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Hachiya K, Masuya M, Kuroda N, Yoneda M, Nishimura K, Shiotani T, Tawara I, Katayama N. Pravastatin prevents colitis-associated carcinogenesis by reducing CX3CR1 high M2-like fibrocyte counts in the inflamed colon. Sci Rep 2024; 14:23021. [PMID: 39362935 PMCID: PMC11449942 DOI: 10.1038/s41598-024-74215-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 09/24/2024] [Indexed: 10/05/2024] Open
Abstract
Colorectal cancer (CRC) resulting from chronic inflammation is a crucial issue in patients with inflammatory bowel disease (IBD). Although many reports established that intestinal resident CX3CR1high macrophages play an essential role in suppressing intestinal inflammation, their function in colitis-related CRC remains unclear. In this study, we found that colonic CX3CR1high macrophages, which were positive for MHC-II, F4/80 and CD319, promoted colitis-associated CRC. They highly expressed Col1a1, Tgfb, II10, and II4, and were considered to be fibrocytes with an immunosuppressive M2-like phenotype. CX3CR1 deficiency led to reductions in the absolute numbers of CX3CR1high fibrocytes through increased apoptosis, thereby preventing the development of colitis-associated CRC. We next focused statins as drugs targeting CX3CR1high fibrocytes. Statins have been actively discussed for patients with IBD and reported to suppress the CX3CL1/CX3CR1 axis. Statin treatment after azoxymethane/dextran sulfate sodium-induced inflammation reduced CX3CR1high fibrocyte counts and suppressed colitis-associated CRC. Therefore, CX3CR1high fibrocytes represent a potential target for carcinogenesis-preventing therapy, and statins could be safe therapeutic candidates for IBD.
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Affiliation(s)
- Kensuke Hachiya
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, Japan
| | - Masahiro Masuya
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan.
- Course of Nursing Science, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan.
| | - Naoki Kuroda
- Department of Gastroenterology, Saiseikai Matsusaka General Hospital, Matsusaka, 515- 8557, Mie, Japan
| | - Misao Yoneda
- Department of Clinical Nutrition Medical Technology Course, Suzuka University of Medical Science, Suzuka, 510-0293, Mie, Japan
| | - Komei Nishimura
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan
| | - Takuya Shiotani
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan
| | - Isao Tawara
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan
| | - Naoyuki Katayama
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan
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2
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Liu H, Guo W, Wang T, Cao P, Zou T, Peng Y, Yan T, Liao C, Li Q, Duan Y, Han J, Zhang B, Chen Y, Zhao D, Yang X. CD36 inhibition reduces non-small-cell lung cancer development through AKT-mTOR pathway. Cell Biol Toxicol 2024; 40:10. [PMID: 38319449 PMCID: PMC10847192 DOI: 10.1007/s10565-024-09848-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 01/18/2024] [Indexed: 02/07/2024]
Abstract
Lung cancer is the most common cause of cancer-related deaths worldwide and is caused by multiple factors, including high-fat diet (HFD). CD36, a fatty acid receptor, is closely associated with metabolism-related diseases, including cardiovascular disease and cancer. However, the role of CD36 in HFD-accelerated non-small-cell lung cancer (NSCLC) is unclear. In vivo, we fed C57BL/6J wild-type (WT) and CD36 knockout (CD36-/-) mice normal chow or HFD in the presence or absence of pitavastatin 2 weeks before subcutaneous injection of LLC1 cells. In vitro, A549 and NCI-H520 cells were treated with free fatty acids (FFAs) to mimic HFD situation for exploration the underlying mechanisms. We found that HFD promoted LLC1 tumor growth in vivo and that FFAs increased cell proliferation and migration in A549 and NCI-H520 cells. The enhanced cell or tumor growth was inhibited by the lipid-lowering agent pitavastatin, which reduced lipid accumulation. More importantly, we found that plasma soluble CD36 (sCD36) levels were higher in NSCLC patients than those in healthy ones. Compared to that in WT mice, the proliferation of LLC1 cells in CD36-/- mice was largely suppressed, which was further repressed by pitavastatin in HFD group. At the molecular level, we found that CD36 inhibition, either with pitavastatin or plasmid, reduced proliferation- and migration-related protein expression through the AKT/mTOR pathway. Taken together, we demonstrate that inhibition of CD36 expression by pitavastatin or other inhibitors may be a viable strategy for NSCLC treatment.
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Affiliation(s)
- Hui Liu
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wentong Guo
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Tianxiang Wang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Peichang Cao
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Tingfeng Zou
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Ying Peng
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Tengteng Yan
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Chenzhong Liao
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Qingshan Li
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Yajun Duan
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Jihong Han
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
- College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Baotong Zhang
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Yuanli Chen
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Dahai Zhao
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
| | - Xiaoxiao Yang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
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3
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Yang H, Yue GGL, Leung PC, Wong CK, Lau CBS. A review on the molecular mechanisms, the therapeutic treatment including the potential of herbs and natural products, and target prediction of obesity-associated colorectal cancer. Pharmacol Res 2021; 175:106031. [PMID: 34896542 DOI: 10.1016/j.phrs.2021.106031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. Obesity has been proven to be closely related to colorectal carcinogenesis. This review summarized the potential underlying mechanisms linking obesity to CRC in different aspects, including energy metabolism, inflammation, activities of adipokines and hormones. Furthermore, the potential therapeutic targets of obesity-associated CRC were predicted using network-based target analysis, with total predicted pathways not only containing previously reported pathways, but also putative signaling pathways pending for investigation. In addition, the current conventional therapeutic treatment options, plus the potential use of herbs and natural products in the management of obesity-associated CRC were also discussed. Taken together, the aim of this review article is to provide strong theoretical basis for future drug development, particularly herbs and natural products, in obesity-associated CRC.
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Affiliation(s)
- Huihai Yang
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Grace Gar Lee Yue
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Ping Chung Leung
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Chun Kwok Wong
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Clara Bik San Lau
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
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4
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Prado DS, Damasceno LEA, Sonego AB, Rosa MH, Martins TV, Fonseca MDM, Cunha TM, Cunha FQ, Alves-Filho JC. Pitavastatin ameliorates autoimmune neuroinflammation by regulating the Treg/Th17 cell balance through inhibition of mevalonate metabolism. Int Immunopharmacol 2021; 91:107278. [PMID: 33341737 DOI: 10.1016/j.intimp.2020.107278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/02/2020] [Accepted: 12/02/2020] [Indexed: 12/16/2022]
Abstract
While Treg cells are responsible for self-tolerance and immune homeostasis, pathogenic autoreactive Th17 cells produce pro-inflammatory cytokines that lead to tissue damage associated with autoimmunity, as observed in multiple sclerosis. Therefore, the immunological balance between Th17 and Treg cells may represent a promising option for immune therapy. Statin drugs are used to treat dyslipidemia; however, besides their effects on preventing cardiovascular diseases, statins also have anti-inflammatory effects. Here, we investigated the role of pitavastatin on experimental autoimmune encephalomyelitis (EAE) and the differentiation of Treg and Th17 cells. EAE was induced by immunizing C57BL/6 mice with MOG35-55. EAE severity was determined by analyzing the clinical score and inflammatory parameters in the spinal cord. Naive CD4 T cells were cultured under Treg and Th17-skewing conditions in vitro in the presence of pitavastatin. We found that pitavastatin decreased EAE development, which was accompanied by a reduction of all parameters investigated. Pitavastatin also reduced the expression of IBA1 and pSTAT3 (Y705 and S727) in the spinal cords of EAE mice. Interestingly, the reduction of Th17 cell frequency in the draining lymph nodes of EAE mice treated with pitavastatin was followed by an increase of Treg cells. Indeed, pitavastatin directly affects T cell differentiation in vitro by decreasing Th17 and increasing Treg cell differentiation. Mechanistically, pitavastatin effects are dependent on mevalonate synthesis. Thus, our data show the potential anti-inflammatory effect of pitavastatin on the pathogenesis of the experimental neuroinflammation by modulating the Th17/Treg axis.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/pharmacology
- Cell Differentiation/drug effects
- Cells, Cultured
- Cytokines/genetics
- Cytokines/metabolism
- Disease Models, Animal
- Encephalomyelitis, Autoimmune, Experimental/chemically induced
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/prevention & control
- Inflammation Mediators/metabolism
- Lymph Nodes/drug effects
- Lymph Nodes/immunology
- Lymph Nodes/metabolism
- Male
- Mevalonic Acid/metabolism
- Mice, Inbred C57BL
- Myelin-Oligodendrocyte Glycoprotein
- Peptide Fragments
- Quinolines/pharmacology
- Spinal Cord/drug effects
- Spinal Cord/immunology
- Spinal Cord/metabolism
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Th17 Cells/drug effects
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Mice
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Affiliation(s)
- D S Prado
- Center for Research in Inflammatory Diseases, CRID, Ribeirão Preto Medical School, University of São Paulo, SP, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - L E A Damasceno
- Center for Research in Inflammatory Diseases, CRID, Ribeirão Preto Medical School, University of São Paulo, SP, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - A B Sonego
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - M H Rosa
- Center for Research in Inflammatory Diseases, CRID, Ribeirão Preto Medical School, University of São Paulo, SP, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - T V Martins
- Center for Research in Inflammatory Diseases, CRID, Ribeirão Preto Medical School, University of São Paulo, SP, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - M D M Fonseca
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - T M Cunha
- Center for Research in Inflammatory Diseases, CRID, Ribeirão Preto Medical School, University of São Paulo, SP, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - F Q Cunha
- Center for Research in Inflammatory Diseases, CRID, Ribeirão Preto Medical School, University of São Paulo, SP, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - J C Alves-Filho
- Center for Research in Inflammatory Diseases, CRID, Ribeirão Preto Medical School, University of São Paulo, SP, Brazil; Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
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5
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Beyond lipid-lowering: role of statins in endometrial cancer. Mol Biol Rep 2020; 47:8199-8207. [PMID: 32897522 DOI: 10.1007/s11033-020-05760-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 08/05/2020] [Accepted: 08/28/2020] [Indexed: 12/24/2022]
Abstract
As the obesity rates dramatically increased across the globe, the risk of endometrial cancer (EC) has substantially increased. Measures to improve the EC outcome is utmost important, especially data have shown that women at their reproductive age are commonly affected. No doubt, surgical intervention is a standard treatment for EC. However, the fact that this cancer could arise from metabolic diseases, additional therapy by lipid-lowering agent could be utilized to change the tumour environment. We review available evidence to support the use of this agent in the clinical setting. We search available evidence on the use of statin in EC, in various settings including cell lines, animal and human study. The possible actions at different molecular pathways leading to cellular changes and proliferation of cell were evaluated. The venture in drug repositioning of statins as a chemo-preventive potential agent in EC has gained attention in gynaecological oncology practice worldwide. Lipid-lowering effect by statins may exerted a chemoprotective effect in EC, but there is still lack of evidence on statins use to improve prognosis and survival in EC. Through the cholesterol-lowering effect of statins; theoretically, it could inhibit cell growth, proliferation, migration, and lead to apoptosis. Epidemiological studies suggested that statins may improve survival rate among EC patients. However, some evidence revealed the effects were only more prominent in type II EC. Notwithstanding that several studies also showed no benefit of statins in EC. Hence we highlight the limitations of these studies in this review. In line with recent literature on the topic, statins may play a role in EC management. Future studies for a proper systematic review and randomized controlled study are needed to answer some uncertainties of statins effect in EC.
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E S, Yamamoto K, Sakamoto Y, Mizowaki Y, Iwagaki Y, Kimura T, Nakagawa K, Miyazawa T, Tsuduki T. Intake of mulberry 1-deoxynojirimycin prevents colorectal cancer in mice. J Clin Biochem Nutr 2017; 61:47-52. [PMID: 28751809 PMCID: PMC5525018 DOI: 10.3164/jcbn.16-94] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 11/23/2016] [Indexed: 12/21/2022] Open
Abstract
The effect of 1-deoxynojirimycin, a caloric restriction mimetic, was examined in ICR mice with azoxymethane dextran sodium sulfate-induced colorectal cancer. Azoxymethane is a carcinogen (10 mg/kg body weight), and 2% dextran sodium sulfate (w/v) used as a colitis-inducing agent. Mice were separated into 5 groups: a group without colorectal cancer fed a normal diet (CO– group), and groups with colorectal cancer fed a normal diet (CO+ group), a calorie-restricted diet (caloric restriction group), and diets including 0.02% and 0.1% 1-deoxynojirimycin (l-1-deoxynojirimycin and H-1-deoxynojirimycin groups). The tumor incidence and number were reduced significantly in the caloric restriction group compared to the CO+ group, and were also suppressed in a dose-dependent manner by 1-deoxynojirimycin. mRNA for anti-apoptotic Bcl-2 was decreased and that for pro-apoptotic Bax was increased in the carcinoma tissue of CR, l-1-deoxynojirimycin and H-1-deoxynojirimycin groups. These results suggest that caloric restriction and 1-deoxynojirimycin inhibit growth of colorectal cancer by inducing apoptosis in an induced cancer model in mice.
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Affiliation(s)
- Shuang E
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, 468-1 Aoba, Aramaki, Aoba-ku, Sendai 980-0845, Japan
| | - Kazushi Yamamoto
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, 468-1 Aoba, Aramaki, Aoba-ku, Sendai 980-0845, Japan
| | - Yu Sakamoto
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, 468-1 Aoba, Aramaki, Aoba-ku, Sendai 980-0845, Japan
| | - Yui Mizowaki
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, 468-1 Aoba, Aramaki, Aoba-ku, Sendai 980-0845, Japan
| | - Yui Iwagaki
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, 468-1 Aoba, Aramaki, Aoba-ku, Sendai 980-0845, Japan
| | - Toshiyuki Kimura
- Institute of Food Research, National Agriculture and Food Research Organization (NARO), 2-1-12 Kannondai, Tsukuba, Ibaraki 305-8642, Japan
| | - Kiyotaka Nakagawa
- Food and Biodynamic Chemistry Laboratory, Graduate School of Agriculture, Tohoku University, 468-1 Aoba, Aramaki, Aoba-ku, Sendai 980-0845, Japan
| | - Teruo Miyazawa
- Food and Biodynamic Chemistry Laboratory, Graduate School of Agriculture, Tohoku University, 468-1 Aoba, Aramaki, Aoba-ku, Sendai 980-0845, Japan
| | - Tsuyoshi Tsuduki
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, 468-1 Aoba, Aramaki, Aoba-ku, Sendai 980-0845, Japan
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Shirakami Y, Ohnishi M, Sakai H, Tanaka T, Shimizu M. Prevention of Colorectal Cancer by Targeting Obesity-Related Disorders and Inflammation. Int J Mol Sci 2017; 18:ijms18050908. [PMID: 28445390 PMCID: PMC5454821 DOI: 10.3390/ijms18050908] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 04/17/2017] [Accepted: 04/20/2017] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer is a major healthcare concern worldwide. Many experimental and clinical studies have been conducted to date to discover agents that help in the prevention of this disease. Chronic inflammation in colonic mucosa and obesity, and its related metabolic abnormalities, are considered to increase the risk of colorectal cancer. Therefore, treatments targeting these factors might be a promising strategy to prevent the development of colorectal cancer. Among a number of functional foods, various phytochemicals, including tea catechins, which have anti-inflammatory and anti-obesity properties, and medicinal agents that ameliorate metabolic disorders, might also be beneficial in the prevention of colorectal cancer. In this review article, we summarize the strategies for preventing colorectal cancer by targeting obesity-related disorders and inflammation through nutraceutical and pharmaceutical approaches, and discuss the mechanisms of several phytochemicals and medicinal drugs used in basic and clinical research, especially focusing on the effects of green tea catechins.
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Affiliation(s)
- Yohei Shirakami
- Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
| | - Masaya Ohnishi
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
| | - Hiroyasu Sakai
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
| | - Takuji Tanaka
- Department of Pathological Diagnosis, Gifu Municipal Hospital, Gifu 500-8513, Japan.
| | - Masahito Shimizu
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
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Abstract
Statins are among the most widely prescribed medications in the world. In addition to lowering cholesterol, statins have been shown to have immunomodulatory effects in multiple studies. For example, statins modulate the interaction between T cells and antigen-presenting cells, resulting in decreased T-cell activation and reduced levels of inflammatory cytokines. Statins have also been demonstrated to inhibit the migration of leukocytes across vascular endothelium into tissues. Although most research on the immune effects of statins has been conducted in the context of cardiovascular, rheumatological, or metabolic disease, various studies have shown that statins may have a significant impact on intestinal immunity and mucosal inflammation. Clinical research has suggested that statins may have benefit in inflammatory bowel disease. In this article, we review the effect of statins on the immune system and gastrointestinal tract, highlighting the potential for novel therapeutic applications in inflammatory bowel disease.
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9
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Strawberry phytochemicals inhibit azoxymethane/dextran sodium sulfate-induced colorectal carcinogenesis in Crj: CD-1 mice. Nutrients 2015; 7:1696-715. [PMID: 25763529 PMCID: PMC4377876 DOI: 10.3390/nu7031696] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Revised: 01/16/2015] [Accepted: 02/26/2015] [Indexed: 01/04/2023] Open
Abstract
Human and experimental colon carcinogenesis are enhanced by a pro-inflammatory microenvironment. Pharmacologically driven chemopreventive agents and dietary variables are hypothesized to have future roles in the prevention of colon cancer by targeting these processes. The current study was designed to determine the ability of dietary lyophilized strawberries to inhibit inflammation-promoted colon carcinogenesis in a preclinical animal model. Mice were given a single i.p. injection of azoxymethane (10 mg kg−1 body weight). One week after injection, mice were administered 2% (w/v) dextran sodium sulfate in drinking water for seven days and then an experimental diet containing chemically characterized lyophilized strawberries for the duration of the bioassay. Mice fed control diet, or experimental diet containing 2.5%, 5.0% or 10.0% strawberries displayed tumor incidence of 100%, 64%, 75% and 44%, respectively (p < 0.05). The mechanistic studies demonstrate that strawberries reduced expression of proinflammatory mediators, suppressed nitrosative stress and decreased phosphorylation of phosphatidylinositol 3-kinase, Akt, extracellular signal-regulated kinase and nuclear factor kappa B. In conclusion, strawberries target proinflammatory mediators and oncogenic signaling for the preventive efficacies against colon carcinogenesis in mice. This works supports future development of fully characterized and precisely controlled functional foods for testing in human clinical trials for this disease.
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10
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Shirakami Y, Shimizu M, Kubota M, Araki H, Tanaka T, Moriwaki H, Seishima M. Chemoprevention of colorectal cancer by targeting obesity-related metabolic abnormalities. World J Gastroenterol 2014; 20:8939-8946. [PMID: 25083066 PMCID: PMC4112888 DOI: 10.3748/wjg.v20.i27.8939] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 12/20/2013] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Obesity and its related metabolic disorders, including insulin resistance and chronic inflammation, increase the risk of colorectal cancer (CRC). This observation suggests that the metabolic abnormalities associated with obesity can be effective targets for preventing the development of CRC in obese individuals. In recent years, many studies using obese and diabetic animal models have been conducted to investigate the chemoprevention of CRC using pharmaceutical or nutritional interventions. Pitavastatin, a medicine used to treat hyperlipidemia, prevents the development of obesity-related colorectal carcinogenesis by attenuating chronic inflammation. Anti-hypertensive medicines, such as captopril and telmisartan, also suppress the formation of colonic preneoplastic lesions in obese and diabetic mice. In addition, several phytochemicals, including green tea catechins, have been reported to improve metabolic disorders and prevent the development of various cancers, including CRC. Moreover, the administration of branched-chain amino acids, which improves protein malnutrition and prevents the progression of hepatic failure, is effective for suppressing obesity-related colon carcinogenesis, which is thought to be associated with improvements in insulin resistance. In the present article, we summarize the detailed relationship between metabolic abnormalities and the development of CRC. This review also outlines recent evidence, in particular drawing from basic and clinical examinations using either pharmaceutical or nutritional intervention that suggests that targeting metabolic alterations may be an effective strategy for preventing the development of CRC in obese individuals.
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Tsai ML, Chiou YS, Chiou LY, Ho CT, Pan MH. Garcinol suppresses inflammation-associated colon carcinogenesis in mice. Mol Nutr Food Res 2014; 58:1820-9. [PMID: 24981158 DOI: 10.1002/mnfr.201400149] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 05/07/2014] [Accepted: 05/11/2014] [Indexed: 01/04/2023]
Abstract
SCOPE Garcinol is a polyisoprenylated benzophenone derivative isolated from the fruit rind of Garcinia indica and has exhibited chemopreventive effects on azoxymethane)-induced colonic aberrant crypt foci in mice. In this study, we investigated whether garcinol protects against dextran sulfate sodium (DSS) induced colitis/inflammation and azoxymethane/DSS-induced inflammation-related colon tumorigenesis in male ICR mice. We also aimed to delineate the possible molecular mechanisms responsible for these effects. METHODS AND RESULTS Treatment with garcinol prevented shortening of the colon length and the formation of aberrant crypt foci and improved the inflammation score in the mouse colon stimulated by DSS. Moreover, administration of garcinol markedly decreased DSS-induced inducible nitric oxide synthase, cyclooxygenase-2, and proliferating cell nuclear antigen protein expression. The dietary administration of garcinol effectively reduced the tumor size and incidence in the mouse colon. Western blot and immunohistochemical analysis revealed that administration of garcinol significantly downregulated cyclooxygenase-2, cyclin D1, and vascular endothelial growth factor expression via inhibition of the extracellular signal-regulated protein kinase 1/2, phosphatidylinositol 3 kinase/Akt/p70 ribosomal S6 kinase, and Wnt/β-catenin signaling pathways. CONCLUSION Our results suggest that garcinol may merit further clinical investigation as a chemoprophylactic food that helps prevent colitis-associated colon cancer.
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Affiliation(s)
- Mei-Ling Tsai
- Department of Food Science, National Kaohsiung Marine University, Kaohsiung, Taiwan
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Künzl M, Wasinger C, Hohenegger M. Statins role in cancer prevention and development-recent meta-analyses. World J Pharmacol 2013; 2:100-106. [DOI: 10.5497/wjp.v2.i4.100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 08/21/2013] [Accepted: 10/16/2013] [Indexed: 02/06/2023] Open
Abstract
The therapeutic indications of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) include hypercholesterolaemia and the prevention of cardiovascular events. Statins are well tolerated and beyond their unambiguous positive cardiovascular effects there are a steadily increasing number of pleiotropic actions emerging. In this regard, growth inhibition, apoptosis, anti-inflammatory and immunomodulatory actions have been attributed to statins. The anti-proliferative effects have been the basis for massive preclinical investigations to elucidate a functional role for statins in carcinogenesis and tumor cell growth. However, preclinical and clinical studies are conflicting, although there is accumulating evidence that statins are capable to suppress and decrease the incidence and recurrence of some human cancers. Given the fact that statins are well tolerated they might also have some impact in combinations with conventional and targeted chemotherapy. While synergism has been shown for many combinations in vitro this does not hold true yet in the clinics. Here we review the rational behind usage of statins in oncological settings. Positive effects have been observed in patients with melanoma and cancers from the breast, colon, prostate, lung, liver and hematologic tissues. However, substantial evidence from clinical studies is still weak and confounded by several factors, which are inherent in the study design. The majority of the studies are observational or of retrospective nature. Definitely, there is substantial need for larger, prospective randomized, placebo-controlled trials. Finally, we conclude that statins at the current status of evidence should not be recommended in the prevention or during progression of any cancers, however, individual statins may have beneficial effects in specific tumor subgroups.
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Cardnell RJG, Rabender CS, Ross GR, Guo C, Howlett EL, Alam A, Wang XY, Akbarali HI, Mikkelsen RB. Sepiapterin ameliorates chemically induced murine colitis and azoxymethane-induced colon cancer. J Pharmacol Exp Ther 2013; 347:117-25. [PMID: 23912334 PMCID: PMC3781406 DOI: 10.1124/jpet.113.203828] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 07/31/2013] [Indexed: 12/24/2022] Open
Abstract
The effects of modulating tetrahydrobiopterin (BH4) levels with a metabolic precursor, sepiapterin (SP), on dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)-induced colorectal cancer were studied. SP in the drinking water blocks DSS-induced colitis measured as decreased disease activity index (DAI), morphologic criteria, and recovery of Ca(2+)-induced contractility responses lost as a consequence of DSS treatment. SP reduces inflammatory responses measured as the decreased number of infiltrating inflammatory macrophages and neutrophils and decreased expression of proinflammatory cytokines interleukin 1β (IL-1β), IL-6, and IL-17A. High-performance liquid chromatography analyses of colonic BH4 and its oxidized derivative 7,8-dihydrobiopterin (BH2) are inconclusive although there was a trend for lower BH4:BH2 with DSS treatment that was reversed with SP. Reduction of colonic cGMP levels by DSS was reversed with SP by a mechanism sensitive to 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a specific inhibitor of the NO-sensitive soluble guanylate cyclase (sGC). ODQ abrogates the protective effects of SP on colitis. This plus the finding that SP reduces DSS-enhanced protein Tyr nitration are consistent with DSS-induced uncoupling of NOS. The results agree with previous studies that demonstrated inactivation of sGC in DSS-treated animals as being important in recruitment of inflammatory cells and in altered cholinergic signaling and colon motility. SP also reduces the number of colon tumors in AOM/DSS-treated mice from 7 to 1 per unit colon length. Thus, pharmacologic modulation of BH4 with currently available drugs may provide a mechanism for alleviating some forms of colitis and potentially minimizing the potential for colorectal cancer in patients with colitis.
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Affiliation(s)
- Robert J G Cardnell
- Departments of Radiation Oncology (R.J.G.C., C.S.R., E.L.H., A.A., R.B.M.), Pharmacology and Toxicology (C.S.R., G.R.R., H.I.A.), and Human and Molecular Genetics (C.G., X.-Y.W.), Virginia Commonwealth University, Richmond, Virginia
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Broughton T, Sington J, Beales ILP. Statin use is associated with a reduced incidence of colorectal adenomatous polyps. Int J Colorectal Dis 2013; 28:469-476. [PMID: 23114474 DOI: 10.1007/s00384-012-1601-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/15/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been shown to have potentially useful anticancer effects against colorectal cancers in experimental studies, but clinical studies have shown inconsistent results on colorectal cancer incidence. Most colorectal cancers are believed to develop through the polyp-cancer sequence. We hypothesized that statins may protect against the development of adenomatous polyps, and this may contribute to the apparent cancer-protective effects. OBJECTIVE This study aims to compare previous statin use in patients with newly diagnosed adenomatous polyps against a control group without polyps. METHOD A case-control study involving 264 patients attending for diagnostic colonoscopy at the Norfolk and Norwich University Hospital was used. Polyp cases were age and sex matched against controls with normal colonoscopies. Structured patient interviews and clinical notes were used to ascertain drug and risk factor. Logistic regression was used to compare statin exposure and correct for confounding factors. RESULTS There was a significant negative association between prior statin use and a diagnosis of adenomatous polyps [odds ratio (OR) = 0.40 (0.24-0.76)]. The association was significantly stronger with higher statin doses [≥40 mg simvastatin or equivalent; OR 0.33 (0.10-0.53)] or longer duration of use [>5 years; OR 0.36 (0.10-0.67)]. Statin use was negatively associated with both high- and low-risk polyps. CONCLUSIONS Statins may have a protective effect against the development of adenomatous polyps. The negative association between statin use and polyp incidence showed a significant dose and duration relationship.
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Affiliation(s)
- Thomas Broughton
- Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK
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15
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Chao C, Jacobsen SJ, Xu L, Wallner LP, Porter KR, Williams SG. Use of statins and prostate cancer recurrence among patients treated with radical prostatectomy. BJU Int 2013; 111:954-62. [PMID: 23464862 DOI: 10.1111/j.1464-410x.2012.11639.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
UNLABELLED WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Statins have shown broad spectrum anti-cancer properties in laboratory studies. In epidemiological studies, use of statins has been associated with reduced risk of advanced prostate cancer. However, the effects of statins on prostate cancer disease progression following curative treatment have not been extensively studied, and previous studies reported conflicting results. This study found no clear association between overall statin use and risk of disease progression, as well as lack of a monotone dose-response relationship between the use of statins, whether it was use before or after prostatectomy, and prostate cancer disease progression. OBJECTIVE To investigate whether use of HMG-CoA reductase inhibitors ('statins'), which have shown broad spectrum anti-cancer properties in laboratory studies, is associated with a reduced risk of recurrence in patients with prostate cancer who undergo radical prostatectomy. PATIENTS AND METHODS All men with incident prostate cancer diagnosed between 2004 and 2005 who subsequently underwent radical prostatectomy by the end of 2005 in the Kaiser Permanente Southern California (KPSC) health plan were identified using KPSC's cancer registry. Subjects were followed for up to 5 years after prostatectomy for (i) biochemical recurrence, defined as a single PSA measurement >0.2 ng/mL, and (ii) clinical disease progression, defined as diagnosis of metastatic disease or prostate-cancer-related death. Information on statin use, demographics, comorbidities, patho-clinical factors and outcomes were ascertained from KPSC's electronic medical records. The effects of statin use prior to and after prostatectomy were both examined using bivariate and multivariate Cox models, adjusting for known prognostic factors. For postoperative statin exposure, a time-dependent Cox model was used. RESULTS A total of 1200 men were included; 37% had preoperative and 56% had postoperative statin use. Neither preoperative nor postoperative statin use was associated with biochemical recurrence (hazard ratio [HR] = 1.00 [0.72-1.39] and 1.05 [0.76-1.46], respectively) or clinical disease progression (HR = 0.63 [0.31-1.27] and 1.20 [0.63-2.30], respectively). No clear dose-response relationship was found for duration of use. CONCLUSIONS Statin use may not prevent prostate cancer progression following radical prostatectomy. These findings do not provide support for the pursuit of a prospective clinical trial of statin use as a secondary prevention among surgically treated patients with prostate cancer.
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Affiliation(s)
- Chun Chao
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA 91101, USA.
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Tanaka T. Preclinical cancer chemoprevention studies using animal model of inflammation-associated colorectal carcinogenesis. Cancers (Basel) 2012; 4:673-700. [PMID: 24213461 PMCID: PMC3712717 DOI: 10.3390/cancers4030673] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Revised: 06/14/2012] [Accepted: 07/06/2012] [Indexed: 12/21/2022] Open
Abstract
Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.
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Affiliation(s)
- Takuji Tanaka
- Cytopatholgy Division, Tohkai Cytopathology Institute, Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu 500-8285, Japan.
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Bhattacharyya S, Bhattacharyya K, Maitra A. Possible mechanisms of interaction between statins and vitamin D. QJM 2012; 105:487-91. [PMID: 22323613 DOI: 10.1093/qjmed/hcs001] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- S Bhattacharyya
- Aultman Health Foundation, 2600 Sixth St. SW, Canton, OH 44710, USA
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Development of an inflammation-associated colorectal cancer model and its application for research on carcinogenesis and chemoprevention. Int J Inflam 2012; 2012:658786. [PMID: 22518340 PMCID: PMC3299397 DOI: 10.1155/2012/658786] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 10/25/2011] [Indexed: 12/25/2022] Open
Abstract
Chronic inflammation is a well-recognized risk factor for development of human cancer in several tissues, including large bowel. Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer development. Several molecular events involved in chronic inflammatory process may contribute to multistep carcinogenesis of human colorectal cancer in the inflamed colon. They include overproduction of reactive oxygen and nitrogen species, overproduction and upregulation of productions and enzymes of arachidonic acid biosynthesis pathway and cytokines, and intestinal immune system dysfunction. In this paper, I will describe several methods to induce colorectal neoplasm in the inflamed colon. First, I will introduce a protocol of a novel inflammation-associated colon carcinogenesis in mice. In addition, powerful tumor-promotion/progression activity of dextran sodium sulfate in the large bowel of ApcMin/+ mice will be described. Finally, chemoprevention of inflammation-associated colon carcinogenesis will be mentioned.
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Lee JE, Baba Y, Ng K, Giovannucci E, Fuchs CS, Ogino S, Chan AT. Statin use and colorectal cancer risk according to molecular subtypes in two large prospective cohort studies. Cancer Prev Res (Phila) 2011; 4:1808-15. [PMID: 21680706 PMCID: PMC3192239 DOI: 10.1158/1940-6207.capr-11-0113] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Use of statins is hypothesized to reduce colorectal cancer risk but the evidence remains inconsistent. This may be partly explained by differential associations according to tumor location or molecular subtypes of colorectal cancer. We examined the association between statin use and colorectal cancer risk according to tumor location, KRAS mutation status, microsatellite instability (MSI) status, PTGS2 (COX-2) expression, or CpG island methylator phenotype (CIMP) status in two large prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study. We applied Cox regression to a competing risks analysis. We identified 1,818 colorectal cancers during 1990 to 2006. Compared with nonusers, current statin use was not associated with colorectal cancer [relative risk (RR) = 0.99, 95% CI = 0.86-1.14] or colon cancer (RR = 1.10, 95% CI = 0.94-1.29) but was inversely associated with rectal cancer (RR = 0.59, 95% CI = 0.41-0.84, P(heterogeneity) < 0.001). When we examined the association within strata of KRAS mutation status, we found no association with KRAS-mutated cancers (RR = 1.20, 95% CI = 0.87-1.67) but did observe a possible inverse association among KRAS wild-type cancers (RR = 0.80, 95% CI = 0.60-1.06, P(heterogeneity) = 0.06). The association did not substantially differ by PTGS2 expression, MSI status, or CIMP status. Current statin use was not associated with risk of overall colorectal cancer. The possibility that statin use may be associated with lower risk of rectal cancer or KRAS wild-type colorectal cancer requires further confirmation.
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Affiliation(s)
- Jung Eun Lee
- Department of Food and Nutrition, Sookmyung Women's University, Seoul, Korea
| | - Yoshifumi Baba
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston
| | - Kimmie Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston
| | - Edward Giovannucci
- Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts
| | - Charles S. Fuchs
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston
- Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Andrew T. Chan
- Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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Takasu S, Mutoh M, Takahashi M, Nakagama H. Lipoprotein lipase as a candidate target for cancer prevention/therapy. Biochem Res Int 2011; 2012:398697. [PMID: 22028972 PMCID: PMC3199119 DOI: 10.1155/2012/398697] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Accepted: 08/17/2011] [Indexed: 12/30/2022] Open
Abstract
Epidemiological studies have shown that serum triglyceride (TG) levels are linked with risk of development of cancer, including colorectal and pancreatic cancers, and their precancerous lesions. Thus, it is assumed that serum TG plays an important role in carcinogenesis, and the key enzyme lipoprotein lipase (LPL), which catalyzes the hydrolysis of plasma TG, may therefore be involved. Dysregulation of LPL has been reported to contribute to many human diseases, such as atherosclerosis, chylomicronaemia, obesity, and type 2 diabetes. Recently, it has been reported that LPL gene deficiency, such as due to chromosome 8p22 loss, LPL gene polymorphism, and epigenetic changes in its promoter region gene, increases cancer risk, especially in the prostate. In animal experiments, high serum TG levels seem to promote sporadic/carcinogen-induced genesis of colorectal and pancreatic cancers. Interestingly, tumor suppressive effects of LPL inducers, such as PPAR ligands, NO-1886, and indomethacin, have been demonstrated in animal models. Moreover, recent evidence that LPL plays important roles in inflammation and obesity implies that it is an appropriate general target for chemopreventive and chemotherapeutic agents.
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Affiliation(s)
- Shinji Takasu
- Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Michihiro Mutoh
- Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Mami Takahashi
- Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Hitoshi Nakagama
- Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
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Chao C, Xu L, Abrams DI, Towner WJ, Horberg MA, Leyden WA, Silverberg MJ. HMG-CoA reductase inhibitors (statins) use and risk of non-Hodgkin lymphoma in HIV-positive persons. AIDS 2011; 25:1771-7. [PMID: 21681055 PMCID: PMC3846691 DOI: 10.1097/qad.0b013e328349c67a] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Experimental studies suggested that HMG-CoA reductase inhibitors ('statins') may have antilymphoma properties. We investigated whether statin use is associated with reduced risk of non-Hodgkin lymphoma (NHL) in HIV-positive persons. DESIGN A nested case-control study was conducted among HIV-positive members of Kaiser Permanente California, a large managed care organization. METHODS Cases were incident HIV+ NHL diagnosed from 1996 to 2008. Controls were HIV-positive members without NHL matched 5 : 1 to cases by age, sex, race, index year and known duration of HIV infection. Data were collected from Kaiser Permanente's electronic medical records. Conditional logistic regression was used to examine the effect of statin use on HIV + NHL risk, adjusting for potential confounders (matching factors, prior clinical AIDS diagnosis, antiretroviral use, baseline CD4 cell count, and history of selected co-morbidity) and use of nonstatin lipid-lowering therapy (LLT). RESULTS A total of 259 cases and 1295 controls were included. Eight percent of the cases and 14% of the controls had a history of statin use. Statin use was associated with lower risk of HIV + NHL; hazard ratio and 95% confidence intervals for ever use, less than 12, and at least 12 months cumulative use was 0.55 (0.31-0.95), 0.64 (0.31-1.28), and 0.50 (0.23-1.10), respectively. P value for trend for duration of statin use was 0.08. No association between nonstatin LLT use and risk of NHL was observed. CONCLUSION Our results suggested an inverse association between statin use and risk of NHL in HIV-positive persons. Potential limitations include the likelihood of residual confounding by indication and limited study power for some statin use subgroups.
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Affiliation(s)
- Chun Chao
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, USA.
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22
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Yasui Y, Tanaka T. Protein expression analysis of inflammation-related colon carcinogenesis. J Carcinog 2011; 8:10. [PMID: 19491504 PMCID: PMC2699605 DOI: 10.4103/1477-3163.51851] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background: Chronic inflammation is a risk factor for colorectal cancer (CRC) development. The aim of this study was to determine the differences in protein expression between CRC and the surrounding nontumorous colonic tissues in the mice that received azoxymethane (AOM) and dextran sodium sulfate (DSS) using a proteomic analysis. Materials and Methods: Male ICR mice were given a single intraperitoneal injection of AOM (10 mg/kg body weight), followed by 2% (w/v) DSS in their drinking water for seven days, starting one week after the AOM injection. Colonic adenocarcinoma developed after 20 weeks and a proteomics analysis based on two-dimensional gel electrophoresis and ultraflex TOF/TOF mass spectrometry was conducted in the cancerous and nontumorous tissue specimens. Results: The proteomic analysis revealed 21 differentially expressed proteins in the cancerous tissues in comparison to the nontumorous tissues. There were five markedly increased proteins (beta-tropomyosin, tropomyosin 1 alpha isoform b, S100 calcium binding protein A9, and an unknown protein) and 16 markedly decreased proteins (Car1 proteins, selenium-binding protein 1, HMG-CoA synthase, thioredoxin 1, 1 Cys peroxiredoxin protein 2, Fcgbp protein, Cytochrome c oxidase, subunit Va, ETHE1 protein, and 7 unknown proteins). Conclusions: There were 21 differentially expressed proteins in the cancerous tissues of the mice that received AOM and DSS. Their functions include metabolism, the antioxidant system, oxidative stress, mucin production, and inflammation. These findings may provide new insights into the mechanisms of inflammation-related colon carcinogenesis and the establishment of novel therapies and preventative strategies to treat carcinogenesis in the inflamed colon.
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Affiliation(s)
- Yumiko Yasui
- Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan.
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Shimizu M, Yasuda Y, Sakai H, Kubota M, Terakura D, Baba A, Ohno T, Kochi T, Tsurumi H, Tanaka T, Moriwaki H. Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice. BMC Cancer 2011; 11:281. [PMID: 21711565 PMCID: PMC3146939 DOI: 10.1186/1471-2407-11-281] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2010] [Accepted: 06/28/2011] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obesity and related metabolic abnormalities, including inflammation and lipid accumulation in the liver, play a role in liver carcinogenesis. Adipocytokine imbalances, such as decreased serum adiponectin levels, are also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of pitavastatin - a drug used for the treatment of hyperlipidemia - on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-db/db (db/db) obese mice. METHODS Male db/db mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks. RESULTS At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of TNF-α and interleukin-6 mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition. CONCLUSIONS Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals.
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Affiliation(s)
- Masahito Shimizu
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yoichi Yasuda
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hiroyasu Sakai
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Masaya Kubota
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Daishi Terakura
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Atsushi Baba
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tomohiko Ohno
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takahiro Kochi
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hisashi Tsurumi
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takuji Tanaka
- Department of Oncologic Pathology, Kanazawa Medical University, Ishikawa, Japan
| | - Hisataka Moriwaki
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
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Yasui Y, Hosokawa M, Mikami N, Miyashita K, Tanaka T. Dietary astaxanthin inhibits colitis and colitis-associated colon carcinogenesis in mice via modulation of the inflammatory cytokines. Chem Biol Interact 2011; 193:79-87. [PMID: 21621527 DOI: 10.1016/j.cbi.2011.05.006] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Revised: 05/12/2011] [Accepted: 05/13/2011] [Indexed: 01/27/2023]
Abstract
Astaxanthin (AX) is one of the marine carotenoid pigments, which possess powerful biological antioxidant, anti-inflammatory and anti-cancer properties. The purpose of this study is to investigate possible inhibitory effect of AX against inflammation-related mouse colon carcinogenesis and dextran sulfate sodium (DSS)-induced colitis in male ICR mice. We conducted two different experiments. In the first experiment, we evaluated the effects of AX at three dose levels, 50, 100 and 200 ppm in diet, on colitis-associated colon carcinogenesis induced by azoxymethane (AOM)/DSS in mice. In the second, the effects of the AX (100 and 200 ppm) in diet on DSS-induced colitis were determined. We found that dietary AX significantly inhibited the occurrence of colonic mucosal ulcers, dysplastic crypts, and colonic adenocarcinoma at week 20. AX-feeding suppressed expression of inflammatory cytokines, including nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α and interleukin (IL)-1β, inhibited proliferation, and induced apoptosis in the colonic adenocarcinomas. Feeding with 200 ppm AX, but not 100 ppm, significantly inhibited the development of DSS-induced colitis. AX feeding (200 ppm in diet) also lowered the protein expression of NF-κB, and the mRNA expression of inflammatory cytokines, including IL-1β, IL-6, and cyclooxygenase (COX)-2. Our results suggest that the dietary AX suppresses the colitis and colitis-related colon carcinogenesis in mice, partly through inhibition of the expression of inflammatory cytokine and proliferation. Our findings suggest that AX is one of the candidates for prevention of colitis and inflammation-associated colon carcinogenesis in humans.
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Affiliation(s)
- Yumiko Yasui
- School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan.
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Teraoka N, Mutoh M, Takasu S, Ueno T, Yamamoto M, Sugimura T, Wakabayashi K. Inhibition of Intestinal Polyp Formation by Pitavastatin, a HMG-CoA Reductase Inhibitor. Cancer Prev Res (Phila) 2011; 4:445-53. [DOI: 10.1158/1940-6207.capr-10-0028] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Ikeda K, Mutoh M, Teraoka N, Nakanishi H, Wakabayashi K, Taguchi R. Increase of oxidant-related triglycerides and phosphatidylcholines in serum and small intestinal mucosa during development of intestinal polyp formation in Min mice. Cancer Sci 2010; 102:79-87. [PMID: 20946475 DOI: 10.1111/j.1349-7006.2010.01754.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Recent epidemiological studies have shown a positive association of a high-fat diet with the risk of colon cancer. Indeed, increments in the serum levels of triglycerides (TG) and cholesterols are positively related with colon carcinogenesis. We previously reported that an age-dependent hyperlipidemic state is characteristic of Min mice, an animal model for human familial adenomatous polyposis (FAP). However, qualitative and quantitative changes of lipid metabolism are poorly understood in this state. Here, we provide detailed analysis of serum lipids in Min mice using reverse-phased liquid chromatography/electrospray ionization mass spectrometry (RPLC/ESI-MS). We also demonstrate local analysis of lipid droplets in the villi of the small intestine using laser capture microdissection and a sensitive chip-based nanoESI-MS system. As a result, oxidized phosphatidylcholines (PC) such as aldehyde and carboxylic acid types were increased, even at an early stage of intestinal polyp formation in serum. In addition, hydroperoxidizable TG precursors containing linoleic acid (18:2n-6) were deposited at the tip of the villi with aging, and these hydroperoxidized TG were also increased in serum. Meanwhile, increments of the oxidizable TG precursors in serum and small intestinal mucosa were suppressed by treatment with pitavastatin, a novel third generation lipophilic statin. These results suggest that quantitative and qualitative lipid changes such as hydroperoxidizable TG precursors are important in the course of intestinal polyp formation and oxidative stress might lead to the development of intestinal polyp formation in Min mice.
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Affiliation(s)
- Kazutaka Ikeda
- Department of Metabolome, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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27
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Yasuda Y, Shimizu M, Shirakami Y, Sakai H, Kubota M, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H. Pitavastatin inhibits azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Cancer Sci 2010; 101:1701-7. [PMID: 20398056 PMCID: PMC11158884 DOI: 10.1111/j.1349-7006.2010.01579.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Obesity and related metabolic abnormalities are risk factors for colorectal cancer. A state of chronic inflammation and adipocytokine imbalance may play a role in colorectal carcinogenesis. Statins, which are commonly used for the treatment of hyperlipidemia, are known to possess anti-inflammatory effects. Statins also exert chemopreventive properties against various cancers. The present study examined the effects of pitavastatin, a recently developed lipophilic statin, on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were administrated weekly subcutaneous injections of AOM (15 mg/kg body weight) for 4 weeks and then were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 8 weeks. Feeding with either dose of pitavastatin significantly reduced the number of colonic premalignant lesions, beta-catenin accumulated crypts, by inhibiting proliferation and the surrounding inflammation. Pitavastatin increased the serum levels of adiponectin while conversely decreasing the serum levels of total cholesterol, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-18, and leptin. Pitavastatin also caused a significant increase in the expression of phosphorylated form of the AMP-activated kinase (AMPK) protein on the colonic mucosa of AOM-treated mice. In addition, the expression levels of TNF-alpha, IL-6, IL-18, and COX-2 mRNAs on the colonic mucosa of AOM-treated mice were decreased by treatment with this agent. These findings suggest that pitavastatin attenuates chronic inflammation and improves the imbalance of adipocytokines, both of which are caused by the presence of excess adipose tissues, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model. Therefore, some types of statins, including pitavastatin, may be a useful chemoprevention modality for colon cancer in obese individuals.
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Affiliation(s)
- Yoichi Yasuda
- Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
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28
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Jakobisiak M, Golab J. Statins can modulate effectiveness of antitumor therapeutic modalities. Med Res Rev 2010; 30:102-35. [PMID: 19526461 DOI: 10.1002/med.20162] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Despite significant, frequently very strong, antiproliferative and tumoricidal effects of statins demonstrated in vitro, their antitumor effects in animal models are modest, and their efficacy in clinical trials has not been proven. As such, statins seem unlikely to be ever regarded as antitumor agents. However, statins are regularly taken by many elderly cancer patients for the prevention of cardiovascular events. Owing to their pleiotropic effects in normal and tumor cells, statins interact in various ways with many antitumor treatment modalities, either potentiating or diminishing their effectiveness. Elucidation of these interactions might affect the choice of treatment to be planned in cancer patients as some combinations might be contraindicated, whereas others might elicit potentiated antitumor effects but at a cost of increased general toxicity. Some other combinations might induce either comparable or even stronger antitumor effects, but with a beneficial concomitant reduction of specific side effects. Most of the studies reviewed in this article have been carried in vitro or in experimental tumor models, but clinical relevance of the findings is also discussed.
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Affiliation(s)
- Marek Jakobisiak
- Department of Immunology, Center of Biostructure Research, The Medical University of Warsaw, Warsaw, Poland.
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Tanaka T, de Azevedo MBM, Durán N, Alderete JB, Epifano F, Genovese S, Tanaka M, Tanaka T, Curini M. Colorectal cancer chemoprevention by 2 beta-cyclodextrin inclusion compounds of auraptene and 4'-geranyloxyferulic acid. Int J Cancer 2010; 126:830-40. [PMID: 19688830 DOI: 10.1002/ijc.24833] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The inhibitory effects of novel prodrugs, inclusion complexes of 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid (GOFA) and auraptene (AUR) with beta-cyclodextrin (CD), on colon carcinogenesis were investigated using an azoxymethane (AOM)/dextran sodium sulfate (DSS) model. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of AOM (10 mg/kg body weight) were promoted by the addition of 1.5% (w/v) DSS to their drinking water for 7 days. They were then given a basal diet containing 2 dose levels (100 and 500 ppm) of GOFA/beta-CD or AUR/beta-CD for 15 weeks. At Week 18, the development of colonic adenocarcinoma was significantly inhibited by feeding with GOFA/beta-CD at dose levels of 100 ppm (63% reduction in multiplicity, p < 0.05) and 500 ppm (83% reduction in the multiplicity, p < 0.001), when compared with the AOM/DSS group (multiplicity: 3.36 +/- 3.34). In addition, feeding with 100 and 500 ppm (p < 0.01) of AUR/beta-CD suppressed the development of colonic adenocarcinomas. The dietary administration with GOFA/beta-CD and AUR/beta-CD inhibited colonic inflammation and also modulated proliferation, apoptosis and the expression of several proinflammatory cytokines, such as nuclear factor-kappaB, tumor necrosis factor-alpha, Stat3, NF-E2-related factor 2, interleukin (IL)-6 and IL-1beta, which were induced in the adenocarcinomas. Our findings indicate that GOFA/beta-CD and AUR/beta-CD, especially GOFA/beta-CD, are therefore able to inhibit colitis-related colon carcinogenesis by modulating inflammation, proliferation and the expression of proinflammatory cytokines in mice.
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Affiliation(s)
- Takuji Tanaka
- Department of Oncologic Pathology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
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Toyoda T, Tsukamoto T, Takasu S, Hirano N, Ban H, Shi L, Kumagai T, Tanaka T, Tatematsu M. Pitavastatin fails to lower serum lipid levels or inhibit gastric carcinogenesis in helicobacter pylori-infected rodent models. Cancer Prev Res (Phila) 2009; 2:751-8. [PMID: 19622613 DOI: 10.1158/1940-6207.capr-09-0082] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Statins are commonly used lipid-lowering drugs that reduce the risk of cardiovascular morbidity and mortality. Although recent studies have pointed to chemopreventive effects of statins against various cancers, their efficacy for gastric cancer is unclear. Here, we examined the effects of pitavastatin, a lipophilic statin, on Helicobacter pylori (H. pylori)-associated stomach carcinogenesis and gastritis using Mongolian gerbil and mouse models. The animals were allocated to H. pylori + N-methyl-N-nitrosourea administration (gerbils, 52 weeks) or H. pylori infection alone groups (gerbils and mice, 12 weeks). After H. pylori infection, they were fed basal diets containing 0 to 10 ppm of pitavastatin. The incidences of H. pylori-associated gastric adenocarcinomas and degrees of chronic gastritis were not decreased by pitavastatin compared with those of control values. Expression of interleukin-1beta and tumor necrosis factor-alpha mRNAs in the pyloric mucosa was markedly up-regulated in pitavastatin-treated animals. Furthermore, in the H. pylori-infected groups, serum total cholesterol, triglyceride, and low-density lipoprotein levels were significantly increased by pitavastatin treatment, contrary to expectation. In the short-term study, H. pylori-infected gerbils and mice also showed significant up-regulation of serum triglyceride levels by pitavastatin, whereas total cholesterol was markedly reduced and low-density lipoprotein exhibited a tendency for decrease in noninfected animals. These findings indicate pitavastatin to be ineffective for suppressing gastritis and chemoprevention of gastric carcinogenesis in H. pylori-infected gerbils. Our serologic results also suggest that the H. pylori infection and consequent severe chronic gastritis interfere with the cholesterol-lowering effects of pitavastatin.
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Affiliation(s)
- Takeshi Toyoda
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
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Miyamoto S, Epifano F, Curini M, Genovese S, Kim M, Ishigamori-Suzuki R, Yasui Y, Sugie S, Tanaka T. A novel prodrug of 4'-geranyloxy-ferulic acid suppresses colitis-related colon carcinogenesis in mice. Nutr Cancer 2009; 60:675-84. [PMID: 18791932 DOI: 10.1080/01635580802008286] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The inhibitory effects of a novel prodrug, 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoyl-L-alanyl-L-proline (GAP), of the secondary metabolite 4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid (4'-geranyloxy-ferulic acid), on colon carcinogenesis was investigated using an azoxymetahen (AOM)/dextran sodium sulfate (DSS) model. GAP was synthetically derived from ferulic acid. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of azoxymethane (10 mg/kg body weight) were promoted by 1% (wt/vol) DSS in drinking water for 7 days. They were then given modified AIN-76A diet containing 0.01% or 0.05% GAP for 17 wk. At Week 20, the development of colonic adenocarcinoma was significantly inhibited by GAP feeding at dose levels of 0.01% [60% incidence (P = 0.0158) with a multiplicity of and 1.13 +/- 1.13 (P < 0.05)] and 0.05% [53% incidence (P = 0.0057) with a multiplicity of 0.08 +/- 1.08 (P < 0.01)], when compared to the AOM/DSS group (95% incidence with a multiplicity of 3.10 +/- 3.06). Dietary GAP modulated the mitotic and apoptotic indexes in the crypt cells and lowered 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells in the colonic mucosa. Urinary level of 8-OHdG was lowered by GAP feeding. Additionally, dietary GAP elevated the immunoreactivity of an inducible form of heme oxygenase 1 in the colonic mucosa. Our results indicate that GAP is able to inhibit colitis-related colon carcinogenesis by modulating proliferation and oxidative stress in mice.
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Affiliation(s)
- Shingo Miyamoto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
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Melatonin suppresses AOM/DSS-induced large bowel oncogenesis in rats. Chem Biol Interact 2008; 177:128-36. [PMID: 19028472 DOI: 10.1016/j.cbi.2008.10.047] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2008] [Revised: 10/16/2008] [Accepted: 10/22/2008] [Indexed: 12/15/2022]
Abstract
The inhibitory effects of exogenous melatonin (MEL) on colon oncogenesis were investigated using an azoxymethane (AOM)/dextran sodium sulfate (DSS) rat model. Male F344 rats initiated with a single intraperitoneal injection of AOM (20mg/kg bw) were promoted by 1% (w/v) DSS in drinking water for 7 days. They were then given 0.4, 2 or 10ppm MEL in drinking water for 17 weeks. At week 20, the development of colonic adenocarcinoma was significantly inhibited by the administration with MEL dose-dependently. MEL exposure modulated the mitotic and apoptotic indices in the colonic adenocarcinomas that developed and lowered the immunohistochemical expression of nuclear factor kappa B, tumor necrosis factor alpha, interleukin-1beta and STAT3 in the epithelial malignancies. These results may indicate the beneficial effects of MEL on colitis-related colon carcinogenesis and a potential application for inhibiting colorectal cancer development in the inflamed colon.
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Miyamoto S, Yasui Y, Kim M, Sugie S, Murakami A, Ishigamori-Suzuki R, Tanaka T. A novel rasH2 mouse carcinogenesis model that is highly susceptible to 4-NQO-induced tongue and esophageal carcinogenesis is useful for preclinical chemoprevention studies. Carcinogenesis 2008; 29:418-26. [PMID: 18174262 DOI: 10.1093/carcin/bgm225] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
We investigated the susceptibility of 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in male CB6F1-Tg-rasH2 @Jcl mice (Tg mice). The Tg mice were administered 4-NQO (20 p.p.m. in drinking water) for 2, 4, 6 or 8 weeks, and thereafter they were untreated up to week 24. At week 24, a higher incidence (80%) of tongue neoplasm with dysplasia was noted in the mice that received 4-NQO for 8 weeks in comparison with the other groups (20% incidence for each) treated with 4-NQO for 2, 4 and 6 weeks. Esophageal tumors also developed in the Tg mice were 4-NQO. Immunohistochemical observation revealed that the EP receptors, especially EP(1) and EP(2), expressed in the tongue and esophageal lesions induced by 4-NQO, thus suggesting the involvement of prostaglandin (PG) E(2) and EP(1,2) receptors in the tongue and esophageal carcinogenesis. Using this animal model, we investigated the potential chemopreventive ability of pitavastatin (1, 5 and 10 p.p.m. in diet for 15 weeks), starting 1 week after the cessation of 4-NQO-exposure (20 p.p.m. in drinking water for 8 weeks). Dietary pitavastatin at 10 p.p.m. significantly reduced the incidence and multiplicity of the tongue, but not esophageal neoplasms by the modulation of prostaglandin E2 biosynthesis, EP(1) and EP(2) expression and proliferation. Our results thus suggest that a rasH2 mouse model of 4-NQO-induced tongue and esophageal carcinogenesis can be utilized for investigating the pathogenesis of cancer development in these tissues and may well prove to be useful for identifying candidate cancer chemopreventive agents for the upper digestive organs.
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Affiliation(s)
- Shingo Miyamoto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
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