytokeratin 8/18 as a new marker of mouse liver preneoplastic lesions. Toxicol Appl Pharmacol 2009; 242:47-55. [PMID: 19796649 DOI: 10.1016/j.taap.2009.09.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2009] [Revised: 09/04/2009] [Accepted: 09/22/2009] [Indexed: 12/29/2022]
Abstract
To search for a reliable biomarker of preneoplastic lesions arising early in mouse hepatocarcinogenesis the proteomes of microdissected basophilic foci, hepatocellular adenomas (HCAs), carcinomas (HCCs) and normal-appearing liver of B6C3F1 mice initiated with diethylnitrosamine (DEN) were analysed on anionic (Q10) surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) ProteinChip arrays. Significant overexpression of cytokeratin 8 (CK8; m/z 54, 565), cytokeratin 18 (CK18; m/z 47,538) proteins was found in basophilic foci as well as in HCAs and HCCs. Furthermore, immunohistochemistry demonstrated profound overexpression of CK8 and CK18 proteins (CK8/18) in all basophilic foci, mixed cell type foci, HCAs and HCCs in B6C3F1 and C57BL/6J mice initiated with DEN. A strong correlation between CK8/18-positive foci development and multiplicity of liver tumors in B6C3F1 and C57Bl/6J mice was further observed. Moreover, formation of CK8 and CK18 complexes due to CK8 phosphorylation at Ser73 and Ser431 was found to be strongly associated with neoplastic transformation of mice liver basophilic foci. Elevation of CK8/18 was strongly correlated with induction of cell proliferation in basophilic foci and tumors. In conclusion, our data imply that CK8/18 is a novel reliable marker of preneoplastic lesions arising during mouse hepatocarcinogenesis which might be used for prediction of tumor development and evaluation of environmental agents as well as drugs and food additives using mouse liver tests.
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Sivak A. An evaluation of assay procedures for detection of tumor promotors. ACTA PHARMACOLOGICA ET TOXICOLOGICA 2009; 55 Suppl 2:69-88. [PMID: 6385623 DOI: 10.1111/j.1600-0773.1984.tb02483.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Abstract
Neoplasia is a heritably altered, relatively autonomous growth of tissue. Hepatocarcinogenesis, the pathogenesis of neoplasia in liver, as modeled in the rat exhibits three distinct, quantifiable stages: initiation, promotion, and progression. Simple mutations and/or epigenetic alterations may result in the irreversible stage of initiation. The stage of promotion results from selective enhancement of cell replication and selective inhibition of cellular apoptosis of initiated cells dependent on the genetic and/or epigenetic alterations of the latter. The irreversible stage of progression results from initial karyotypic alterations that evolve into greater degrees of genomic instability. The initial genomic alteration in the transition from promotion to progression may involve primarily epigenetic mechanisms driven by epigenetic and genetic alterations fixed during the stage of promotion.
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Affiliation(s)
- Henry C Pitot
- McArdle Laboratory for Cancer Research, Department of Oncology and Pathology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
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Besselink H, Nixon E, McHugh B, Rimkus G, Klungsøyr J, Leonards P, De Boer J, Brouwer A. Evaluation of tumour promoting potency of fish borne toxaphene residues, as compared to technical toxaphene and UV-irradiated toxaphene. Food Chem Toxicol 2008; 46:2629-38. [PMID: 18558458 DOI: 10.1016/j.fct.2008.04.039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2007] [Revised: 03/27/2008] [Accepted: 04/21/2008] [Indexed: 10/22/2022]
Abstract
In this study the potential impact of food chain-based biotransformation and physico-chemical weathering of toxaphene on its tumour promoting potential was investigated in vitro and in vivo. Human exposure to toxaphene is mainly through consumption of contaminated fish, therefore fish-borne residues of toxaphene (cod liver extract, CLE) were prepared by exposing cod to technical toxaphene (TT) for 63 days. UV-irradiated toxaphene (uvT) was included to represent a physico-chemical weathered toxaphene mixture. In vitro, TT, uvT and CLE all showed a dose- and time-dependent inhibition of gap junctional intercellular communication (GJIC) with a relative potency of CLE>TT=uvT. Tumour promoting potency was further studied in vivo in a medium term two-stage initiation/promotion bioassay in female Sprague-Dawley rats, using an increase in altered hepatic foci positive for glutathione-S-transferase-P (AHF-GST-P) as read out. No increase in AHF-GST-P occurred following exposure to either TT, uvT, or CLE, except for the positive control group (2,3,7,8-TCDD). Based on this study the no observed adverse effect level (NOAEL) for tumour promoting potency is at least 12.5mg/kg/week, or higher for CLE. Considering current human exposure levels in Europe it is doubtful that consumption of fish at current levels of toxaphene contamination give rise to human health risk.
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Affiliation(s)
- H Besselink
- BioDetection Systems BV, Kruislaan 406, 1098 SM, Amsterdam, The Netherlands.
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Farber E. Toxicological significance of liver hypertrophy produced by inducers of drug-metabolizing enzymes. CIBA FOUNDATION SYMPOSIUM 2008; 76:261-74. [PMID: 6906264 DOI: 10.1002/9780470720592.ch14] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Changes in enzyme activity due to induction by chemicals is an important property that can determine the type of response seen in tissues exposed to environmental chemicals. Two major types of response, acute irreversible liver cell injury or death (necrosis) and long-term cancer induction, are discussed in terms of their modulation by enzyme induction. Most commonly, enzyme induction leads to a more severe toxic response by the liver, and to more cell death. However, inducers may have a protective effect, especially in carcinogenesis, when they most frequently protect against cancer induction if used early in the process. There is a discrepancy between this observation and the increase in mutagenic activity of liver preparations observed after induction. However, when enzyme induction occurs at a later stage, after initiation, it often accelerates or promotes cancer induction. Also, new cell populations constantly observed during liver carcinogenesis are composed of very hypertrophic hepatocytes containing a large amount of smooth endoplasmic reticulum. This is associated with a radical change in enzyme activities in the reticulum, which may account in part for the characteristic resistance exhibited by initiated cells to hepatotoxins and carcinogens. The resistance is considered to be an important property that may play a key role in the development of cancer under some circumstances.
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Page JL, Strom SC, Omiecinski CJ. Regulation of the human cathepsin E gene by the constitutive androstane receptor. Arch Biochem Biophys 2007; 467:132-8. [PMID: 17888866 PMCID: PMC4064465 DOI: 10.1016/j.abb.2007.08.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2007] [Revised: 08/02/2007] [Accepted: 08/03/2007] [Indexed: 01/28/2023]
Abstract
Cathepsin E (CTSE) is an aspartic protease that has been linked to antigen processing and innate immunity. Elevated levels of CTSE expression have also been associated with several forms of cancer, including carcinomas exhibiting highly invasive character. In this study, we performed DNA microarray experiments, together with quantitative reverse transcriptase PCR analyses and enzymatic activity determinations to identify human CTSE as a novel target gene for regulation by the constitutive androstane receptor (CAR), a nuclear receptor activated by the liver tumor promoting agent, phenobarbital. In particular, two motifs within the 5'-flanking region of the human CTSE gene were identified as direct sites of interaction with CAR/RXRalpha heterodimers, a direct repeat-3 site at position -766 and a direct repeat-4 site at position -1407. Thus, these studies demonstrate CAR-mediated regulation of CTSE within primary hepatocyte cultures from several individual donors and suggest that elevated CTSE activity may play a functional role in the etiology of hepatocarcinogenesis.
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Affiliation(s)
- Jeanine L. Page
- Center for Molecular Toxicology & Carcinogenesis and the Department of Veterinary & Biomedical Sciences, 101 Life Sciences Building, The Pennsylvania State University, University Park, PA 16802, USA
| | - Stephen C. Strom
- Department of Pathology, University of Pittsburgh, 210 Lothrop Street, 450 BST, Pittsburgh, PA 15261, USA
| | - Curtis J. Omiecinski
- Center for Molecular Toxicology & Carcinogenesis and the Department of Veterinary & Biomedical Sciences, 101 Life Sciences Building, The Pennsylvania State University, University Park, PA 16802, USA
- Corresponding author. Fax: +1 814 863 1696. (C.J. Omiecinski)
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Groos J, Bannasch P, Schwarz M, Kopp-Schneider A. Comparison of mode of action of four hepatocarcinogens: a model-based approach. Toxicol Sci 2007; 99:446-54. [PMID: 17636249 DOI: 10.1093/toxsci/kfm183] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Within the scope of the Rat Liver Foci Bioassay the model carcinogens N-nitrosomorpholine (NNM), 2-acetylaminoflouren (2-AAF), phenobarbital (PB), and clofibrate (CF) were analyzed concerning their potency and dose-response relationship to induce foci of altered hepatocytes (FAHs), which are known to be precursor lesions of liver adenoma and carcinoma. The medium-term experiment follows an initiation-promotion protocol using diethylnitrosamine (DEN) as initiator. The present report deals with the application of two biologically based models for hepatocarcinogenesis, the two-stage clonal expansion model (TSCEM), and a color-shift model with beta distributed growth rates (CSMbeta). Both models yield similar conclusions concerning the mode of action of the carcinogens. However, the fit of CSMbeta appears closer to the observations than the fit of TSCEM. The analysis shows that application of a single dose of DEN has a persistent effect on the rate of FAH induction, especially in female rats. Overall, striking differences in the effect of the carcinogens were observed between male and female animals. 2-AAF shows a strong promoting effect in males, whereas in females the initiating effect dominates. NNM has both initiating and promoting effect, but in females, the rate of FAH formation seems to reach saturation at high dose. In the doses applied in the present experiment, PB has the weakest carcinogenic effect. Although PB alone does not induce FAH during the observation period, it increases the rate of FAH formation when applied following initiation with DEN. CF reduces the number and area fraction of GSTP-stained FAH, probably because it suppresses the placental form of glutathione S-transferase-positive phenotype.
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Affiliation(s)
- Jutta Groos
- Central Unit Biostatistics, German Cancer Research Center, Heidelberg, Germany
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Xu Y, Pitot HC. A software package to improve image quality and isolation of objects of interest for quantitative stereology studies of rat hepatocarcinogenesis. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2006; 81:236-45. [PMID: 16458389 DOI: 10.1016/j.cmpb.2005.11.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2005] [Revised: 09/05/2005] [Accepted: 11/30/2005] [Indexed: 05/06/2023]
Abstract
In the studies of quantitative stereology of rat hepatocarcinogenesis, we have used image analysis technology (automatic particle analysis) to obtain data such as liver tissue area, size and location of altered hepatic focal lesions (AHF), and nuclei counts. These data are then used for three-dimensional estimation of AHF occurrence and nuclear labeling index analysis. These are important parameters for quantitative studies of carcinogenesis, for screening and classifying carcinogens, and for risk estimation. To take such measurements, structures or cells of interest should be separated from the other components based on the difference of color and density. Common background problems seen on the captured sample image such as uneven light illumination or color shading can cause severe problems in the measurement. Two application programs (BK_Correction and Pixel_Separator) have been developed to solve these problems. With BK_Correction, common background problems such as incorrect color temperature setting, color shading, and uneven light illumination background, can be corrected. With Pixel_Separator different types of objects can be separated from each other in relation to their color, such as seen with different colors in immunohistochemically stained slides. The resultant images of such objects separated from other components are then ready for particle analysis. Objects that have the same darkness but different colors can be accurately differentiated in a grayscale image analysis system after application of these programs.
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Affiliation(s)
- Yihua Xu
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, 1400 University Avenue, Madison, WI 53706-1599, USA
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35
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Guo YT, Leng XS, Li T, Zhao JM, Lin XH. Peroxisome proliferator-activated receptor γ ligands suppress liver carcinogenesis induced by diethylnitrosamine in rats. World J Gastroenterol 2004; 10:3419-23. [PMID: 15526359 PMCID: PMC4576221 DOI: 10.3748/wjg.v10.i23.3419] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [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: Peroxisome proliferator-activated receptor γ (PPARγ ) is known to regulate growth arrest and terminal differentiation of adipocytes and is used clinically as a new class of antidiabetic drugs. Recently, several studies have reported that treatment of cancer cells with PPARγ ligands could induce cell differentiation and apoptosis, suggesting a potential application as chemopreventive agents against carcinogenesis. In the present study, 3 different kinds of PPARγ ligands were subjected to the experiments to confirm their suppressive effects on liver carcinogenesis.
METHODS: Three PPARγ ligands, pioglitazone (Pio) (200 ppm), rosiglitazone (Rosi) (200 ppm), and troglitazone (Tro) (1000 ppm) were investigated on the induction of the placental form of rat glutathione S-transferase (rGST P) positive foci, a precancerous lesion of the liver,and liver cancer formation using a diethylnitrosamine-induced liver cancer model in Wistar rats, and dose dependency of a PPARγ ligand was also examined.
RESULTS: PPARγ ligands reduced the formation of rGST P-positive foci by diethylnitrosamine and induction of liver cancers was also markedly suppressed by a continuous feeding of Pio at 200 ppm.
CONCLUSION: PPARγ ligands are potential chemopreventive agents for liver carcinogenesis.
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Affiliation(s)
- Yan-Tong Guo
- Department of General Surgery, Beijing Jishuitan Hospital, the Forth Clinical Medical College of Peking University, Beijing 100035, China.
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36
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Xu YH, Lahvis G, Edwards H, Pitot HC. Three-dimensional reconstruction from serial sections in PC-Windows platform by using 3D_Viewer. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2004; 76:143-154. [PMID: 15451163 DOI: 10.1016/j.cmpb.2004.04.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2004] [Accepted: 04/17/2004] [Indexed: 05/24/2023]
Abstract
Three-dimensional (3D) reconstruction from serial sections allows identification of objects of interest in 3D and clarifies the relationship among these objects. 3D_Viewer, developed in our laboratory for this purpose, has four major functions: image alignment, movie frame production, movie viewing, and shift-overlay image generation. Color images captured from serial sections were aligned; then the contours of objects of interest were highlighted in a semi-automatic manner. These 2D images were then automatically stacked at different viewing angles, and their composite images on a projected plane were recorded by an image transform-shift-overlay technique. These composition images are used in the object-rotation movie show. The design considerations of the program and the procedures used for 3D reconstruction from serial sections are described. This program, with a digital image-capture system, a semi-automatic contours highlight method, and an automatic image transform-shift-overlay technique, greatly speeds up the reconstruction process. Since images generated by 3D_Viewer are in a general graphic format, data sharing with others is easy. 3D_Viewer is written in MS Visual Basic 6, obtainable from our laboratory on request.
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Affiliation(s)
- Yi-Hua Xu
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, 1400 University Avenue, 53706-1599, USA
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37
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Xu YH, Pitot HC. An improved stereologic method for three-dimensional estimation of particle size distribution from observations in two dimensions and its application. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2003; 72:1-20. [PMID: 12850293 DOI: 10.1016/s0169-2607(02)00115-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Single enzyme-altered hepatocytes; altered hepatic foci (AHF); and nodular lesions have been implicated, respectively in the processes of initiation, promotion, and progression in rodent hepatocarcinogenesis. Qualitative and quantitative analyses of such lesions have been utilized both to identify and to determine the potency of initiating, promoting, and progressor agents in rodent liver. Of a number of possible parameters determined in the study of such lesions, estimation of the number of foci or nodules in the liver is very important. The method of Saltykov has been used for estimating the number of AHF in rat liver. However, in practice, the Saltykov calculation has at least two weak points: (a) the size class range is limited to 12, which in many instances is too narrow to cover the range of AHF data obtained; and (b) under some conditions, the Saltykov equation generates negative values in several size classes, an obvious impossibility in the real world. In order to overcome these limitations in the Saltykov calculations, a study of the particle size distribution in a wide-range, polydispersed sphere system was performed. A stereologic method, termed the 25F Association method, was developed from this study. This method offers 25 association factors that are derived from the frequency of different-sized transections obtained from transecting a spherical particle, thus expanding the size class range to be analyzed up to 25, which is sufficiently wide to encompass all rat AHF found in most cases. This method exhibits greater flexibility, which allows adjustments to be made within the calculation process when NA((k,k)), the net number of transections from the same size spheres, was found to be a negative value, which is not possible in real situations. The reliability of the 25F Association method was tested thoroughly by computer simulation in both monodispersed and polydispersed sphere systems. The test results were compared with the original Saltykov method. We found that the 25F Association method yielded a better estimate of the total number of spheres in the three-dimensional tissue sample as well as the detailed size distribution information. Although the 25F Association method was derived from the study of a polydispersed sphere system, it can be used for continuous size distribution sphere systems. Application of this method to the estimation of parameters of preneoplastic foci in rodent liver is presented as an example of its utility. An application software program, 3D_estimation.exe, which uses the 25F Association method to estimate the number of AHF in rodent liver, has been developed and is now available at the website of this laboratory.
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Affiliation(s)
- Yi-Hua Xu
- Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, 1400 University Avenue, Madison, WI 53706, USA
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38
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Tsujiuchi T, Tsutsumi M, Konishi Y. Molecular Aspects during Multi-step Chemical Induced Carcinogenesis in the Lung and Pancreas. J Toxicol Pathol 2003. [DOI: 10.1293/tox.16.133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
| | - Masahiro Tsutsumi
- Department of Oncological Pathology, Cancer Center, Nara Medical University
| | - Yoichi Konishi
- Department of Oncological Pathology, Cancer Center, Nara Medical University
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39
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Rahman KM, Sugie S, Tanaka T, Mori H, Reddy BS. Effect of types and amount of dietary fat during the initiation phase of hepatocarcinogenesis. Nutr Cancer 2002; 39:220-5. [PMID: 11759284 DOI: 10.1207/s15327914nc392_10] [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: 10/31/2022]
Abstract
The effects of various levels of corn oil and lard fed during the initiation stage of azoxymethane (AOM)-induced hepatocarcinogenesis were studied in male Fischer 344 rats. The animals were fed diets containing 5%, 13.6%, and 23.5% corn oil or lard two weeks before, during, and until one week after injections of AOM (15 mg/kg body wt s.c.) once weekly for two weeks. One week after AOM treatment, groups of animals fed the 13.6% and 23.5% corn oil or lard diet were transferred to their respective 5% corn oil or lard diet and fed these diets until the termination of the study (34 wk). Immunohistochemical staining of glutathione S-transferase placental form was performed in the liver, and the number of glutathione S-transferase placental form-positive foci was determined. Density, average area, and unit area of foci were significantly inhibited in the animals fed the 13.6% and 23.5% lard diets compared with those fed the 13.6% and 23.5% corn oil diets. These results indicate that the effect of dietary fat during the initiation phase of AOM-induced hepatocarcinogenesis depends on the type of fat and its fatty acid composition. Additionally, the enhancing effect of a corn oil diet in hepatocarcinogenesis is mainly present during the initiation phase of carcinogenesis compared with a lard diet.
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Affiliation(s)
- K M Rahman
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
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40
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de Luján Alvarez M, Cerliani JP, Monti J, Carnovale C, Ronco MT, Pisani G, Lugano MC, Carrillo MC. The in vivo apoptotic effect of interferon alfa-2b on rat preneoplastic liver involves Bax protein. Hepatology 2002; 35:824-33. [PMID: 11915028 DOI: 10.1053/jhep.2002.32099] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
To determine whether interferon alfa (IFN-alpha) prevents in vivo oncogenesis in very-early-stage cancer cells, we evaluated the action of IFN-alpha2b over preneoplastic foci in rats. Animals were divided into 6 groups: subjected to a 2-phase model (diethylnitrosamine [DEN] plus 2-acetylaminofluorene [2-AAF]) of preneoplasia development (group 1), treated with IFN-alpha2b during the 2 phases (group 2), only during initiation with DEN (group 3), only during administration of 2-AAF (group 4), subjected only to an initiation stage (group 5), and treated with IFN-alpha2b during this period (group 6). The numbers of placental form of rat glutathione S-transferase (rGST-P)-positive foci per liver and the foci as percentage of liver were significantly reduced in groups 2, 3, and 6 but not in group 4. Rats treated with IFN-alpha2b showed a higher apoptotic index (AI) in altered hepatic foci (AHF). Levels of p53 and Bax protein in liver lysates were significantly increased in those animals. Similarly, levels of antiapoptotic proteins Bcl-2 and Bcl-x(L) in mitochondrial fraction were decreased. Finally, increased levels of Bax protein were localized in the mitochondria of rats that received IFN-alpha2b, at least during the DEN phase (groups 2, 3, and 6), whereas mitochondrial Bax expression was not increased in group 4. In conclusion, the preneoplastic hepatocytes in rats that received IFN-alpha2b during the initiation stage undergo programmed cell death as a primary result of a significant increase in the amount and translocation to the mitochondria of Bax protein.
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Affiliation(s)
- María de Luján Alvarez
- Instituto de Fisiología Experimental (IFISE-CONICET) and Area de Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Rosario, Argentina
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41
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Qin G, Ning Y, Lotlikar PD. Chemoprevention of aflatoxin B1-initiated and carbon tetrachloride-promoted hepatocarcinogenesis in the rat by green tea. Nutr Cancer 2002; 38:215-22. [PMID: 11525600 DOI: 10.1207/s15327914nc382_11] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Chemoprevention of hepatocarcinogenesis by green tea (GT) has been examined in young male Fischer rats fed AIN-76A diet with aflatoxin B1 (AFB1) and CCl4 as the initiator and promoter, respectively. Animals were administered AFB1 (0.25 mg/kg body wt ip) twice a week for 2 weeks, and 2 weeks later, CCl4 was injected (0.8 ml/kg body wt ip) once per week for 11 weeks. Rats given 0.5% GT in their drinking water before and during initiation (0-4 wk) or during promotion (6-16 wk) or throughout the experimental period were sacrificed 24 hours after the last dose of CCl4. Bromodeoxyuridine incorporation as a measure of cell proliferation and glutathione S-transferase placentalform- and gamma-glutamyl transpeptidase-positive hepatic foci were analyzed by histochemical methods. Feeding of GT during initiation or promotion inhibited the number of glutathione S-transferase placental form- and gamma-glutamyl transpeptidase-positive hepatic foci by 30-40% and the area and volume by 50%. GT treatment throughout the period inhibited the number of both types of hepatic foci by 60% and the area and volume by 75-80%. Cell proliferation was inhibited 35% by GT given during promotion, whereas inhibition was 65% when GT was given during initiation or throughout the period. These results indicate that GT feeding inhibits initiation and promotion steps of AFB1 hepatocarcinogenesis and that the inhibition of cell proliferation is responsible for the inhibition of promotion.
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Affiliation(s)
- G Qin
- Fels Institute for Cancer Research and Molecular Biology and the Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA
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42
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Kubozoe T, Tsutsumi M, Murata N, Tsujiuchi T, Tsunoda T, Sugimura T, Wakabayashi K, Konishi Y. Possible Lack of Carcinogenic Potential of 9-(4'-Aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorbarman) for the Pancreatic Duct Epithelium in Hamsters. J Toxicol Pathol 2002. [DOI: 10.1293/tox.15.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Tadahiko Kubozoe
- Department of Oncological Pathology, Cancer Center, Nara Medical University
- Department of Gastroenterological Surgery, Kawasaki Medical University
| | - Masahiro Tsutsumi
- Department of Oncological Pathology, Cancer Center, Nara Medical University
| | - Nao Murata
- Department of Oncological Pathology, Cancer Center, Nara Medical University
| | | | - Tsukasa Tsunoda
- Department of Gastroenterological Surgery, Kawasaki Medical University
| | - Takashi Sugimura
- Cancer Prevention Division, National Cancer Center Research Institute
| | - Keiji Wakabayashi
- Cancer Prevention Division, National Cancer Center Research Institute
| | - Yoichi Konishi
- Department of Oncological Pathology, Cancer Center, Nara Medical University
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43
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Hiruma S, Gopalan-Kriczky P, Qin G, Gaughan JP, Lotlikar PD. Differential effects of acetaminophen pretreatment on hepatic aflatoxin B(1)-DNA binding, cellular proliferation, and aflatoxin B1-induced hepatic foci in rats and hamsters. Cancer Lett 2001; 170:117-24. [PMID: 11463488 DOI: 10.1016/s0304-3835(01)00594-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Effects of acetaminophen (AAP) pretreatment on hepatic aflatoxin B1 (AFB(1))-DNA binding, cellular proliferation, and AFB(1)-induced glutathione S-transferase placental form (GST-P) positive hepatocytes and foci have been examined in young male rats and hamsters. Intraperitoneal (i.p.) dosing of 600mg AAP 3h before AFB(1) i.p. injection showed three-fold more AFB(1)-DNA binding in hamsters and 40% less binding in rats. Cell proliferation analyzed by bromodeoxyuridine incorporation was not significant (0.4-0.6%) 24-96h after AAP (600mg) treatment of rats; however, proliferation was stimulated and was maximum (11%) in hamsters at 72h after AAP treatment. Dosing of rats with AFB(1) alone at 0.5 or 2.5mg level gave an appreciable number of GST-P positive minifoci (two to nine cells) with a few foci larger than 100 microm; pretreatment with AAP (300 or 600mg) 48h before 0.5 or 2.5mg AFB(1) had no effect on the number and focal area of foci. In hamsters, 1 or 2mg AFB(1) alone yielded GST-P positive hepatocytes without any minifoci. Pretreatment with AAP (600mg) 48 or 72h before 1 or 2mg AFB(1) produced increases in both GST-P positive hepatocytes and minifoci. Thus, marked changes are observed after AAP pretreatment in hamsters compared to rats.
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Affiliation(s)
- S Hiruma
- Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
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44
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Sugie S, Okamoto K, Watanabe T, Tanaka T, Mori H. Suppressive effect of irsogladine maleate on N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-initiated and glyoxal-promoted gastric carcinogenesis in rats. Toxicology 2001; 166:53-61. [PMID: 11518611 DOI: 10.1016/s0300-483x(01)00447-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The modifying effect of irsogladine maleate (IRG) on N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-initiated and glyoxal-promoted gastric carcinogenesis was examined in male Wistar rats. Six-week-old rats were divided into ten groups. Groups 1 through 6 were given MNNG (100 mg/l in drinking water) for 25 weeks from the start of the experiment, whereas groups 7 through 10 received distilled water in the initiation phase as the vehicle treatment. Groups 1 and 8 were kept on the basal diet and distilled water throughout the experiment (55 weeks). Groups 2-8 were given 0.5% glyoxal in the drinking water for 30 weeks from 26th week of the experiment. Group 3 was fed the diet mixed with 100 ppm IRG for 25 weeks from the start of experiment. Groups 4 and 8 were fed the diet mixed with 100 ppm IRG for 30 weeks from 26th week of experiment. Groups 5 and 9 or 6 were given 100 or 25 ppm IRG containing diet, respectively throughout the experiment. Group 10 was given the basal diet and distilled water as the vehicle treated control. Tumors of upper digestive tracts (stomach and duodenum) were developed in groups: 1 (12/17 rats, 71%), 2 (11/12 rats, 92%), 3 (9/16 rats, 56%), 4 (5/12 rats, 42%), 5 (6/15 rats, 40%) and 6 (7/12 rats, 58%). High dose of IRG in initiation and/or promotion phase significantly reduced the incidence of tumors of the upper digestive tracts. The average numbers of the digestive tracts neoplasms in groups 3,5 and 6 given glyoxal and IRG were less than those in group 2 which received only glyoxal. These results suggest that IRG could be a preventive agent against the occurrence of neoplasms of the upper digestive tract.
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Affiliation(s)
- S Sugie
- Institute of Laboratory Animals, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan.
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45
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Kubozoe T, Tsujiuchi T, Murata N, Sasaki Y, Tsunoda T, Konishi Y, Tsutsumi M. Absence of beta-catenin gene mutations in pancreatic duct lesions induced by N-nitrosobis(2-oxopropyl)amine in hamsters. Cancer Lett 2001; 168:1-6. [PMID: 11368870 DOI: 10.1016/s0304-3835(01)00406-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The involvement of beta-catenin gene alterations in pancreatic duct carcinogenesis induced by N-nitrosobis(2-oxopropyl)amine (BOP) in hamsters was examined by polymerase chain reaction-single strand conformation polymorphism analysis and the expression of beta-catenin protein was examined by immunohistochemistry. No mutations of the beta-catenin gene were detected in 20 pancreatic duct adenocarcinomas (PDAs). Immunohistochemical staining showed the beta-catenin protein to be ubiquitously localized in the cell membranes. beta-Catenin accumulation was not identified in the cytoplasm and/or nucleus in any of 102 hyperplasias, 35 atypical hyperplasias, and 73 PDAs, as well as normal pancreatic duct cells. These results suggest that the Wnt/beta-catenin signaling pathway may not play an important role in pancreatic duct carcinogenesis induced by BOP in hamsters.
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Affiliation(s)
- T Kubozoe
- Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara, 634-8521, Nara, Japan
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46
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Carrillo MC, Favre C, Carnovale CE, Monti JA, Alvarez ML, Scapini C, Pisani GB, Lugano MC. Involvement of mu class glutathione S-transferase subunit M2 (rGST M2) levels in the initiation and promotion of hepatocellular carcinogenesis in old rats. Exp Gerontol 2001; 36:255-65. [PMID: 11226741 DOI: 10.1016/s0531-5565(00)00209-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Age-associated differences in the response of the initiation and promotion of hepatocellular carcinogenesis in the rat were analyzed. Male Wistar rats 5 and 18 months-old were used throughout. They underwent an experimental design of multistage model of hepatocarcinogenesis: hepatic cells were initiated with the complete carcinogen Aflatoxin B1 (0.5mg/Kg b.w.) and the promotion was performed through a combined treatment of proliferation (partial hepatectomy, 65%) and administration of the tumorigenic promoter phenobarbital (0.1% in drinking water for 21 days). After the treatment, rats were sacrificed and the following parameters were determined: activity and subunit composition of the glutathione S-transferase enzyme system, the number of liver preneoplastic foci and the proliferation cell index. The combined treatment (initiation + promotion) lowered the expression of the mu class GST (rGST M1, rGST M2). The inhibition in rGST M2 in old animals (which in basal conditions had already been lower) was significant. On the other hand, the treatment increased the alpha class GST (rGST A, rGST A3). The number of preneoplastic foci was higher in old rats (number of foci/cm(2): 6.9+/-0.3 vs 3.9+/-0.3 in young rats, p< 0.05). The proliferation cell index did not show age-related differences. Because rGST M2 deficiency coexisted with induced expression of alpha class, the livers would be resistant to some toxic insults, being selectively sensitive to potentially genotoxic substances for which M2 is an essential detoxification pathway. The transition to a rGST M2-deficient phenotype during aging could induce higher responsiveness to genotoxic effects, and might favor the likelihood of further progression, indicating a higher susceptibility of aged animals to the development of carcinogenesis.
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Affiliation(s)
- M C Carrillo
- Instituto de Fisiología Experimental (CONICET), Suipacha 570, 2000, Rosario, Argentina.
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van der Plas SA, Sundberg H, van den Berg H, Scheu G, Wester P, Jensen S, Bergman A, de Boer J, Koeman JH, Brouwer A. Contribution of planar (0-1 ortho) and nonplanar (2-4 ortho) fractions of Aroclor 1260 to the induction of altered hepatic foci in female Sprague-Dawley rats. Toxicol Appl Pharmacol 2000; 169:255-68. [PMID: 11133348 DOI: 10.1006/taap.2000.9058] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The hepatic tumor promoting activity of the planar 0-1 ortho ( approximately 9.7% w/w) and the nonplanar 2-4 ortho ( approximately 90.3% w/w) fraction of the commercial PCB mixture Aroclor 1260 was studied using a medium-term two-stage initiation/promotion bioassay in female Sprague-Dawley rats. Fractionation was carried out on an activated charcoal column. The composition of the effluent from the column was tested by GC-ECD. The absence of planar compounds in the 2-4 ortho fraction was confirmed by GC-MS analysis. The dioxin-like toxic potency of the fractions was determined with the DR-CALUX assay. The animal experiment was started with the initiation procedure (diethylnitrosamine injection, 30 mg/kg body wt ip, 24 h after (2)/(3) hepatectomy), followed 6 weeks later by the promotion treatment, which consisted of a weekly subcutaneous injection during 20 weeks. Exposure groups (n = 10) received the following treatments (dose/kg body wt/week): Aroclor 1260 (10 mg), 0-1 ortho fraction (0.97 mg), 2-4 ortho fraction (1, 3, or 9 mg), a reconstituted 0-4 ortho fraction (9.97 mg), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153; 1 or 9 mg), 2,3,7,8-TCDD (1 microg; positive control) or corn oil (1 ml; vehicle control). One group did not receive a promotion treatment. All exposure groups exhibited a significantly increased volume fraction of the liver occupied by hepatic foci positive for the placental form of glutathione-S-transferase-p compared to the corn oil control, except for the groups treated with 0-1 ortho fraction and 1 mg PCB 153/kg body wt/week. Approximately 80% of the total tumor promoting capacity of the reconstituted 0-4 ortho fraction could be explained by the 2-4 ortho PCB fraction while the 0-1 ortho fraction had only a negligible contribution. These results suggest that the majority of the tumor promotion potential of PCB mixtures resides in the non-dioxin-like fraction, which is not taken into account in the toxic equivalency factor (TEF) approach for risk assessment of PCBs. This may result in an underestimation of the tumor promotion potential of environmental PCB mixtures.
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Affiliation(s)
- S A van der Plas
- Department of Food Technology and Nutritional Sciences, Agricultural University Wageningen, 6700 EA Wageningen, The Netherlands
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Tsutsumi M, Kadomatsu K, Tsujiuchi T, Sakitani H, Ikematsu S, Kubozoe T, Yoshimoto M, Muramatsu T, Sakuma S, Konishi Y. Overexpression of midkine in pancreatic duct adenocarcinomas induced by N-Nitrosobis(2-oxopropyl)amine in hamsters and their cell lines. Jpn J Cancer Res 2000; 91:979-86. [PMID: 11050467 PMCID: PMC5926258 DOI: 10.1111/j.1349-7006.2000.tb00874.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
The expression of midkine (MK) was investigated in pancreatic ductal hyperplasias, atypical hyperplasias and adenocarcinomas induced by N-nitrosobis(2-oxopropyl)amine (BOP) in hamsters, and in hamster ductal adenocarcinoma cell lines (HPD-1NR, -2NR and -3NR). MK mRNA was clearly overexpressed in invasive pancreatic duct adenocarcinomas (PCs) and the three cell lines as assessed by northern blot analysis, and MK protein expression increased from ductal hyperplasia through atypical hyperplasias, intraductal carcinomas and invasive PCs by immunohistochemistry. The extent of overexpression of MK mRNA in PCs was almost the same as in hamster whole embryonic tissue. MK is reported to be a retinoid-responsive gene, but MK mRNA expression was not affected by treatment with all-trans retinoic acid (tRA) or N-(4-hydroxyphenyl)retinamide (4-HPR) in HPD-1NR cells. The results thus suggest that MK expression is involved in the development and progression of pancreatic ductal adenocarcinomas induced by BOP in hamsters, with loss of upregulation by retinoic acid.
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Affiliation(s)
- M Tsutsumi
- Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara, Nara 634-8521, Japan.
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Basak R, Basu M, Chatterjee M. Combined supplementation of vanadium and 1alpha,25-dihydroxyvitamin D(3) inhibit diethylnitrosamine-induced rat liver carcinogenesis. Chem Biol Interact 2000; 128:1-18. [PMID: 10996297 DOI: 10.1016/s0009-2797(00)00183-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
A combination of a differentiation-inducing agent like 1alpha, 25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] with a compound that blocks entry of calcium into cells like vanadium (V) may offer a new approach to differentiation therapy and address the problem of hypercalcemia. Initiation of hepatocarcinogenesis was performed by a single intraperitoneal injection of diethylnitrosamine (DEN) (200 mg/kg b.wt.) in male Sprague-Dawley rats. Supplementation of V, 1, 25(OH)(2)D(3), or both V and 1,25(OH)(2)D(3) were started 4 weeks prior to DEN injection and continued thereafter till 20th week. It was observed that supplementation of V (0.5 ppm) in drinking water ad libitum or 1,25(OH)(2)D(3) (3 microg/ml propylene glycol) per os twice weekly for the entire period of the experiment significantly reduces the number and size of hyperplastic nodules while the combination treatment offered an additive effect in reducing it to 37.5% from 83.3%. V-1,25(OH)(2)D(3) combination was also effective in elevating the level of hepatic microsomal cytochrome P-450 (Cyt. P-450) (P<0.001). Moreover, A significant reduced level of cytosolic glutathione (GSH) (P<0.001) and glutathione S-transferase (GST) (P<0.001) activity as well as reduction in the appearance of gamma-glutamyltranspeptidase (GGT)-positive foci (P<0.001) as compared to carcinogen control were observed in V plus 1, 25(OH)(2)D(3) treated group. These results suggest that V may be useful in combination with 1,25(OH)(2)D(3) in the inhibition of experimental rat hepatocarcinogenesis.
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Affiliation(s)
- R Basak
- Division of Biochemistry, Department of Pharmaceutical Technology, Jadavpur University, PO Box 17028, 700 032, Calcutta, India.
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Plewka A, Kamiński M, Plewka D, Nowaczyk G. Glucose-6-phosphatase and age: biochemical and histochemical studies. Mech Ageing Dev 2000; 113:49-59. [PMID: 10708249 DOI: 10.1016/s0047-6374(99)00097-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Glucose-6-phosphatase catalyzes the final reactions in both gluconeogenesis and glycolysis. It occurs mainly in glycogenic tissues, such as the liver, where it plays an important role in the synthesis of glucose, a carbohydrate essential for tissue functioning. The effect of age on liver glucose-6-phosphatase activity was evaluated in male Wistar rats treated with mixed function oxidase system (MFO) inducers. The rats were divided into the following age groups: 0.5, 1, 2, 4, 8, 12, 20 and 28 months of age. Glucose-6-phosphatase activity was evaluated biochemically and histochemically. Biochemical glucose-6-phosphatase activity increased up to the 20th month of rat life and then decreased rapidly. A similar tendency was observed in inducer-treated groups, though only dexamethasone stimulated this enzyme activity in all age groups studied. Histochemical glucose-6-phosphatase activity was strongest in the periportal zones. Glucose-6-phosphatase activity decreased significantly at month 8 and then it increased significantly until month 20. In the oldest age group, glucose-6-phosphatase activity decreased again. On histochemical analysis, the inducers used variably affected glucose-6-phosphatase activity.
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Affiliation(s)
- A Plewka
- Department of Histology and Embryology, Silesian School of Medicine, Katowice-Ligota, Poland.
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