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Gao T, Li M, Wu D, Xiao N, Huang D, Deng L, Yang L, Tian C, Cao Y, Zhang J, Gu J, Yu Y. Exploring the pathogenesis of colorectal carcinoma complicated with hepatocellular carcinoma via microarray data analysis. Front Pharmacol 2023; 14:1201401. [PMID: 37383715 PMCID: PMC10293624 DOI: 10.3389/fphar.2023.1201401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 05/30/2023] [Indexed: 06/30/2023] Open
Abstract
Background: Despite the increasing number of research endeavors dedicated to investigating the relationship between colorectal carcinoma (CRC) and hepatocellular carcinoma (HCC), the underlying pathogenic mechanism remains largely elusive. The aim of this study is to shed light on the molecular mechanism involved in the development of this comorbidity. Methods: The gene expression profiles of CRC (GSE90627) and HCC (GSE45267) were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the common differentially expressed genes (DEGs) of psoriasis and atherosclerosis, three kinds of analyses were performed, namely, functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification, survival analysis and co-expression analysis. Results: A total of 150 common downregulated differentially expressed genes and 148 upregulated differentially expressed genes were selected for subsequent analyses. The significance of chemokines and cytokines in the pathogenesis of these two ailments is underscored by functional analysis. Seven gene modules that were closely connected were identified. Moreover, the lipopolysaccharide-mediated signaling pathway is intricately linked to the development of both diseases. Finally, 10 important hub genes were identified using cytoHubba, including CDK1, KIF11, CDC20, CCNA2, TOP2A, CCNB1, NUSAP1, BUB1B, ASPM, and MAD2L1. Conclusion: Our study reveals the common pathogenesis of colorectal carcinoma and hepatocellular carcinoma. These common pathways and hub genes may provide new ideas for further mechanism research.
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Affiliation(s)
- Tianqi Gao
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mengping Li
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Oncology, The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, China
| | - Dailin Wu
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ni Xiao
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dan Huang
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li Deng
- Department of Oncology, The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lunwei Yang
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chunhong Tian
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yang Cao
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jun Zhang
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jihong Gu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yang Yu
- Department of Gastrointestinal and Thyroid Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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Bada L, Pereira RB, Pereira DM, Lores M, Celeiro M, Quezada E, Uriarte E, Gil-Longo J, Viña D. Phytochemical Analysis and Antiproliferative Activity of Ulex gallii Planch. (Fabaceae), a Medicinal Plant from Galicia (Spain). MOLECULES (BASEL, SWITZERLAND) 2023; 28:molecules28010351. [PMID: 36615543 PMCID: PMC9822445 DOI: 10.3390/molecules28010351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/23/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023]
Abstract
The genus Ulex comprises thirteen accepted species of perennial shrubs in the family Fabaceae. In Galicia (Spain) many of these are considered spontaneous colonizing species, which are easy to establish and maintain. Among them, Ulex gallii Planch. is used in traditional medicine for the same anti-infective, hypotensive and diuretic purposes as Ulex europaeus L., which is the most studied species. Likewise, some studies have described the antitumoral properties of several species. However, there are few scientific studies that justify the use of Ulex gallii Planch. and nothing has been reported about its composition to date. In our study, the entire plant was extracted with methanol and the crude extract was subjected to liquid phase extraction with distinct solvents, yielding three fractions: hexane (H), dichloromethane (D) and methanol (M), which were subsequently fractionated. The dichloromethane (D5, D7 and D8) and methanol (M4) sub-fractions showed antiproliferative activity on A549 (lung cancer) and AGS (stomach cancer) cell lines, and caspase 3/7 activity assessment and DNA quantification were also performed. Targeted analysis via UHPLC-QToF, in combination with untargeted analysis via MS-Dial, MS-Finder and Global Natural Products Social Molecular Networking (GNPS), allowed us to tentatively identify different metabolites in these sub-fractions, mostly flavonoids, that might be involved in their antiproliferative activity.
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Affiliation(s)
- Lucía Bada
- Group of Pharmacology of Chronic Diseases (CD Pharma), Molecular Medicine and Chronic Diseases Research Centre (CIMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Renato B. Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal
| | - David M. Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal
- Correspondence: (D.M.P.); (D.V.); Tel.: +351-22-042-8655 (D.M.P.); +34-881-815-424 (D.V.)
| | - Marta Lores
- Laboratory of Research and Development of Analytical Solutions (LIDSA), Department of Analytical Chemistry, Nutrition and Food Science, Faculty of Chemistry, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - María Celeiro
- CRETUS Institute, Department of Analytical Chemistry, Nutrition and Food Science, Campus Vida, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Elías Quezada
- Department of Organic Chemistry, Faculty of Pharmacy, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Eugenio Uriarte
- Department of Organic Chemistry, Faculty of Pharmacy, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
- Instituto de Ciencias Químicas Aplicadas, Universidad Autónoma de Chile, Santiago 7500912, Chile
| | - José Gil-Longo
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Dolores Viña
- Group of Pharmacology of Chronic Diseases (CD Pharma), Molecular Medicine and Chronic Diseases Research Centre (CIMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
- Correspondence: (D.M.P.); (D.V.); Tel.: +351-22-042-8655 (D.M.P.); +34-881-815-424 (D.V.)
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Homayoonfal M, Asemi Z, Yousefi B. Potential anticancer properties and mechanisms of thymoquinone in osteosarcoma and bone metastasis. Cell Mol Biol Lett 2022; 27:21. [PMID: 35236304 PMCID: PMC8903697 DOI: 10.1186/s11658-022-00320-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 02/08/2022] [Indexed: 12/14/2022] Open
Abstract
Despite great advances, therapeutic approaches of osteosarcoma, the most prevalent class of preliminary pediatric bone tumors, as well as bone-related malignancies, continue to demonstrate insufficient adequacy. In recent years, a growing trend toward applying natural bioactive compounds, particularly phytochemicals, as novel agents for cancer treatment has been observed. Bioactive phytochemicals exert their anticancer features through two main ways: they induce cytotoxic effects against cancerous cells without having any detrimental impact on normal cell macromolecules such as DNA and enzymes, while at the same time combating the oncogenic signaling axis activated in tumor cells. Thymoquinone (TQ), the most abundant bioactive compound of Nigella sativa, has received considerable attention in cancer treatment owing to its distinctive properties, including apoptosis induction, cell cycle arrest, angiogenesis and metastasis inhibition, and reactive oxygen species (ROS) generation, along with inducing immune system responses and reducing side effects of traditional chemotherapeutic drugs. The present review is focused on the characteristics and mechanisms by which TQ exerts its cytotoxic effects on bone malignancies.
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Affiliation(s)
- Mina Homayoonfal
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Chu Q, Gu X, Zheng Q, Guo Z, Shan D, Wang J, Zhu H. Long noncoding RNA SNHG4: a novel target in human diseases. Cancer Cell Int 2021; 21:583. [PMID: 34717631 PMCID: PMC8557547 DOI: 10.1186/s12935-021-02292-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/21/2021] [Indexed: 12/21/2022] Open
Abstract
Recently, long noncoding RNAs (lncRNAs) have attracted great attention from researchers. LncRNAs are non-protein-coding RNAs of more than 200 nucleotides in length. Multiple studies have been published on the relationship between lncRNA expression and the progression of human diseases. LncRNA small nucleolar RNA host gene 4 (SNHG4), a member of the lncRNA SNHG family, is abnormally expressed in a variety of human diseases, including gastric cancer, renal cell carcinoma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, osteosarcoma, cervical cancer, liver cancer, lung cancer, non-small-cell lung cancer, neonatal pneumonia, diabetic retinopathy, neuropathic pain, acute cerebral infarction, acute myeloid leukaemia, and endometriosis. In this paper, the structure of SNHG4 is first introduced, and then studies in humans, animal models and cells are summarized to highlight the expression and function of SNHG4 in the above diseases. In addition, the specific mechanism of SNHG4 as a competing endogenous RNA (ceRNA) is discussed. The findings indicate that SNHG4 can be used as a biomarker for disease prognosis evaluation and as a potential target for disease diagnosis and treatment.
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Affiliation(s)
- Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Qiuxian Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Zixuan Guo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Dandan Shan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Jing Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
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lncRNA SNHG4 modulates colorectal cancer cell cycle and cell proliferation through regulating miR-590-3p/CDK1 axis. Aging (Albany NY) 2021; 13:9838-9858. [PMID: 33744866 PMCID: PMC8064176 DOI: 10.18632/aging.202737] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 02/08/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is a prevalent malignancy worldwide. The development of genome sequencing technology has allowed the discovery that epigenetic regulation might play a critical role in CRC tumorigenesis. In the present study, we found that the long noncoding RNA (lncRNA) SNHG4 was dramatically increased in CRC tissue samples and cell lines based on both publicly available and experimental data. SNHG4 knockdown suppressed the viability and colony formation capacity of CRC cells. The expression of CDK1 was considerably increased in CRC tissue samples and cells and had a positive correlation with the expression of SNHG4 in CRC. SNHG4 silencing not only caused S phase cell cycle arrest but also significantly downregulated the CDK1, cyclin B1, and cyclin A2 protein levels in CRC cells. miR-590-3p simultaneously bound to SNHG4 and CDK1. miR-590-3p functioned to inhibit CDK1 expression. miR-590-3p overexpression exerted the same effects on the CRC cell phenotype as SNHG4 knockdown. The effects of si-SNHG4 on CRC cells were significantly reversed by anti-miR-590-3p, indicating that SNHG4 relieved the miR-590-3p-induced inhibition of CDK1 by acting as a competing endogenous RNA (ceRNA). In vivo, SNHG4 silencing inhibited subcutaneously transplanted tumor growth and decreased cell cycle marker levels, whereas miR-590-3p inhibition exerted the opposite effects. The in vivo effects of SNHG4 silencing were also reversed by miR-590-3p inhibition. The SNHG4/miR-590-3p/CDK1 axis influences the cell cycle to modulate CRC cell proliferation and subcutaneously transplanted tumor growth. Further application of this axis still requires analysis using more animal models and clinical investigations.
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SDCBP/MDA-9/syntenin phosphorylation by AURKA promotes esophageal squamous cell carcinoma progression through the EGFR-PI3K-Akt signaling pathway. Oncogene 2020; 39:5405-5419. [PMID: 32572158 DOI: 10.1038/s41388-020-1369-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 05/19/2020] [Accepted: 06/11/2020] [Indexed: 01/02/2023]
Abstract
SDCBP is an adapter protein containing two tandem PDZ domains mediating cell adhesion. The role and underlying molecular mechanism of SDCBP in ESCC remain obscure. Here, we report that SDCBP is frequently overexpressed in ESCC tissues and cells compared to normal controls and that its overexpression is correlated with late clinical stage and predicts poor prognosis in ESCC patients. Functionally, high expression of SDCBP is positively related to ESCC progression both in vitro and in vivo. Furthermore, mechanistic studies show that SDCBP activates the EGFR-PI3K-Akt signaling pathway by binding to EGFR and preventing EGFR internalization. Moreover, we provide evidence that AURKA binds to SDCBP and phosphorylates it at the Ser131 and Thr200 sites to inhibit ubiquitination-mediated SDCBP degradation. More importantly, the sites at which AURKA phosphorylates SDCBP are crucial for the EGFR signaling-mediated oncogenic function of SDCBP. Taken together, we propose that SDCBP phosphorylation by AURKA prevents SDCBP degradation and promotes ESCC tumor growth through the EGFR-PI3K-Akt signaling pathway. Our findings unveil a new AURKA-SDCBP-EGFR axis that is involved in ESCC progression and provide a promising therapeutic target for ESCC treatment in the clinic.
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El-Sisi AE, Sokkar SS, Ibrahim HA, Hamed MF, Abu-Risha SE. Targeting MDR-1 gene expression, BAX/BCL2, caspase-3, and Ki-67 by nanoencapsulated imatinib and hesperidin to enhance anticancer activity and ameliorate cardiotoxicity. Fundam Clin Pharmacol 2020; 34:458-475. [PMID: 32080901 DOI: 10.1111/fcp.12549] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 02/08/2020] [Accepted: 02/19/2020] [Indexed: 12/21/2022]
Abstract
There is a great demand to introduce new approaches into cancer treatment field due to incidence of increased breast cancer all over the world. The current study was designed to evaluate the role of imatinib mesylate (IM) and/or hesperidin (HES) nanoparticles alone or in combination in enhancing the anticancer activity and to investigate the ability of nanoencapsulation to reduce cardiotoxicity of IM in solid Ehrlich carcinoma (SEC)-bearing mice. IM and HES were loaded into PLGA (poly(lactic-co-glycolic acid) polymer. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into eight groups (n = 10). On day 28 from tumor inoculation, mice were sacrificed and blood samples were collected in heparinized tubes for hematological studies, biochemical determination of lactate dehydrogenase (LDH), and glutamic oxaloacetic transaminase (SGOT) levels. In addition, tumor and cardiac tissues were utilized for histopathological examination as well as determination of MDR-1 gene expression. Immunohistochemical staining of BAX and BCL-2 was done. Nano IM- and/or Nano HES-treated groups showed a significant reduction in tumor volume, weight, hematological, cardiac markers, and tumor MDR-1 gene downregulation compared to free conventional treated groups. In conclusion, the use of HES as an adjuvant therapy with IM could improve its cytotoxic effects and limit its cardiac toxicity. Furthermore, nanoencapsulation of IM and/or HES with PLGA polymer showed a remarkable anticancer activity.
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Affiliation(s)
- Alaa E El-Sisi
- Pharmacology and Toxicology department, College of Pharmacy, University of Tanta, Tanta, Egypt
| | - Samia S Sokkar
- Pharmacology and Toxicology department, College of Pharmacy, University of Tanta, Tanta, Egypt
| | - Hanaa A Ibrahim
- Pharmacology and Toxicology department, College of Pharmacy, University of Tanta, Tanta, Egypt
| | - Mohamed F Hamed
- Department of Pathology, College of Veterinary Medicine, University of El-Mansoura, Mansoura, Egypt
| | - Sally E Abu-Risha
- Pharmacology and Toxicology department, College of Pharmacy, University of Tanta, Tanta, Egypt
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Park GH, Hong SC, Jeong JB. Anticancer Activity of the Safflower Seeds (Carthamus tinctorius L.) through Inducing Cyclin D1 Proteasomal Degradation in Human Colorectal Cancer Cells. ACTA ACUST UNITED AC 2016. [DOI: 10.7732/kjpr.2016.29.3.297] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Kuno T, Takahashi S, Tomita H, Hisamatsu K, Hara A, Hirata A, Kobayashi H, Mori H. Preventive effects of fermented brown rice and rice bran against N-nitrosobis (2-oxopropyl) amine-induced pancreatic tumorigenesis in male hamsters. Oncol Lett 2015; 10:3377-3384. [PMID: 26788138 PMCID: PMC4665686 DOI: 10.3892/ol.2015.3809] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 08/05/2015] [Indexed: 01/06/2023] Open
Abstract
Fermented brown rice by Aspergillus oryzae (FBRA) is known to have the potential to prevent chemical carcinogenesis of the colon, liver, esophagus, urinary bladder, stomach and lungs in rodents. The present study examined the possible chemopreventive effects of FBRA on N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic tumorigenesis in hamsters. Five-week-old male Syrian golden hamsters were divided into seven groups. Groups 1–5 were subcutaneously injected with BOP (10 mg/kg body weight) four times during week 6 to induce pancreatic tumors, while groups 6 and 7 were injected with saline. Groups 2 and 3 were fed diets containing 5 and 10% FBRA, respectively, during the initiation phase. By contrast, groups 4 and 5 were fed diets containing 5 and 10% FBRA, respectively, during the post-initiation phase. Group 6 received a diet containing 10% FBRA throughout the experiment, and group 7 was kept on the basal diet alone and served as the untreated control. At the termination of the study (week 22), oral intake of 10% FBRA (group 5) during the post-initiation phase was identified to have significantly reduced the multiplicity (number of lesions/animal) of ductal adenocarcinoma [pancreatic intraepithelial neoplasia 3 (PanIN3); carcinoma in situ and invasive carcinoma] in comparison with group 1 control hamsters (0.24±0.44 vs. 0.71±0.72; P<0.05). Treatment with 10% FBRA in the post-initiation phase inhibited the progression of normal/precancerous lesions (PanIN1, mild hyperplastic lesions; and PanIN2, papillary hyperplasia) to ductal adenocarcinomas. Furthermore, dietary exposure to 10% FBRA during the initiation (group 3) and post-initiation phases (group 5) significantly reduced the multiplicity of PanIN2 (group 3, 0.55±0.69; group 5, 0.45±0.69; versus group 1, 1.26±1.24; P<0.05 and P<0.01, respectively). A significant reduction of Ki-67 positivity of PanIN2 in group 5 was also confirmed (group 5, 0.05±0.03; group 1, 0.22±0.12; P<0.01). Using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, augmentation of apoptosis by FBRA exposure in the non-lesional ductal epithelium and proliferative lesions was not evident. These findings indicate that FBRA exhibits inhibitory effects on BOP-induced pancreatic tumorigenesis in hamsters due to the reduced proliferation rate of tumor cells. Thus, FBRA may be a promising chemopreventive agent in human pancreatic cancer.
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Affiliation(s)
- Toshiya Kuno
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Kenji Hisamatsu
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Akira Hara
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Akihiro Hirata
- Division of Animal Experiment, Life Science Research Center, Gifu University, Gifu 501-1193, Japan
| | | | - Hideki Mori
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
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Shimpo K, Chihara T, Kaneko T, Beppu H, Wakamatsu K, Shinzato M, Yukitake J, Sonoda S. Inhibitory effects of low-dose aloe-emodin on the development of colorectal tumors in min mice. Asian Pac J Cancer Prev 2015; 15:5587-92. [PMID: 25081669 DOI: 10.7314/apjcp.2014.15.14.5587] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Aloe-emodin (AE), a natural anthraquinone compound, has been reported to exhibit anticancer activity in various cancer cell lines and anti-inflammatory effects in murine macrophages. In the present study, we investigated the cancer chemopreventive effects of AE in an Apc-deficient Min mouse model. In the first experiment, male Min mice were fed a basal diet or diets containing 5 ppm AE and 10 ppm AE for 12 weeks. The dietary administration of 5 ppm AE significantly reduced the number of colorectal tumors. In a second experiment, we investigated the effects of AE on colitis-related colon carcinogenesis in Min mouse treated with dextran sodium sulfate (DSS). Female Min mice were administered 1% DSS in their drinking water for 7 days. AE was given to mice in their diet at a dose of 5 or 50 ppm for 5 weeks. Feeding with AE significantly reduced the number of colorectal tumors. When proliferation of cells in normal-appearing colonic mucosa was assessed by monoclonal anti-rat Ki-67 antibody (MIB-5) immunohistochemistry in experiments 1 and 2, the AE treatment significantly decreased the mean MIB-5-labeling index. These results suggest that the dietary administration of low-dose AE may have chemopreventive effects against development of colorectal tumors in Min mice, possibly in part by reducing cell proliferation in colorectal mucosa.
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Affiliation(s)
- Kan Shimpo
- Division of Biochemistry, Fujita Memorial Nanakuri Institute, Fujita Health University, Tsu, Japan E-mail :
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Yu Z, Guo W, Ma X, Zhang B, Dong P, Huang L, Wang X, Wang C, Huo X, Yu W, Yi C, Xiao Y, Yang W, Qin Y, Yuan Y, Meng S, Liu Q, Deng W. Gamabufotalin, a bufadienolide compound from toad venom, suppresses COX-2 expression through targeting IKKβ/NF-κB signaling pathway in lung cancer cells. Mol Cancer 2014; 13:203. [PMID: 25175164 PMCID: PMC4161895 DOI: 10.1186/1476-4598-13-203] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 08/25/2014] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Gamabufotalin (CS-6), a major bufadienolide of Chansu, has been used for cancer therapy due to its desirable metabolic stability and less adverse effect. However, the underlying mechanism of CS-6 involved in anti-tumor activity remains poorly understood. METHODS The biological functions of gamabufotalin (CS-6) were investigated by migration, colony formation and apoptosis assays in NSCLC cells. The nuclear localization and interaction between transcriptional co-activator p300 and NF-κB p50/p65 and their binding to COX-2 promoter were analyzed after treatment with CS-6. Molecular docking study was used to simulate the interaction of CS-6 with IKKβ. The in vivo anti-tumor efficacy of CS-6 was also analyzed in xenografts nude mice. Western blot was used to detect the protein expression level. RESULTS Gamabufotalin (CS-6) strongly suppressed COX-2 expression by inhibiting the phosphorylation of IKKβ via targeting the ATP-binding site, thereby abrogating NF-κB binding and p300 recruitment to COX-2 promoter. In addition, CS-6 induced apoptosis by activating the cytochrome c and caspase-dependent apoptotic pathway. Moreover, CS-6 markedly down-regulated the protein levels of COX-2 and phosphorylated p65 NF-κB in tumor tissues of the xenograft mice, and inhibited tumor weight and size. CONCLUSIONS Our study provides pharmacological evidence that CS-6 exhibits potential use in the treatment of COX-2-mediated diseases such as lung cancer.
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Affiliation(s)
- Zhenlong Yu
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Wei Guo
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Xiaochi Ma
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Baojing Zhang
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Peipei Dong
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Lin Huang
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Xiuli Wang
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Chao Wang
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Xiaokui Huo
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Wendan Yu
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Canhui Yi
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Yao Xiao
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Wenjing Yang
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Yu Qin
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Yuhui Yuan
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Songshu Meng
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
| | - Quentin Liu
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
- />Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Canter of Cancer Medicine, Guangzhou, China
| | - Wuguo Deng
- />Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian, 116044 China
- />Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Canter of Cancer Medicine, Guangzhou, China
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Jaganathan SK, Vellayappan MV, Narasimhan G, Supriyanto E. Role of pomegranate and citrus fruit juices in colon cancer prevention. World J Gastroenterol 2014; 20:4618-4625. [PMID: 24782614 PMCID: PMC4000498 DOI: 10.3748/wjg.v20.i16.4618] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 11/13/2013] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Recent studies prove that though chemotherapeutic agents are being used for the treatment of colon cancer, they become non-effective when the cancer progresses to an invasive stage. Since consumption of certain dietary agents has been linked with various cancers, fruit juices have been investigated for their consistently protective effect against colon cancer. The unique biochemical composition of fruit juices is responsible for their anticancer properties. In this review, the chemo-preventive effect of fruit juices such as pomegranate and citrus juices against colon cancer are discussed. For this purpose, the bioavailability, in vitro and in vivo effects of these fruit juices on colorectal cancer are highlighted. Moreover, there is a scarcity of studies involving human trials to estimate the preventive nature of these juices against colon cancer. This review will support the need for more preclinical tests with these crude juices and their constituents in different colorectal cancer cell lines and also some epidemiological studies in order to have a better understanding and promote pomegranate and citrus juices as crusaders against colon cancer.
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Niu Y, Li Y, Zang J, Huang H, Deng J, Cui Z, Yu D, Deng J. Death receptor 5 and neuroproliferation. Cell Mol Neurobiol 2012; 32:255-65. [PMID: 21938487 PMCID: PMC11498502 DOI: 10.1007/s10571-011-9757-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Accepted: 09/08/2011] [Indexed: 02/06/2023]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand or Apo2 ligand is a member of the tumor necrosis factor superfamily of cytokines that induces apoptosis upon binding to its death domain-containing transmembrane receptors, death receptors 4 and 5 (DR4, DR5). However, DR5 is also expressed in the developing CNS where it appears to play a role unrelated to apoptosis, and instead may be involved in the regulation of neurogenesis. We report on the distribution of DR5 expression in mouse hippocampus, cerebellum, and rostral migratory stream (RMS) of olfactory bulb from embryonic (E) day 16 (E16) to postnatal (P) day (P180). At E16, DR5-positive cells were distributed widely in embryonic hippocampus with strong immunostaining in the developing dentate gyrus. In newborn hippocampus, DR5-positive cells were predominantly located in proliferative zones, such as dentate gyrus, subventricular zone, and RMS. After postnatal day 7 (P7), the number of DR5-positive cells decreased, and cells with intense fluorescence were primarily restricted to the subgranular layer (SGL), although the granular cell layer showed weak fluorescence. After P30, only few DR5-positive cells were found in SGL, and mature granule cells were negative for DR5 expression. To address whether DR5 expression is a restricted to progenitor cells and newborn neurons, we performed 5-bromo-deoxyuridine labeling. We report that proliferative cells in the SGL selectively express DR5, with lower levels of expression in cells positive for doublecortin, a marker of newborn neurons. In addition, the stem cells in intestine, cerebellum, and RMS were also demonstrated to be DR5-positive. In the meantime, in cerebellum, DR5-positive cells were also positive for glial fibrillary acidic protein, a marker of proliferative Bergmann cells. We conclude that DR5 is selectively expressed by neuroprogenitor cells and newborn neurons, suggesting that the DR5 death receptor is likely to play a key role in neuroproliferation and differentiation.
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Affiliation(s)
- Yanli Niu
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
| | - Yongqiang Li
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
| | - Jianfeng Zang
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
| | - Hongen Huang
- Jiujiang Traditional Hospital, Jiujiang, 332000 China
| | - Jiexin Deng
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
| | - Zhanjun Cui
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
| | - Dongming Yu
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
| | - Jinbo Deng
- Institute of Neurobiology, College of Life Science, Henan University, Kaifeng, 475004 Henan People’s Republic of China
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Cancer chemoprevention by citrus pulp and juices containing high amounts of β-cryptoxanthin and hesperidin. J Biomed Biotechnol 2011; 2012:516981. [PMID: 22174562 PMCID: PMC3228311 DOI: 10.1155/2012/516981] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Accepted: 08/29/2011] [Indexed: 02/06/2023] Open
Abstract
β-Cryptoxanthin, a carotenoid, and hesperidin, a flavonoid, possess inhibitory effects on carcinogenesis in several tissues. We recently have prepared a pulp (CHRP) and citrus juices (MJ2 and MJ5) from a satsuma mandarin (Citrus unshiu Mar.) juice (MJ). They contain high amounts of β-cryptoxanthin and hesperidin. We have demonstrated that CHRP and/or MJs inhibit chemically induced rat colon, rat tongue, and mouse lung tumorigenesis. Gavage with CHRP resulted in an increase of activities of detoxifying enzymes in the liver, colon, and tongue rats'. CHRP and MJs were also able to suppress the expression of proinflammatory cytokines and inflammatory enzymes in the target tissues. This paper describes the findings of our in vivo preclinical experiments to develop a strategy for cancer chemoprevention of colon, tongue, and lung neoplasms by use of CHRP and MJs.
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Liu QY, Chen DW, Xie LP, Zhang RQ, Wang HZ. Decitabine, independent of apoptosis, exerts its cytotoxic effects on cell growth in melanoma cells. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2011; 32:423-429. [PMID: 22004962 DOI: 10.1016/j.etap.2011.08.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Accepted: 08/14/2011] [Indexed: 05/31/2023]
Abstract
Decitabine is a synthesized cytosine analog that is a potent inhibitor of DNA methylation. There have been a few reports on the in vitro anti-melanoma effect of decitabine or its functional mechanisms. We investigated the anti-proliferation effect of decitabine on the cultured murine melanoma cell line K1735M2. MTT assay showed that decitabine had strong inhibition on melanoma K1735M2 in a time- and dose-dependent manner in vitro. Morphological observation showed that decitabine could induce melanoma K1735M2 cells to produce dendrite-like structures with the increase of decitabine concentration and incubation time. Decitabine could effectively induce K1735M2 cells to differentiate in vitro. Additionally, decitabine could induce a dose-dependent G2/M cell cycle arrest in K1735M2 cells. We provided experimental evidences that the anti-proliferation effect of decitabine on murine K1735M2 melanoma cells was associated predominately with G2/M cell cycle arrest and the induction of differentiation rather than apopotosis.
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Affiliation(s)
- Qian-Ying Liu
- School of Life Science, Tsinghua University, Beijing 100084, China
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16
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Ji Z, Tang Q, Zhang J, Yang Y, Liu Y, Pan Y. Oridonin-induced apoptosis in SW620 human colorectal adenocarcinoma cells. Oncol Lett 2011; 2:1303-1307. [PMID: 22848306 DOI: 10.3892/ol.2011.408] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2011] [Accepted: 08/15/2011] [Indexed: 12/16/2022] Open
Abstract
Oridonin, a diterpenoid isolated from Rabdosia rubescens (Hemsl.) Hara, inhibited the growth of human tumor cell lines SW620 (colon), MCF-7 (breast) and K562 (bone marrow), and induced significant levels of apoptosis in SW620. Morphological changes indicative of cell apoptosis were observed after the cells were exposed to oridonin for 24 h. Growth inhibition was associated with G1 phase arrest, and with time- and dose-dependent increases in caspase-3 activity. We therefore conclude that oridonin inhibits the proliferation of SW620 cells by induction of apoptosis via the activation of caspase-3. Our data suggest that oridonin may have significant potential as an anti-colorectal adenocarcinoma agent.
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Affiliation(s)
- Zhe Ji
- National Engineering Research Center of Edible Fungi; Key Laboratory of Applied Mycological Resources and Utilization, Ministry of Agriculture; Shanghai Key Laboratory of Agricultural Genetics and Breeding; Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, Shanghai 201106
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17
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Fernandes CR, Turatti A, Gouvea DR, Gobbo-Neto L, Diniz A, Ribeiro-Silva A, Lopes NP, Garcia SB. The Protective Role of Lychnophora ericoides Mart. (Brazilian Arnica) in 1,2-Dimethylhydrazine-Induced Experimental Colon Carcinogenesis. Nutr Cancer 2011; 63:593-9. [DOI: 10.1080/01635581.2011.539310] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Affiliation(s)
| | - Aline Turatti
- a Department of Pathology, Ribeirão Preto Medical School , University of São Paulo , Ribeirão Preto, Brazil
| | - Dayana Rubio Gouvea
- b Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences , University of São Paulo , Ribeirão Preto, Brazil
| | - Leonardo Gobbo-Neto
- b Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences , University of São Paulo , Ribeirão Preto, Brazil
| | - Andrea Diniz
- b Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences , University of São Paulo , Ribeirão Preto, Brazil
| | - Alfredo Ribeiro-Silva
- a Department of Pathology, Ribeirão Preto Medical School , University of São Paulo , Ribeirão Preto, Brazil
| | - Norberto Peporine Lopes
- b Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences , University of São Paulo , Ribeirão Preto, Brazil
| | - Sérgio Britto Garcia
- a Department of Pathology, Ribeirão Preto Medical School , University of São Paulo , Ribeirão Preto, Brazil
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18
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Qi F, Li A, Inagaki Y, Kokudo N, Tamura S, Nakata M, Tang W. Antitumor activity of extracts and compounds from the skin of the toad Bufo bufo gargarizans Cantor. Int Immunopharmacol 2010; 11:342-9. [PMID: 21185919 DOI: 10.1016/j.intimp.2010.12.007] [Citation(s) in RCA: 183] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Accepted: 12/10/2010] [Indexed: 11/25/2022]
Abstract
The skin of the toad Bufo bufo gargarizans Cantor is known to be rich in bufadienolides, peptides and alkaloids. It has been found to be a source of some extracts and biologically active compounds with antitumor activity. Cinobufacini (Huachansu), a Chinese medicine prepared from the dried toad skin, has been widely used in clinical therapy for various cancers in China. Bufadienolides, such as bufalin, cinobufagin, resibufogenin, and telocinobufagin, are the major active compounds derived from the toad skin. They are the maker biologically active compounds of cinobufagin while the antitumor activity of cinobufagin may be due to this kind of components. Experimental research has suggested that cinobufacini and its active compounds (e.g. bufalin and cinobufagin) exhibit significant antitumor activity, including inhibition of cell proliferation, induction of cell differentiation, induction of apoptosis, disruption of the cell cycle, inhibition of cancer angiogenesis, reversal of multi-drug resistance, and regulation of the immune response. Clinical data have indicated that cinobufacini may have effective anticancer activity with low toxicity and few side effects. Data to date suggest it may also enhance quality of life for patients with cancer. Thus, this review briefly summarizes recent studies on the anticancer activity of cinobufacini and some of its active compounds from the skin of the toad Bufo bufo gargarizans Cantor. This might provide additional evidence for further study of the extracts and active compounds from the toad skin in cancer treatment.
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Affiliation(s)
- Fanghua Qi
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
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19
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Jeong JB, Jeong HJ. 2-Methoxy-4-vinylphenol can induce cell cycle arrest by blocking the hyper-phosphorylation of retinoblastoma protein in benzo[a]pyrene-treated NIH3T3 cells. Biochem Biophys Res Commun 2010; 400:752-7. [DOI: 10.1016/j.bbrc.2010.08.142] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2010] [Accepted: 08/31/2010] [Indexed: 01/01/2023]
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Prabhu PN, Ashokkumar P, Sudhandiran G. Antioxidative and antiproliferative effects of astaxanthin during the initiation stages of 1,2-dimethyl hydrazine-induced experimental colon carcinogenesis. Fundam Clin Pharmacol 2009; 23:225-34. [PMID: 19645817 DOI: 10.1111/j.1472-8206.2009.00669.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Colon cancer is one of the major causes of cancer mortality worldwide. Several carotenoids with antioxidant properties are reported for their chemopreventive nature. In this study, we have evaluated the chemopreventive efficacy of astaxanthin on lipid peroxidation, antioxidant status, total number of aberrant crypt foci (ACF), and cell proliferation in 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis using a rat model. DMH was induced subcutaneously at a dosage of 40 mg/kg body weight, twice a week for 2 weeks. Astaxanthin was administered before and after the DMH induction, orally at a concentration of 15 mg/kg body weight throughout the experimental period. At the end of 16 weeks, pre-treatment with astaxanthin markedly reduced the degree of histological lesions, ACF development and also lowered the number of argyrophilic nucleolar organizer regions. Our results also showed the decreased levels of colon enzymic and non-enzymic antioxidants and increased levels of lipid peroxidation marker levels in DMH-induced rats, which were significantly reversed on astaxanthin administration. In conclusion, the results of this study suggest that astaxanthin has an affirmative and beneficial effect against chemically induced colonic pre-neoplastic progression in rats induced by DMH.
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Affiliation(s)
- Ponnuraj Nagendra Prabhu
- Department of Biochemistry, University of Madras, Guindy campus, Chennai - 600 025, Tamil Nadu, India
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Lee SJ, Lim KT. Glycine- and proline-rich glycoprotein regulates the balance between cell proliferation and apoptosis for ACF formation in 1,2-dimethylhydrazine-treated A/J mice. Mol Cell Biochem 2009; 325:187-97. [PMID: 19184365 DOI: 10.1007/s11010-009-0033-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2008] [Accepted: 01/15/2009] [Indexed: 12/27/2022]
Abstract
The objective of this study was to investigate the chemopreventive potentials of glycine- and proline-rich glycoprotein (SNL glycoprotein, 150-kDa) isolated from Solanum nigrum Linne on formation of colonic aberrant crypt foci (ACF) induced by 1,2-dimethylhydrazine (DMH, 20 mg/kg) in A/J mice. Administration of SNL glycoprotein inhibited phosphorylation of extracellular signal-regulated kinase (ERK), expression of colonic proliferating cell nuclear antigen (PCNA), and frequency of colonic ACF in DMH-stimulated mice colon carcinogenesis. In addition, SNL glycoprotein increased expression of cyclin-dependent kinase inhibitors (p21(WAF/Cip1) and p27(Kip1)), whereas reduced expression of precursor form of apoptosis-related proteins [pro-caspase-3 and pro-poly(ADP-ribose)polymerase (PARP)] in the mice. Interestingly, the results in this study revealed that SNL glycoprotein has suppressive effects on activity of nuclear factor-kappa B (NF-kappaB), whereas it has stimulatory effect on the expression of p53, accompanying inhibitory effects on expression of NF-kappaBp50, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha in DMH-stimulated ACF formation. Also, SNL glycoprotein has inhibitory effects on the formation of thiobarbituric acid reactive substances (TBARS), on the production of inducible nitric oxide (NO), and on the release of lactate dehydrogenase (LDH) in the mice plasma. Collectively, our findings in this study suggest that SNL glycoprotein has chemopreventive activity via modulation of cell proliferation and apoptosis in DMH-treated A/J mice.
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Affiliation(s)
- Sei-Jung Lee
- Molecular Biochemistry Laboratory, Biotechnology Research Institute, Chonnam National University, 300 Yongbong-Dong, Kwang-ju, 500-757, South Korea
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22
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Lin HH, Li WW, Lee YC, Chu ST. Apoptosis induced by uterine 24p3 protein in endometrial carcinoma cell line. Toxicology 2007; 234:203-15. [PMID: 17420078 DOI: 10.1016/j.tox.2007.02.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2007] [Revised: 02/26/2007] [Accepted: 02/26/2007] [Indexed: 11/16/2022]
Abstract
The biological functions and reaction pathways of lipocalins in mammalian system were sought. Mouse uterine 24p3 protein is a secreted lipocalin from mouse uterus. To evaluate the effect of uterine 24p3 protein on the reproductive system, endometrial carcinoma cell line (RL95-2) was an experimental target for achieving the in vitro study. The cells were treated with 0.75 microM dexamethasone (DEX) or under serum-free medium to mimic the stress environment for various time periods, then employing Western blot to measure the 24p3 protein secretion. It showed the time-dependent induction effect on 24p3 protein and suggested the level of protein secretion correlating to environmental stress. Furthermore, the supplementation of 24p3 protein to the medium accompanied the reduction of cell viability. It showed that the 24p3 protein may be a death factor under conditional media via PI and annexinV-FITC assay. Based on the autocrine hypothesis, we investigated the effect of 24p3 protein on cultured RL95-2 cells upon the 24p3 protein interaction. We have demonstrated significant increase in intracellular reactive oxygen species upon 24p3 protein interaction. While the changes of mitochondrial membrane potential and cytochrome c release from mitochondria occurred, the activities of caspase-8, -9 and -3 were found to have increased. The condensation of DNA was occurred suggesting that 24p3 protein induced irreparable DNA damage, which in turn triggered the process of apoptosis. It shows evidence for the direct effect of this protein on endometrial cells. These findings suggest that 24p3 protein creates an intracellular oxidative environment that induces apoptosis in RL95-2 cells.
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Affiliation(s)
- Hsiu Hsia Lin
- Institute of Biochemical Science, College of Life Science, National Taiwan University, Taipei, Taiwan
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Katsuki T, Hirata K, Ishikawa H, Matsuura N, Sumi SI, Itoh H. Aged garlic extract has chemopreventative effects on 1,2-dimethylhydrazine-induced colon tumors in rats. J Nutr 2006; 136:847S-851S. [PMID: 16484578 DOI: 10.1093/jn/136.3.847s] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Garlic has been reported to have chemopreventive effects against a variety of cancers. However, different garlic preparations contain different constituents. We investigated the chemopreventive effect of aged garlic extract (AGE), an odorless product from prolonged extraction of fresh garlic, on colon carcinogenesis and cell proliferation in 1,2-dimethylhydrazine (DMH)-induced colon neoplastic rats. Rats were given weekly subcutaneous injections of DMH (20 mg/kg) for 20 wk, and fed either a basal diet or one containing 4% AGE. Serum from AGE-treated rats contained detectable S-allylcysteine. The AGE diet significantly reduced the number of colon tumors and aberrant crypt foci compared to the basal diet. Cell proliferation of normal-appearing colonic mucosa was assessed by MIB-5 immunohistochemistry. AGE treatment significantly decreased the mean MIB-5-labeling index. These findings suggest AGE has a chemopreventive effect on colon carcinogenesis through suppression of cell proliferation.
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Affiliation(s)
- Takefumi Katsuki
- Department of Surgery 1, University of Occupational and Environmental Health, Kitakyushu, Japan
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24
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Ren KK, Wang HZ, Xie LP, Chen DW, Liu X, Sun J, Nie YC, Zhang RQ. The effects of oridonin on cell growth, cell cycle, cell migration and differentiation in melanoma cells. JOURNAL OF ETHNOPHARMACOLOGY 2006; 103:176-80. [PMID: 16169170 DOI: 10.1016/j.jep.2005.07.020] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2004] [Revised: 07/24/2005] [Accepted: 07/27/2005] [Indexed: 05/04/2023]
Abstract
Oridonin, a diterpenoid isolated from Rabdosia rubescens (Hemsl.) Hara, is currently one of the most important traditional Chinese herbal medicines. We investigated the anti-proliferation effect of oridonin on the cultured murine melanoma cell line K1735M2. The growth inhibition activity of oridonin for K1735M2 cells occurred in a time- and dose-dependent manner (IC50 was 7.4+/-0.6 microM). Further studies showed that these inhibition effects were associated with dose-dependent G2/M phase arrest and differentiation induction. Detection of morphological observation showed that oridonin could induce K1735M2 cells to produce dendrite-like structures. The results of the migration indicated that oridonin affected motility of K1735M2 cells in a dose-dependent manner. These results suggested that oridonin is a potential candidate for melanoma cancer therapy.
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Affiliation(s)
- Kui-Kui Ren
- Department of Biological Science and Biotechnology, Tsinghua University, Beijing 100084, China
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Sugie S, Vinh PQ, Rahman KMW, Ushida J, Kohno H, Suzuki R, Hara A, Quang LB, Tanaka T, Mori H. Suppressive effect of 1,4-phenylene diisothiocyanate on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice. Int J Cancer 2005; 117:524-30. [PMID: 15929075 DOI: 10.1002/ijc.21233] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The modifying effects of dietary administration of 1,4-phenylene diisothiocyanate (DITC) on N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced urinary bladder carcinogenesis during the initiation and post-initiation phases were examined in male ICR mice. Five-week-old animals were divided into 5 groups. Groups 1-3 were given BBN (500 ppm) in drinking water for 6 weeks starting at age 6 week. Mice in Group 2 were given the diet containing 100 ppm DITC for 8 weeks during the initiation phase, starting 1 week before BBN exposure. Animals in Group 3 were fed the experimental diet for 24 weeks during the post-initiation phase starting 1 week after the cessation of BBN exposure. Mice in Group 4 were given only the diet containing the test compound, and those in Group 5 were given the basal diet alone throughout the experiment (32 weeks). The frequency of bladder lesions, neoplasms, dysplasia and hyperplasia, was analyzed histopathologically. The cell-proliferation activity estimated by the 5-bromodeoxyuridine labeling index (BrdU-LI), and cell cycle progression by counting cyclin D1-positive cell ratios were compared among the groups using immunohistochemistry. Administration of DITC in the initiation phase reduced significantly the incidence of urinary bladder carcinoma and dysplasia. The frequencies of any lesions of urinary bladder were not reduced by DITC in post-initiation phase. Dietary exposure of this agent in initiation phase reduced significantly both BrdU-LI and cyclin D1-positive cell ratios in any bladder lesions. Administration of DITC in post-initiation phase also significantly reduced BrdU-LI in bladder neoplasms and hyperplasia and cyclin D1-positive cell ratios in urinary bladder carcinoma as well as dysplasia. These results suggest that dietary DITC could be a preventive agent against BBN-induced bladder carcinogenesis in mice when fed during the initiation phase.
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Affiliation(s)
- Shigeyuki Sugie
- Department of Pathology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
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Yoshida K, Tanaka T, Hirose Y, Yamaguchi F, Kohno H, Toida M, Hara A, Sugie S, Shibata T, Mori H. Dietary garcinol inhibits 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in rats. Cancer Lett 2005; 221:29-39. [PMID: 15797624 DOI: 10.1016/j.canlet.2004.08.016] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2004] [Revised: 08/02/2004] [Accepted: 08/09/2004] [Indexed: 11/22/2022]
Abstract
The effects of dietary feeding with a polyisoprenylated benzophenone, garcinol, isolated from Garcinia indica fruit rind on the development of 4-nitroquinoline 1-oxide (4-NQO)-induced oral carcinogenesis were investigated in male F344 rats. At 7 weeks of age, animals were given 4-NQO at 20 ppm in the drinking water for 8 weeks to induce tongue neoplasms. They also received the diets containing 100 or 500 ppm garcinol either during (for 10 weeks) or after (for 22 weeks) the carcinogen exposure. The other rats were given tap water without 4-NQO throughout the experiment, and fed garcinol (500 ppm)-containing diet or basal diet alone. At the end of the study (week 32), incidences of tongue neoplasms and preneoplastic lesions, cell proliferation activity in the normal-like tongue epithelium estimated by 5-bromodeoxyurideine (BrdU)-labeling index and cyclin D1-positive cell ratio, and immunohistochemical expression of cyclooxygenase-2 (COX-2) in the tongue lesions were determined. Dietary garcinol significantly decreased the incidence and multiplicity of 4-NQO-induced tongue neoplasms and/or preneoplasms as compared to the control diet. Dietary administration of garcinol also significantly reduced the BrdU-labeling index and cyclin D1-positive cell ratio, suggesting reduction in cell proliferation activity in the tongue by garcinol. The COX-2 expression in the tongue lesions was also suppressed by feeding with garcinol. These results indicate that dietary administration of garcinol inhibited 4-NQO-induced tongue carcinogenesis through suppression of increased cell proliferation activity in the target tissues and/or COX-2 expression in the tongue lesions.
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Affiliation(s)
- Koujiro Yoshida
- Department of Oral and Maxillofacial Surgery, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan
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Sakata K, Hara A, Hirose Y, Yamada Y, Kuno T, Katayama M, Yoshida K, Zheng Q, Murakami A, Ohigashi H, Ikemoto K, Koshimizu K, Tanaka T, Mori H. Dietary supplementation of the citrus antioxidant auraptene inhibits N,N-diethylnitrosamine-induced rat hepatocarcinogenesis. Oncology 2004; 66:244-52. [PMID: 15218316 DOI: 10.1159/000078001] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2003] [Accepted: 09/04/2003] [Indexed: 11/19/2022]
Abstract
OBJECTIVES We have previously reported that an antioxidant, auraptene (AUR), isolated from citrus fruit effectively inhibits chemically induced carcinogenesis in digestive tracts, such as the oral cavity, esophagus and large bowel. In this study, we investigated the modifying effects of dietary supplementation with AUR on N,N-diethylnitrosamine (DEN)-initiated hepatocarcinogenesis in male F344 rats in two different experiments to determine whether the compound exerts a cancer-chemopreventive action in other organs. METHODS In the first experiment, animals were fed diets containing AUR at dose levels of 100 and 500 ppm for 7 weeks 1 week before, during, and 1 week after the start of liver carcinogenesis induced by DEN (40 ppm in drinking water for 5 weeks) to predict the modulatory effect on hepatocarcinogenesis. After 7 weeks, the numbers of hepatocellular enzyme-altered foci (EAF; cm(2)) which stained positive for the placental form of glutathione S-transferase (GST-P) and transforming growth factor (TGF)-alpha were determined on immunohistochemically stained sections. In the second experiment conducted to confirm the findings, animals subjected to DEN treatment were fed AUR-containing diets (100 and 500 ppm) during either the initiation stage ('initiation' feeding for 7 weeks) or post-initiation phase ('post-initiation' feeding for 25 weeks) of DEN-induced hepatocarcinogenesis. RESULTS In the first experiment, feeding with AUR at both doses during DEN exposure decreased the mean numbers of GST-P-positive and TGF-alpha-positive EAF/cm(2), and the reduction in the number of TGF-alpha-positive EAF by feeding 500 ppm AUR was statistically significant (p < 0.005). In the second experiment, the 'initiation' feeding with 500 ppm AUR significantly inhibited the incidence (33 vs. 83%, p = 0.000511) and multiplicity (0.67 +/- 1.09 vs. 1.96 +/- 1.85, p < 0.005) of liver cell carcinoma. Also, the 'post-initiation' feeding with AUR at both doses significantly reduced the development of hepatocellular carcinoma (100 ppm: incidence, 15%, p = 0.000006; multiplicity: 0.25 +/- 0.64, p < 0.001; 500 ppm: incidence, 11%, p = 0.000002; multiplicity, 0.26 +/- 0.81, p < 0.001). In addition, AUR feeding reduced cell proliferation and the apoptotic index in liver cell neoplasms. CONCLUSIONS The results suggest that the citrus antioxidant AUR is a potential chemopreventive agent against DEN-induced hepatocarcinogenesis in rats.
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Affiliation(s)
- Keiko Sakata
- Department of Pathology, Gifu University School of Medicine, Gifu, Japan.
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Roncalés M, Achón M, Manzarbeitia F, Maestro de las Casas C, Ramírez C, Varela-Moreiras G, Pérez-Miguelsanz J. Folic acid supplementation for 4 weeks affects liver morphology in aged rats. J Nutr 2004; 134:1130-3. [PMID: 15113958 DOI: 10.1093/jn/134.5.1130] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Several countries have approved universal folic acid (FA) fortification to prevent neural tube defects and/or high homocysteine levels; this has led to a chronic intake of FA. Traditionally, the vitamin is considered to be safe and nontoxic, except for the potential masking of vitamin B-12 deficiency. Recent reports from our laboratories showed several effects of high-dose folate supplementation in rats. In this work, we compared the effect of FA on the liver of weanling (3 wk) and aged (18 mo) male rats fed either a diet supplemented with 40 mg FA/kg diet or a control diet (1 mg FA/kg diet) for 4 wk. FA supplementation did not alter serum aspartate aminotransferase, alanine aminotransferase, urea, glucose oxidase, total bilirubin, or uric acid. Routine histological staining as well as immunohistochemistry with proliferating cell nuclear antibody for dividing cells, and cytokeratin-8 against bile ductal cells, showed that aged, supplemented rats had the same number of hepatocytes as both control and supplemented weanling rats, and tended to have more (17%, P = 0.07) hepatocytes than aged, control rats. Moreover, the bile duct cells of aged, control rats proliferated and transformed into cholestatic rosettes at a higher frequency than in aged, supplemented rats. The morphology of the liver in weanling rats was similar in both diet groups, and comparable to the supplemented, aged rats, thus indicating that a high intake of FA improves normal liver morphology in livers of aged rats.
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Affiliation(s)
- María Roncalés
- Departamento Anatomía y Embriología Humana I. Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain
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Kohno H, Suzuki R, Sugie S, Tsuda H, Tanaka T. Lack of modifying effects of 4-ter t-octylphenol and benzyl butyl phthalate on 3,2-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in rats. Cancer Sci 2004; 95:300-5. [PMID: 15072586 PMCID: PMC11158560 DOI: 10.1111/j.1349-7006.2004.tb03206.x] [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] [Received: 12/18/2003] [Revised: 02/05/2004] [Accepted: 02/06/2004] [Indexed: 11/30/2022] Open
Abstract
The modifying effects of dietary feeding of two estrogenic compounds, 4-tert-octylphenol (tOP) and benzyl butyl phthalate (BBP), on 3,2-dimethyl-4-aminobiphenol (DMAB)-induced prostatic carcinogenesis were investigated in male F344 rats. We also assessed the effects of the test compounds on the proliferating cell nuclear antigen (PCNA) index in induced neoplasms, prostatic intra-epithelial neoplasm (PIN), and non-lesional glands in the prostate. To induce prostatic neoplasms, rats were given subcutaneous injections of DMAB (25 mg/kg body weight) every other week, 10 times in total. They also received the experimental diet containing 10 or 100 ppm tOP and BBP for 40 weeks, starting 1 week after the last dosing of DMAB. DMAB exposure produced prostatic adenocarcinoma with an incidence of 41.2% at the end of the study (week 60). Dietary administration of tOP and BBP did not affect the incidence of prostatic adenocarcinoma: 43.8% in the DMAB --> 10 ppm tOP group; 25.0% in the DMAB --> 100 ppm tOP group; 43.8% in the DMAB --> 10 ppm BBP group; and 43.8% in the DMAB --> 100 ppm BBP group. The PCNA indices in adenocarcinomas, PIN, and non-lesional glands in rats treated with DMAB and tOP or BBP were slightly lower than that of the DMAB alone group, but the differences were not statistically significant. These results might suggest that dietary feeding of the estrogenic compounds tOP and BBP did not modulate DMAB-induced prostatic carcinogenesis in rats.
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Affiliation(s)
- Hiroyuki Kohno
- Department of Pathology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
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Davies RJ, Scott IS, Morris LS, Rushbrook SM, Bird K, Vowler SL, Arends M, Miller R, Coleman N. Increased expression of minichromosome maintenance protein 2 in active inflammatory bowel disease. Colorectal Dis 2004; 6:103-110. [PMID: 15008907 DOI: 10.1111/j.1463-1318.2004.00567.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Minichromosome maintenance protein 2 (Mcm2) is an accurate indicator of cell cycle entry in tissue samples, but its expression in inflammatory bowel disease (IBD) has not previously been investigated. We have used immunohistochemistry to assess the expression of Mcm2, in comparison to the existing proliferation marker Ki-67, in active IBD and IBD without inflammatory activity. MATERIALS AND METHODS For this experimental study, sections from colonic biopsy and resection specimens of 48 patients with IBD (5 inactive/quiescent Crohn's disease (CD), 13 active CD, 19 inactive/quiescent ulcerative colitis (UC) and 11 active UC) and 15 normal controls were immunostained with antibodies to Mcm2 and Ki-67. The percentage of immunopositive epithelial nuclei was determined by calculating a labelling index (LI) for entire glands and for gland thirds (superficial, middle and basal). RESULTS The Mcm2 LI was significantly increased in the superficial third of glands in active vs. inactive/quiescent UC (P < 0.0001) and active vs. inactive/quiescent CD (P = 0.001). The Mcm2 LI was significantly greater than the Ki-67 LI in active IBD, both in entire glands (P < 0.0001) and in the superficial third of glands (UC, P = 0.001; CD, P = 0.0002). Mcm2 LIs for entire glands were significantly higher in UC (all cases) compared to CD (all cases) (P = 0.032). CONCLUSIONS There is increased cell cycle entry, as indicated by expression of Mcm2 and to a lesser extent Ki-67, in the superficial third of colonic glands in active IBD compared to inactive/quiescent IBD. Detection of Mcm2 may contribute to improved histological assessment of small tissue biopsies and may enable the development of a direct stool-based test for detection of active IBD and potentially for assessment of disease activity.
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Affiliation(s)
- R J Davies
- Department of General Surgery, Addenbrooke's Hospital MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK
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Yoshida K, Hirose Y, Tanaka T, Yamada Y, Kuno T, Kohno H, Katayama M, Qiao Z, Sakata K, Sugie S, Shibata T, Mori H. Inhibitory effects of troglitazone, a peroxisome proliferator-activated receptor gamma ligand, in rat tongue carcinogenesis initiated with 4-nitroquinoline 1-oxide. Cancer Sci 2003; 94:365-71. [PMID: 12824906 PMCID: PMC11160187 DOI: 10.1111/j.1349-7006.2003.tb01448.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2002] [Revised: 01/20/2003] [Accepted: 01/23/2003] [Indexed: 12/12/2022] Open
Abstract
Ligands for peroxisome proliferator-activated receptor (PPAR) gamma have been implicated in growth inhibition and cell differentiation in certain malignancies. In this study, the effects of troglitazone, a PPAR gamma ligand, given during the postinitiation phase of oral carcinogenesis initiated with 4-nitroquinoline 1-oxide (4-NQO) were investigated in male F344 rats. Rats aged 6 weeks were given 4-NQO at 20 ppm for 8 weeks to induce tongue neoplasms. Starting 1 week after the cessation of 4-NQO exposure, animals were fed diets containing 0, 30 or 100 ppm troglitazone for 22 weeks. At the end of the study (week 32), the incidences of 4-NQO-induced tongue neoplasms and preneoplasms were determined histopathologically and cell proliferation activity was estimated by counting bromodeoxyuridine (BrdU)-labeling indices and cyclin D1-positive cell ratios. In addition, immunohistochemical expression of cyclooxygenase (COX)-2 and PPAR gamma was assessed in the tongue lesions. Feeding with 100 ppm troglitazone significantly decreased the incidence of squamous cell carcinoma when compared to the group without troglitazone treatment (5.0% vs. 45.8%, P < 0.005). Interestingly, the BrdU-labeling index and cyclin D1-positive cell ratio assessed in the non-lesional tongue squamous epithelium were reduced by dietary administration of troglitazone (P < 0.0001-0.005). Additionally, the immunoreactivity of COX-2 in the tongue lesions was also decreased by the treatment (P < 0.01-0.05). These results clearly showed that dietary troglitazone inhibits 4-NQO-induced tongue carcinogenesis and such inhibition is related to suppression of increased cell proliferation and/or COX-2 expression. This study warrants further investigation on the use of PPAR gamma ligands as a novel preventive approach for oral malignancy.
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Affiliation(s)
- Koujiro Yoshida
- Department of Tumor Pathology, Gifu University School of Medicine, Gifu 500-8705, Japan.
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Kohno H, Maeda M, Tanino M, Tsukio Y, Ueda N, Wada K, Sugie S, Mori H, Tanaka T. A bitter diterpenoid furanolactone columbin from Calumbae Radix inhibits azoxymethane-induced rat colon carcinogenesis. Cancer Lett 2002; 183:131-9. [PMID: 12065087 DOI: 10.1016/s0304-3835(02)00159-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The modifying effect of dietary administration of a diterpenoid furanolactone columbin isolated from the crude drug Calumbae Radix (the root of Jateorhiza columba MIERS, Menispermacea) on azoxymethane (AOM)-induced was investigated in male F344 rats. Animals were initiated with AOM (three weekly subcutaneous injections of 15 mg/kg body weight) to induce colonic neoplasms. They were fed the experimental diets mixed with columbin (4, 20, and 100 ppm) for 4 weeks, starting 1 week before the first dosing of AOM and thereafter maintained on the basal diet without columbin. Additional experimental groups included the AOM alone group, the columbin alone group (100 ppm in diet for 4 weeks), and the untreated control group. Dietary feeding of columbin (4, 20, and 100 ppm) during the initiation phase of AOM-induced colon carcinogenesis reduced the incidence and multiplicity of colonic adenocarcinoma and the inhibition by feeding of 20 ppm (incidence: 20%, P=0.0242 and multiplicity: 0.20+/-0.40, P<0.02) and 100 ppm (incidence: 10%, P=0.0029 and multiplicity: 0.10+/-0.30, P<0.002) columbin was significant when compared with the AOM alone group (incidence: 55% and multiplicity: 0.55+/-0.50). Also, columbin administration in diet lowered the number of argyrophilic nucleolar organizer regions protein per nucleus in non-lesional colonic crypts and the blood polyamine content, which are reflected in cell proliferation activity. These results indicate chemopreventive ability of dietary columbin against chemically induced colon tumorigenesis when fed during the initiation phase, providing a scientific basis for chemopreventive ability of columbin against human colon cancer.
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Affiliation(s)
- Hiroyuki Kohno
- Department of Pathology, Kanazawa Medical University, Uchinada, 920-0293, Ishikawa, Japan
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Tanaka T, Kohno H, Sakata K, Yamada Y, Hirose Y, Sugie S, Mori H. Modifying effects of dietary capsaicin and rotenone on 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis. Carcinogenesis 2002; 23:1361-7. [PMID: 12151355 DOI: 10.1093/carcin/23.8.1361] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The effects of dietary administration of capsaicin and rotenone on 4-nitroquinoline 1-oxide (4-NQO)-induced tongue tumorigenesis were investigated in male F344 rats. In pilot studies, gavage with capsaicin and rotenone elevated the phase II enzymes glutathione S-transferase (GST) and quinone reductase (QR), in the liver and tongue. Also, a 10 week period of feeding of 500 p.p.m. capsaicin or rotenone together with 4-NQO exposure inhibited the occurrence of tongue dysplasia. Subsequently, a long-term study was conducted to test the protective effects of both compounds on 4-NQO-induced tongue carcinogenesis. One group was treated with 4-NQO alone (20 p.p.m. in drinking water for 8 weeks) and four other groups received the carcinogen treatment plus diets containing 500 p.p.m. test compounds for 10 weeks (initiation phase) or for 28 weeks (post-initiation phase). At the termination of the study (38 weeks), feeding of rotenone during the initiation phase, but not during the post-initiation phase, was found to significantly reduce the incidence of tongue squamous cell carcinoma (53% vs. 16%, 70% reduction, P b=e 0.0250) and severe dysplasia (80% vs. 42%, 70% reduction, P = 0.028). Capsaicin feeding during either the initiation or promotion phase and rotenone feeding during the promotion phase also reduced the frequency of tongue carcinoma without statistical significance. The treatment with two compounds especially rotenone lowered cell proliferation activity in the tongue, elevated phase II enzymes' activities of the liver and tongue, and increased the apoptotic index of tongue carcinoma. Although our results suggest that rotenone feeding during the initiation stage prevented 4-NQO-induced tongue carcinoma, chronic intravenous exposure of rotenone reproduces several features of human Parkinson's disease in rats (Nat. Neurosci., 3, 1301-1306, 2000), suggesting that additional studies to confirm the safety of rotenone are warranted.
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Affiliation(s)
- Takuji Tanaka
- Department of Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, Japan.
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Abstract
Many epidemiologic, animal and human studies suggest that folate status modulates carcinogenesis. Although these observations have been made in a number of tissues, the data are clearly most compelling for the colorectum. The mechanism(s) by which this modulation is mediated remains ill defined. Alterations in either genome-wide or gene-specific DNA methylation and/or alterations in DNA stability, resulting from DNA strand breaks or uracil misincorporation, are leading candidates in this regard. Folate has a central role in biological methylation and nucleotide synthesis, and therefore it is not surprising that folate depletion has been observed to alter DNA methylation and diminish DNA stability. The hypothesis that these two pathways are the means by which folate modulates cancer risk is also supported by the epidemiological observation that a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) gene differentially affects the relative risk of colon cancer depending on folate status, because MTHFR catalyzes the reaction that determines whether cellular folate is diverted into biological methylation or nucleotide synthesis. This phenomenon suggests that it is an imbalance between biological methylation and nucleotide synthesis that is responsible for folate-related carcinogenesis. The control of cell proliferation, which also is related to DNA methylation, is another candidate mechanism by which folate status modulates carcinogenesis. In cell culture studies, folate supplementation has been observed to suppress excessive cell proliferation. Understanding the mechanisms by which folate status modulates carcinogenesis is important for advancing insight into cancer biology and for facilitating those efforts to translate research in folate and carcinogenesis into effective and safe public health initiatives.
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Affiliation(s)
- Sang-Woon Choi
- Vitamin Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA
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Kohno H, Tsukio Y, Yanaida Y, Tanino M, Tanaka T. Lack of modifying effects of 4-n-octylphenol on 3,2'-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in rats. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2002; 51:210-215. [PMID: 11971643 DOI: 10.1006/eesa.2002.2132] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
The modifying effects of dietary feeding of an estrogenic compound 4-n-octylphenol on 3,2'-dimethyl-4-aminobiphenyl (DMAB) induced prostatic carcinogenesis were investigated in male F344 rats. The authors also assessed the effects of test compound on proliferating cell nuclear antigen (PCNA) index in induced neoplasms, hyperplastic lesions, and nonlesional glands in the prostrate. Rats were given intraperitoneal injections of DMAB (25 mg/kg body wt) every other week, 10 times, to induce prostatic neoplasms. They also received the experimental diet containing 10 or 100 ppm 4-n-octylphenol for 20 weeks, starting one week after the last dosing of DMAB. DMAB exposure produced prostatic adenocarcinoma with an incidence of 21% at the end of the study (Week 39). Dietary administration of 4-n-octylphenol did not affect the incidence of prostatic adenocarcinoma: 17% in DMAB-->10 ppm 4-n-octylphenol group; and 12% in DMAB-->100 ppm 4-n-octylphenol group. The PCNA indices in adenocarcinomas, hyperplastic lesions, and nonlesional glands in rats treated with DMAB and 4-n-octylphenol were slightly lower than that of the DMAB alone group, but the differences were not statistically significant. These results might suggest that dietary feeding of the weak estrogenic compound 4-n-octylphenol did not have modulating effects on DMAB-induced rat prostatic carcinogenesis.
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Affiliation(s)
- Hiroyuki Kohno
- Department of Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan
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Vinh PQ, Sugie S, Tanaka T, Hara A, Yamada Y, Katayama M, Deguchi T, Mori H. Chemopreventive effects of a flavonoid antioxidant silymarin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice. Jpn J Cancer Res 2002; 93:42-9. [PMID: 11802807 PMCID: PMC5926872 DOI: 10.1111/j.1349-7006.2002.tb01199.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The modifying effects of dietary administration of a flavonoid antioxidant, silymarin, a mixture of three flavonoids isolated from milk thistle seeds, on N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder carcinogenesis were examined in male ICR mice. Animals were divided into 5 groups, and groups 1 to 3 were given OH-BBN (500 ppm) in drinking water for 6 weeks. Mice in group 2 were fed a diet containing 1000 ppm silymarin for 8 weeks during the initiation phase starting 1 week before OH-BBN exposure, and mice in group 3 were fed the diet for 24 weeks during the postinitiation phase. Animals in group 4 were given only the test compound, and those in group 5 were given the basal diet alone throughout the experiment. Animals were sacrificed at the end of week 32. The frequency of bladder lesions, cell proliferation and cell cycle progression activity estimated in terms of the 5-bromodeoxyuridine (BrdU) labeling index or cyclin D1-positive cell ratio were compared among the groups. Administration of silymarin in the initiation or postinitiation phase significantly decreased the incidences of bladder neoplasms and preneoplastic lesions. Dietary exposure to this agent significantly reduced the labeling index for BrdU and the cyclin D1-positive cell ratio in various bladder lesions. These findings suggest that silymarin is effective in preventing OH-BBN-induced bladder carcinogenesis in mice.
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Affiliation(s)
- Pham Quang Vinh
- Department of Urology, Gifu University School of Medicine, Gifu 500-8705, Japan.
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Mori H, Niwa K, Zheng Q, Yamada Y, Sakata K, Yoshimi N. Cell proliferation in cancer prevention; effects of preventive agents on estrogen-related endometrial carcinogenesis model and on an in vitro model in human colorectal cells. Mutat Res 2001; 480-481:201-7. [PMID: 11506814 DOI: 10.1016/s0027-5107(01)00200-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Proto-oncogenes such as c-fos, c-jun and c-myc are known to relate to cell proliferation and differentiation. Some oriental herbal medicines like Glycyrrhizae radix or Juzen-taiho-to were found to suppress estradiol-17 beta (E2)-induced expression of c-fos/jun in uterine corpus and inhibited N-methyl-N-nitrosourea and E2-induced endometrial carcinogenesis in mice. It is suggested that the effects of such oriental drugs are exerted probably through suppression of estrogen-induced c-fos/jun expression and they are promising preventing agents for endometrial cancers. In the combined in vitro assay for cell proliferation (MTS assay) and apoptosis (DNA fragmentation) in human colorectal cancer cells (Colo 320), a number of naturally occurring chemopreventive agents such as curcumin, quercetin, auraptene, 1'-acetoxychavicol acetate (ACA) and indole-3-carbinol were shown to generate apoptosis as well as to inhibit cell proliferation. The results suggest a mode of action of these chemopreventive agents and also imply that such in vitro short term assay is useful for detection of new agents for cancer prevention.
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Affiliation(s)
- H Mori
- Department of Pathology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan.
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Choi SW, Friso S. Is it worthwhile to try different coenzymatic forms of folate in future chemoprevention trials? Nutrition 2001; 17:738-9. [PMID: 11527666 DOI: 10.1016/s0899-9007(01)00619-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Watanabe T, Sugie S, Okamoto K, Rahman KM, Ushida J, Mori H. Chemopreventive effects of scordinin on diethylnitrosamine and phenobarbital-induced hepatocarcinogenesis in male F344 rats. Jpn J Cancer Res 2001; 92:603-9. [PMID: 11429047 PMCID: PMC5926765 DOI: 10.1111/j.1349-7006.2001.tb01137.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Modifying effects of scordinin, a biological active component in garlic, on diethylnitrosamine (DEN)- and phenobarbital (PB)-induced hepatocarcinogenesis were examined in rats. Male F344 rats, 5 weeks old, were divided into 8 groups. After a week, groups 1 - 5 were given DEN (100 mg / kg body weight, i.p.) once a week for 3 weeks, whereas groups 6 - 8 received vehicle treatment. Group 2 was given 600 ppm scordinin-containing diet in the initiation phase. From 4 weeks after the start of experiment, groups 3 and 5 were fed scordinin, and groups 1 - 3 and 7 received drinking water containing 500 ppm PB. Group 6 was given scordinin diet alone throughout the experiment (24 weeks). The incidences of hepatocellular adenoma and carcinoma were significantly smaller in group 3 than those in group 1 (P < 0.005 and P < 0.05, respectively). The average numbers of liver neoplasms in groups 2 and 3 were significantly smaller than in group 1 (P < 0.01 and P < 0.0001, respectively). Glutathione S-transferase placental form-positive foci were also significantly decreased by scordinin treatment in the initiation or promotion phase. Scordinin significantly decreased the mean number of nucleolar organizer regions' protein (AgNORs) / nucleus in hepatocellular adenoma and carcinoma. AgNORs / nucleus in the non-lesional area was also significantly decreased by scordinin treatment during the promotion phase. These results suggest that scordinin is a promising chemopreventive agent for liver neoplasia.
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Affiliation(s)
- T Watanabe
- Department of Pathology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan
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40
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Kohno H, Yoshitani S, Takashima S, Okumura A, Hosokawa M, Yamaguchi N, Tanaka T. Troglitazone, a ligand for peroxisome proliferator-activated receptor gamma, inhibits chemically-induced aberrant crypt foci in rats. Jpn J Cancer Res 2001; 92:396-403. [PMID: 11346461 PMCID: PMC5926733 DOI: 10.1111/j.1349-7006.2001.tb01108.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
The biological roles of peroxisome proliferator-activated receptors (PPARs) in various diseases, including inflammation and cancer, have been highlighted recently. Although PPARgamma ligand is suspected to play an important role in carcinogenesis, its effects on colon tumorigenesis remain undetermined. The present time-course study was conducted to investigate possible modifying effects of a PPARgamma ligand, troglitazone, on the development and growth of aberrant crypt foci (ACF), putative precursor lesions for colon carcinoma, induced by azoxymethane (AOM) or dextran sodium sulfate (DSS) in male F344 rats. Oral troglitazone (10 or 30 mg / kg body weight (b.w.)) significantly reduced AOM (two weekly subcutaneous injections, 20 mg / kg b.w.)-induced ACF. Treatment with troglitazone increased apoptosis and decreased polyamine content and ornithine decarboxylase (ODC) activity in the colonic mucosa of rats treated with AOM. Gastric gavage of troglitazone also inhibited colitis and ACF induced by DSS (1% in drinking water), in conjunction with increased apoptosis and reduced colonic mucosal polyamine level and ODC activity. Our results suggest that troglitazone, a synthetic PPARgamma ligand, can inhibit the early stage of colon tumorigenesis with or without colitis.
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Affiliation(s)
- H Kohno
- Department of Pathology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
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41
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Pae HO, Seo WG, Shin M, Lee HS, Lee HS, Kim SB, Chung HT. Heat shock treatment protects human HL-60 cells from apoptosis induced by lectin II isolated from Korean mistletoe, Visum album var. Coloratum. Immunopharmacol Immunotoxicol 2000; 22:237-52. [PMID: 10952029 DOI: 10.3109/08923970009016418] [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: 11/13/2022]
Abstract
Mistletoe lectin II (ML II) isolated from Korean mistletoe (Viscum album var. Coloratum), an effective therapeutic agent for cancers, is known to induce cell death via apoptosis. In the present study, we found the protective effect of heat shock treatment of human leukemia HL-60 cells against ML II-induced apoptosis. Exposure of HL-60 cells to ML II for 4 h resulted in apoptosis of the cells, which was evaluated by examining "DNA ladder" formation and DNA fragmentation assay. The DNA fragmentation was significantly reduced in the cells subjected to heat shock treatment by incubation at 42 degrees C for 1 h and subsequently allowed to recover for 2-16 h at 37 degrees C, prior to exposure to ML II. HL-60 cells transfected with heat shock protein (hsp) 70 gene exhibited resistance to ML II-induced apoptosis very similar to that seen when untransfected cells were heat-shocked. These results indicate that ML II-induced apoptosis in HL-60 cells is inhibited by heat shock treatment, at least in part, via a hsp 70-mediated mechanism.
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Affiliation(s)
- H O Pae
- Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, Chonbug, Korea
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42
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Mori H, Kawabata K, Matsunaga K, Ushida J, Fujii K, Hara A, Tanaka T, Murai H. Chemopreventive effects of coffee bean and rice constituents on colorectal carcinogenesis. Biofactors 2000; 12:101-5. [PMID: 11216469 DOI: 10.1002/biof.5520120116] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Polyphenolic compound chlorogenic acid (CGA) known to be much contained in coffee beans was found to have a regressive effect on induced aberrant crypt foci (ACF) as well as on development of ACF in azoxymethane (AOM)-induced colorectal carcinogenesis in rats. Rice germ and gamma-aminobutyric acid-enriched defatted rice germ inhibited AOM-induced ACF formation and colorectal carcinogenesis in rats. Ferulic acid (FA) also known to be contained in coffee beans and rice prevented AOM-induced ACF formation and intestinal carcinogenesis in rats. Both of food factors, coffee and rice may be of benefit to prevention of human colorectal cancers.
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Affiliation(s)
- H Mori
- Department of Pathology, Gifu University School of Medicine, Japan
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