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Xiao Q, Xia M, Tang W, Zhao H, Chen Y, Zhong J. The lipid metabolism remodeling: A hurdle in breast cancer therapy. Cancer Lett 2024; 582:216512. [PMID: 38036043 DOI: 10.1016/j.canlet.2023.216512] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/14/2023] [Accepted: 11/21/2023] [Indexed: 12/02/2023]
Abstract
Lipids, as one of the three primary energy sources, provide energy for all cellular life activities. Lipids are also known to be involved in the formation of cell membranes and play an important role as signaling molecules in the intracellular and microenvironment. Tumor cells actively or passively remodel lipid metabolism, using the function of lipids in various important cellular life activities to evade therapeutic attack. Breast cancer has become the leading cause of cancer-related deaths in women, which is partly due to therapeutic resistance. It is necessary to fully elucidate the formation and mechanisms of chemoresistance to improve breast cancer patient survival rates. Altered lipid metabolism has been observed in breast cancer with therapeutic resistance, indicating that targeting lipid reprogramming is a promising anticancer strategy.
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Affiliation(s)
- Qian Xiao
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China; Department of Clinical Laboratory Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
| | - Min Xia
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
| | - Weijian Tang
- Queen Mary School of Nanchang University, Nanchang University, Nanchang, 330031, PR China
| | - Hu Zhao
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
| | - Yajun Chen
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.
| | - Jing Zhong
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China; Institute of Clinical Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.
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Jayathilake AG, Luwor RB, Nurgali K, Su XQ. Molecular Mechanisms Associated with the Inhibitory Role of Long Chain n-3 PUFA in Colorectal Cancer. Integr Cancer Ther 2024; 23:15347354241243024. [PMID: 38708673 PMCID: PMC11072084 DOI: 10.1177/15347354241243024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 02/14/2024] [Accepted: 03/11/2024] [Indexed: 05/07/2024] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related death in the world. Multiple evidence suggests that there is an association between excess fat consumption and the risk of CRC. The long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential for human health, and both in vitro and in vivo studies have shown that these fatty acids can prevent CRC development through various molecular mechanisms. These include the modulation of arachidonic acid (AA) derived prostaglandin synthesis, alteration of growth signaling pathways, arrest of the cell cycle, induction of cell apoptosis, suppression of angiogenesis and modulation of inflammatory response. Human clinical studies found that LC n-3 PUFA combined with chemotherapeutic agents can improve the efficacy of treatment and reduce the dosage of chemotherapy and associated side effects. In this review, we discuss comprehensively the anti-cancer effects of LC n-3 PUFA on CRC, with a main focus on the underlying molecular mechanisms.
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Affiliation(s)
| | - Rodney Brain Luwor
- The University of Melbourne, Melbourne, VIC, Australia
- Fiona Elsey Cancer Research Institute, Ballarat, VIC, Australia
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
- The University of Melbourne, Melbourne, VIC, Australia
- Australian Institute for Muscular Skeletal Science (AIMSS), Melbourne, VIC, Australia
| | - Xiao Qun Su
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
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Pettersen CHH, Samdal H, Sætrom P, Wibe A, Hermansen E, Schønberg SA. The Salmon Oil OmeGo Reduces Viability of Colorectal Cancer Cells and Potentiates the Anti-Cancer Effect of 5-FU. Mar Drugs 2023; 21:636. [PMID: 38132957 PMCID: PMC10744414 DOI: 10.3390/md21120636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/08/2023] [Accepted: 12/09/2023] [Indexed: 12/23/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancer types worldwide. Chemotherapy is toxic to normal cells, and combinatory treatment with natural well-tolerated products is being explored. Some omega-3 polyunsaturated fatty acids (n-3 PUFAs) and marine fish oils have anti-cancer effects on CRC cells. The salmon oil OmeGo (Hofseth BioCare) contains a spectrum of fatty acids, including the n-3 PUFAs docosahexaenoic acid (DHA) and eicosahexaenoic acid (EPA). We explored a potential anti-cancer effect of OmeGo on the four CRC cell lines DLD-1, HCT-8, LS411N, and LS513, alone and in combination with the chemotherapeutic agent 5-Fluorouracil (5-FU). Screening indicated a time- and dose-dependent effect of OmeGo on the viability of the DLD-1 and LS513 CRC cell lines. Treatment with 5-FU and OmeGo (IC20-IC30) alone indicated a significant reduction in viability. A combinatory treatment with OmeGo and 5-FU resulted in a further reduction in viability in DLD-1 and LS513 cells. Treatment of CRC cells with DHA + EPA in a concentration corresponding to the content in OmeGo alone or combined with 5-FU significantly reduced viability of all four CRC cell lines tested. The lowest concentration of OmeGo reduced viability to a higher degree both alone and in combination with 5-FU compared to the corresponding concentrations of DHA + EPA in three of the cell lines. Results suggest that a combination of OmeGo and 5-FU could have a potential as an alternative anti-cancer therapy for patients with CRC.
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Affiliation(s)
- Caroline H. H. Pettersen
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; (H.S.); (P.S.); (A.W.); (S.A.S.)
- Department of Surgery, St. Olav’s University Hospital, 7006 Trondheim, Norway
- Hofseth BioCare, Kipervikgata 13, 6003 Ålesund, Norway;
| | - Helle Samdal
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; (H.S.); (P.S.); (A.W.); (S.A.S.)
- Department of Surgery, St. Olav’s University Hospital, 7006 Trondheim, Norway
| | - Pål Sætrom
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; (H.S.); (P.S.); (A.W.); (S.A.S.)
- Department of Computer Science, Faculty of Information Technology and Electrical Engineering, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
- Bioinformatics Core Facility—BioCore, Norwegian University of Science and Technology (NTNU), 7006 Trondheim, Norway
- K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology (NTNU), 7006 Trondheim, Norway
| | - Arne Wibe
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; (H.S.); (P.S.); (A.W.); (S.A.S.)
- Department of Surgery, St. Olav’s University Hospital, 7006 Trondheim, Norway
| | | | - Svanhild A. Schønberg
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway; (H.S.); (P.S.); (A.W.); (S.A.S.)
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Khan I, Hussain M, Jiang B, Zheng L, Pan Y, Hu J, Khan A, Ashraf A, Zou X. Omega-3 long-chain polyunsaturated fatty acids: Metabolism and health implications. Prog Lipid Res 2023; 92:101255. [PMID: 37838255 DOI: 10.1016/j.plipres.2023.101255] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 10/04/2023] [Accepted: 10/09/2023] [Indexed: 10/16/2023]
Abstract
Recently, omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) have gained substantial interest due to their specific structure and biological functions. Humans cannot naturally produce these fatty acids (FAs), making it crucial to obtain them from our diet. This comprehensive review details n-3 LC-PUFAs and their role in promoting and maintaining optimal health. The article thoroughly analyses several sources of n-3 LC-PUFAs and their respective bioavailability, covering marine, microbial and plant-based sources. Furthermore, we provide an in-depth analysis of the biological impacts of n-3 LC-PUFAs on health conditions, with particular emphasis on cardiovascular disease (CVD), gastrointestinal (GI) cancer, diabetes, depression, arthritis, and cognition. In addition, we highlight the significance of fortification and supplementation of n-3 LC-PUFAs in both functional foods and dietary supplements. Additionally, we conducted a detailed analysis of the several kinds of n-3 LC-PUFAs supplements currently available in the market, including an assessment of their recommended intake, safety, and effectiveness. The dietary guidelines associated with n-3 LC-PUFAs are also highlighted, focusing on the significance of maintaining a well-balanced intake of n-3 PUFAs to enhance health benefits. Lastly, we highlight future directions for further research in this area and their potential implications for public health.
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Affiliation(s)
- Imad Khan
- State Key Laboratory of Food Science and Resources, National Engineering Research Center for Functional Food, National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, Jiangsu, China
| | - Mudassar Hussain
- State Key Laboratory of Food Science and Resources, National Engineering Research Center for Functional Food, National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, Jiangsu, China
| | - Bangzhi Jiang
- State Key Laboratory of Food Science and Resources, National Engineering Research Center for Functional Food, National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, Jiangsu, China
| | - Lei Zheng
- State Key Laboratory of Food Science and Resources, National Engineering Research Center for Functional Food, National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, Jiangsu, China
| | - Yuechao Pan
- State Key Laboratory of Food Science and Resources, National Engineering Research Center for Functional Food, National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, Jiangsu, China
| | - Jijie Hu
- State Key Laboratory of Food Science and Resources, National Engineering Research Center for Functional Food, National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, Jiangsu, China
| | - Adil Khan
- Key Laboratory of Industrial Biotechnology, Ministry of Education, Jiangnan University, Wuxi 214122, China
| | - Azqa Ashraf
- School of Food Science and Engineering, Ocean University of China, Qingdao 2666100, China
| | - Xiaoqiang Zou
- State Key Laboratory of Food Science and Resources, National Engineering Research Center for Functional Food, National Engineering Research Center of Cereal Fermentation and Food Biomanufacturing, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, Jiangsu, China.
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Pharmaceutical nanoformulation strategies to spatiotemporally manipulate oxidative stress for improving cancer therapies — exemplified by polyunsaturated fatty acids and other ROS-modulating agents. Drug Deliv Transl Res 2022; 12:2303-2334. [DOI: 10.1007/s13346-021-01104-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/30/2021] [Indexed: 12/18/2022]
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Choi WS, Xu X, Goruk S, Wang Y, Patel S, Chow M, Field CJ, Godbout R. FABP7 Facilitates Uptake of Docosahexaenoic Acid in Glioblastoma Neural Stem-like Cells. Nutrients 2021; 13:2664. [PMID: 34444824 PMCID: PMC8402214 DOI: 10.3390/nu13082664] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/26/2021] [Accepted: 07/29/2021] [Indexed: 01/14/2023] Open
Abstract
Glioblastoma (GBM) is an aggressive tumor with a dismal prognosis. Neural stem-like cells contribute to GBM's poor prognosis by driving drug resistance and maintaining cellular heterogeneity. GBM neural stem-like cells express high levels of brain fatty acid-binding protein (FABP7), which binds to polyunsaturated fatty acids (PUFAs) ω-6 arachidonic acid (AA) and ω-3 docosahexaenoic acid (DHA). Similar to brain, GBM tissue is enriched in AA and DHA. However, DHA levels are considerably lower in GBM tissue compared to adult brain. Therefore, it is possible that increasing DHA content in GBM, particularly in neural stem-like cells, might have therapeutic value. Here, we examine the fatty acid composition of patient-derived GBM neural stem-like cells grown as neurosphere cultures. We also investigate the effect of AA and DHA treatment on the fatty acid profiles of GBM neural stem-like cells with or without FABP7 knockdown. We show that DHA treatment increases DHA levels and the DHA:AA ratio in GBM neural stem-like cells, with FABP7 facilitating the DHA uptake. We also found that an increased uptake of DHA inhibits the migration of GBM neural stem-like cells. Our results suggest that increasing DHA content in the GBM microenvironment may reduce the migration/infiltration of FABP7-expressing neural stem-like cancer cells.
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Affiliation(s)
- Won-Shik Choi
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; (W.-S.C.); (X.X.); (Y.W.); (S.P.)
| | - Xia Xu
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; (W.-S.C.); (X.X.); (Y.W.); (S.P.)
| | - Susan Goruk
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada; (S.G.); (C.J.F.)
| | - Yixiong Wang
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; (W.-S.C.); (X.X.); (Y.W.); (S.P.)
| | - Samir Patel
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; (W.-S.C.); (X.X.); (Y.W.); (S.P.)
| | - Michael Chow
- Department of Surgery, University of Alberta, Edmonton, AB T6G 2B7, Canada;
| | - Catherine J. Field
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada; (S.G.); (C.J.F.)
| | - Roseline Godbout
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; (W.-S.C.); (X.X.); (Y.W.); (S.P.)
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Gonzalez Toledo SY, Wu J. Effect of Phospholipase A 1 and High-Pressure Homogenization on the Stability, Toxicity, and Permeability of Egg Yolk/Fish Oil Emulsions. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:9081-9089. [PMID: 32806113 DOI: 10.1021/acs.jafc.0c02478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Enzymatic treatment of egg yolk with phospholipases can enhance its emulsifying properties and thermal stability. Additionally, a two-step process (primary and secondary homogenization) could form emulsions with better stability. Thus, in this study we used a split-split-plot in time design to assess the effect of enzymatic treatment, processing, and storage conditions on the encapsulation efficiency, stability, toxicity, and permeability of egg yolk/fish oil emulsions stored up to 10 days at 45 °C. Egg yolk solutions before and after treatment with phospholipase A1 were used as carriers of fish oil containing ≥82% eicosapentaenoic and docosahexaenoic acids. Emulsions were formed by primary (24,000 rpm, 4 min) and secondary (200 MPa) homogenization. The combined effect of treatment with phospholipase A1 and secondary homogenization resulted in emulsions with improved stability, increased the encapsulation efficiency of the carriers, and reduced the release of oil to the particle surface, resulting in lower formation of oxidation products. At the end of storage time, none of the emulsions were toxic to Caco-2 cells at a concentration of 75 μg/mL medium, while nonencapsulated fish oil reduced cell viability to 81%. Only eicosapentaenoic acid was detected in the basolateral side of Caco-2:HT29 monolayers, and its apparent permeability from nonencapsulated fish oil was significantly lower than that from emulsions.
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Affiliation(s)
- Selene Yadira Gonzalez Toledo
- Department of Agricultural, Food and Nutritional Science, 4-10 Ag/For Centre, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - Jianping Wu
- Department of Agricultural, Food and Nutritional Science, 4-10 Ag/For Centre, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
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Xie X, Yu J, Zhao Z, Zheng Z, Xie M, Wang X, Han Z, Li G. Fabrication and drug release properties of curcumin-loaded silk fibroin nanofibrous membranes. ADSORPT SCI TECHNOL 2018. [DOI: 10.1177/0263617418820416] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
| | | | | | | | | | | | - Zhifen Han
- Shanghai University of Traditional Chinese Medicine, China
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Xu Y, Yang X, Gao D, Yang L, Miskimins K, Qian SY. Dihomo-γ-linolenic acid inhibits xenograft tumor growth in mice bearing shRNA-transfected HCA-7 cells targeting delta-5-desaturase. BMC Cancer 2018; 18:1268. [PMID: 30567534 PMCID: PMC6299961 DOI: 10.1186/s12885-018-5185-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 12/05/2018] [Indexed: 12/12/2022] Open
Abstract
Background We previously demonstrated that knockdown of delta-5-desaturase via siRNA transfection together with dihomo-γ-linolenic acid supplementation inhibited colon cancer cell growth and migration, by promoting the production of the anti-cancer byproduct 8-hydroxyoctanoic acid from Cyclooxygenase-2-catalyzed dihomo-γ-linolenic acid peroxidation. Here, we extend our study to investigate the effects of delta-5-desaturase-knockdown and the resulting intensified dihomo-γ-linolenic acid peroxidation in xenograft tumor mice model. Methods Four-week old nude mice bearing the human colon cancer cell HCA-7/C29 vs. its delta-5-desaturase knockdown analog (via shRNA transfection) were subject to 4-week treatments of: vehicle control, dihomo-γ-linolenic acid supplementation, 5-Fluorouracil, and combination of dihomo-γ-linolenic acid and 5-Fluorouracil. Tumor growth was monitored during the treatment. At the endpoint, the mice were euthanized and the tumor tissues were collected for further mechanism analysis. Results Delta-5-desaturase knockdown (shRNA) together with dihomo-γ-linolenic acid supplementation increased 8-hydroxyoctanoic acid production to a threshold level in xenograft tumors, which consequently induced p53-dependent apoptosis and reduced tumors significantly. The promoted 8-hydroxyoctanoic acid formation was also found to suppress the tumors’ metastatic potential via regulating MMP-2 and E-cadherin expressions. In addition, our in vivo data showed that delta-5-desaturase knockdown along with dihomo-γ-linolenic acid supplementation resulted in anti-tumor effects comparable to those of 5-Fluorouracil. Conclusions We have demonstrated that our paradigm-shifting strategy of knocking down delta-5-desaturase and taking advantage of overexpressed Cyclooxygenase-2 in tumor cells can be used for colon cancer suppression. Our research outcome will lead us to develop a better and safer anti-cancer therapy for patients. Electronic supplementary material The online version of this article (10.1186/s12885-018-5185-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yi Xu
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58105, USA
| | - Xiaoyu Yang
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58105, USA
| | - Di Gao
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58105, USA
| | - Liu Yang
- Department of Transplantation, Mayo Clinic Florida, Jacksonville, FL, 32224, USA
| | - Keith Miskimins
- Cancer Biology Research Center, Sanford Research, Sioux Falls, SD, 57104, USA
| | - Steven Y Qian
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58105, USA.
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Picou F, Debeissat C, Bourgeais J, Gallay N, Ferrié E, Foucault A, Ravalet N, Maciejewski A, Vallet N, Ducrocq E, Haddaoui L, Domenech J, Hérault O, Gyan E. n-3 Polyunsaturated fatty acids induce acute myeloid leukemia cell death associated with mitochondrial glycolytic switch and Nrf2 pathway activation. Pharmacol Res 2018; 136:45-55. [DOI: 10.1016/j.phrs.2018.08.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 08/03/2018] [Accepted: 08/20/2018] [Indexed: 12/31/2022]
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Fuentes NR, Kim E, Fan YY, Chapkin RS. Omega-3 fatty acids, membrane remodeling and cancer prevention. Mol Aspects Med 2018; 64:79-91. [PMID: 29627343 DOI: 10.1016/j.mam.2018.04.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 03/27/2018] [Accepted: 04/04/2018] [Indexed: 12/20/2022]
Abstract
Proteins are often credited as the macromolecule responsible for performing critical cellular functions, however lipids have recently garnered more attention as our understanding of their role in cell function and human health becomes more apparent. Although cellular membranes are the lipid environment in which many proteins function, it is now apparent that protein and lipid assemblies can be organized to form distinct micro- or nanodomains that facilitate signaling events. Indeed, it is now appreciated that cellular function is partly regulated by the specific spatiotemporal lipid composition of the membrane, down to the nanosecond and nanometer scale. Furthermore, membrane composition is altered during human disease processes such as cancer and obesity. For example, an increased rate of lipid/cholesterol synthesis in cancerous tissues has long been recognized as an important aspect of the rewired metabolism of transformed cells. However, the contribution of lipids/cholesterol to cellular function in disease models is not yet fully understood. Furthermore, an important consideration in regard to human health is that diet is a major modulator of cell membrane composition. This can occur directly through incorporation of membrane substrates, such as fatty acids, e.g., n-3 polyunsaturated fatty acids (n-3 PUFA) and cholesterol. In this review, we describe scenarios in which changes in membrane composition impact human health. Particular focus is placed on the importance of intrinsic lipid/cholesterol biosynthesis and metabolism and extrinsic dietary modification in cancer and its effect on plasma membrane properties.
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Affiliation(s)
- Natividad R Fuentes
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, USA; Faculty of Toxicology, Texas A&M University, USA
| | - Eunjoo Kim
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, USA; Department of Molecular and Cellular Medicine, Texas A&M University, USA
| | - Yang-Yi Fan
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, USA; Department of Nutrition & Food Science, Texas A&M University, USA
| | - Robert S Chapkin
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, USA; Faculty of Toxicology, Texas A&M University, USA; Department of Nutrition & Food Science, Texas A&M University, USA; Center for Translational Environmental Health Research, Texas A&M University, USA.
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12
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Eltweri AM, Howells LM, Thomas AL, Dennison AR, Bowrey DJ. Effects of Omegaven®, EPA, DHA and oxaliplatin on oesophageal adenocarcinoma cell lines growth, cytokine and cell signal biomarkers expression. Lipids Health Dis 2018; 17:19. [PMID: 29378575 PMCID: PMC5789622 DOI: 10.1186/s12944-018-0664-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 01/17/2018] [Indexed: 12/15/2022] Open
Abstract
Background There is limited evidence assessing the effects of omega-3 polyunsaturated fatty acids (PUFAs) on oesophageal adenocarcinoma, both in vitro and in vivo. We evaluated the effects of the omega-3 PUFA and oxaliplatin on OE33 and OE19 cells. Method The two oesophageal cells were treated with Omegaven® (fish oil emulsion), EPA, DHA and oxaliplatin and incubated for up to 144 h. Results The following inhibitory effects were observed on OE33 cells: EPA reduced cell growth by 39% (p = 0.001), DHA by 59% (p < 0.000) and Oxaliplatin by 77% (p < 0.000). For OE19 cells, the EPA reduced growth by 1% (p = 0.992), DHA by 26% (p = 0.019) and oxaliplatin by 76% (p < 0.000). For both cells, Omegaven® resulted in reduced cell growth at intermediate concentrations (20-40 μM) and increased cell growth at low (10 μM) and high (50 μM) concentrations. DHA, Omegaven® and oxaliplatin were associated with significant downregulation of VEGF and p53 protein, and upregulation of p21 protein. DHA, Omegaven® and Oxaliplatin also led to significant downregulation of the total ERK1/2 and Akt proteins. Conclusion DHA, Omegaven® and oxaliplatin were associated with downregulation of p53 and VEGF in both cells. Of the PUFAs studied, DHA alone or in combination (Omegaven®) had greater in vitro anti-cancer effects than EPA alone. Electronic supplementary material The online version of this article (10.1186/s12944-018-0664-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Amar M Eltweri
- Department of Surgery, University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Leicester, LE1 5WW, UK.
| | - Lynne M Howells
- Department of Cancer Studies, University of Leicester, Leicester, LE2 7LX, UK
| | - Anne L Thomas
- Department of Cancer Studies, University of Leicester, Leicester, LE2 7LX, UK
| | - Ashley R Dennison
- Department of Surgery, University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Leicester, LE1 5WW, UK
| | - David J Bowrey
- Department of Surgery, University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Leicester, LE1 5WW, UK.,Department of Cancer Studies, University of Leicester, Leicester, LE2 7LX, UK
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Yang CC, Hung CF, Chen BH. Preparation of coffee oil-algae oil-based nanoemulsions and the study of their inhibition effect on UVA-induced skin damage in mice and melanoma cell growth. Int J Nanomedicine 2017; 12:6559-6580. [PMID: 28919754 PMCID: PMC5592955 DOI: 10.2147/ijn.s144705] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Coffee grounds, a waste by-product generated after making coffee, contains approximately 15% coffee oil which can be used as a raw material in cosmetics. Algae oil rich in docosahexaenoic acid (DHA) has been demonstrated to possess anticancer and anti-inflammation functions. The objectives of this study were to develop a gas chromatography-mass spectrometry (GC-MS) method for the determination of fatty acids in coffee oil and algae oil and prepare a nanoemulsion for studying its inhibition effect on ultraviolet A-induced skin damage in mice and growth of melanoma cells B16-F10. A total of 8 and 5 fatty acids were separated and quantified in coffee oil and algae oil by GC-MS, respectively, with linoleic acid (39.8%) dominating in the former and DHA (33.9%) in the latter. A nanoemulsion with a particle size of 30 nm, zeta potential -72.72 mV, and DHA encapsulation efficiency 100% was prepared by using coffee oil, algae oil, surfactant (20% Span 80 and 80% Tween 80), and deionized water. Differential scanning calorimetry (DSC) analysis revealed a high stability of nanoemulsion when heated up to 110°C at a pH 6, whereas no significant changes in particle size distribution and pH occurred over a 90-day storage period at 4°C. Animal experiments showed that a dose of 0.1% coffee oil-algae oil nanoemulsion was effective in mitigating trans-epidermal water loss, skin erythema, melanin formation, and subcutaneous blood flow. Cytotoxicity test implied effective inhibition of melanoma cell growth by nanoemulsion with an IC50 value of 26.5 µg/mL and the cell cycle arrested at G2/M phase. A dose-dependent upregulation of p53, p21, cyclin B, and cyclin A expressions and downregulation of CDK1 and CDK2 occurred. Also, both Bax and cytochrome c expressions were upregulated and bcl-2 expression downregulated, accompanied by a rise in caspase-3, caspase-8, and caspase-9 activities for apoptosis execution. Collectively, the apoptosis pathway of melanoma cells B16-F10 may involve both mitochondria and death receptor.
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Affiliation(s)
| | - Chi-Feng Hung
- School of Medicine, Fu Jen Catholic University, Taipei, Taiwan
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A Critical Review on the Effect of Docosahexaenoic Acid (DHA) on Cancer Cell Cycle Progression. Int J Mol Sci 2017; 18:ijms18081784. [PMID: 28817068 PMCID: PMC5578173 DOI: 10.3390/ijms18081784] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 08/14/2017] [Accepted: 08/16/2017] [Indexed: 11/17/2022] Open
Abstract
Globally, there were 14.1 million new cancer diagnoses and 8.2 million cancer deaths in 2012. For many cancers, conventional therapies are limited in their successes and an improved understanding of disease progression is needed in conjunction with exploration of alternative therapies. The long chain polyunsaturated fatty acid, docosahexaenoic acid (DHA), has been shown to enhance many cellular responses that reduce cancer cell viability and decrease proliferation both in vitro and in vivo. A small number of studies suggest that DHA improves chemotherapy outcomes in cancer patients. It is readily incorporated into cancer cell membranes and, as a result there has been considerable research regarding cell membrane initiated events. For example, DHA has been shown to mediate the induction of apoptosis/reduction of proliferation in vitro and in vivo. However, there is limited research into the effect of DHA on cell cycle regulation in cancer cells and the mechanism(s) by which DHA acts are not fully understood. The purpose of the current review is to provide a critical examination of the literature investigating the ability of DHA to stall progression during different cell cycle phases in cancer cells, as well as the consequences that these changes may have on tumour growth, independently and in conjunction with chemotherapy.
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Lee JY, Sim TB, Lee JE, Na HK. Chemopreventive and Chemotherapeutic Effects of Fish Oil derived Omega-3 Polyunsaturated Fatty Acids on Colon Carcinogenesis. Clin Nutr Res 2017; 6:147-160. [PMID: 28770178 PMCID: PMC5539209 DOI: 10.7762/cnr.2017.6.3.147] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 07/13/2017] [Accepted: 07/17/2017] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is the third most common cause of cancer related death in the world. Multiple lines of evidence suggest that there is an association between consumption of dietary fat and colon cancer risk. Not only the amount but also the type and the ratio of fatty acids comprising dietary fats consumed have been implicated in the etiology and pathogenesis of colon cancer. Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have been known to inhibit development of colon cancer by downregulating the expression of genes involved in colon carcinogenesis and also by altering the membrane lipid composition. Data from laboratory, epidemiological, and clinical studies substantiate the beneficial role of n-3 PUFAs in preventing colitis and subsequent development of colon cancer. In addition, recent studies suggest that some n-3 PUFAs can be effective as an adjuvant with chemotherapeutic agents and other natural anticancer compounds in the management of colon cancer. In this review, we discuss chemopreventive and therapeutic effects of fish oil derived long chain n-3 PUFAs, particularly EPA and DHA, with focus on synergetic effects of which they exert when combined with chemotherapeutic agents and other natural compounds.
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Affiliation(s)
- Ja Young Lee
- Department of Food and Nutrition, College of Health and Wellness, Sungshin Women's University, Seoul 01133, Korea
| | - Tae-Bu Sim
- Department of Food and Nutrition, College of Health and Wellness, Sungshin Women's University, Seoul 01133, Korea
| | - Jeong-Eun Lee
- Department of Food and Nutrition, College of Health and Wellness, Sungshin Women's University, Seoul 01133, Korea
| | - Hye-Kyung Na
- Department of Food and Nutrition, College of Health and Wellness, Sungshin Women's University, Seoul 01133, Korea.,Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women's University, Seoul 01133, Korea
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Rani I, Sharma B, Kumar S, Kaur S, Agnihotri N. Apoptosis mediated chemosensitization of tumor cells to 5-fluorouracil on supplementation of fish oil in experimental colon carcinoma. Tumour Biol 2017; 39:1010428317695019. [PMID: 28349837 DOI: 10.1177/1010428317695019] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
5-Fluorouracil has been considered as a cornerstone therapy for colorectal cancer; however, it suffers from low therapeutic response rate and severe side effects. Therefore, there is an urgent need to increase the clinical efficacy of 5-fluorouracil. Recently, fish oil rich in n-3 polyunsaturated fatty acids has been reported to chemosensitize tumor cells to anti-cancer drugs. This study is designed to understand the underlying mechanisms of synergistic effect of fish oil and 5-fluorouracil by evaluation of tumor cell-associated markers such as apoptosis and DNA damage. The colon cancer was developed by administration of N,N-dimethylhydrazine dihydrochloride and dextran sulfate sodium salt. Further these animals were treated with 5-fluorouracil, fish oil, or a combination of both. In carcinogen-treated animals, a decrease in DNA damage and apoptotic index was observed. There was also a decrease in the expression of Fas, FasL, caspase 8, and Bax, and an increase in Bcl-2. In contrast, administration of 5-fluorouracil and fish oil as an adjuvant increased both DNA damage and apoptotic index by activation of both extrinsic and intrinsic apoptotic pathways as compared to the other groups. The increased pro-apoptotic effect by synergism of 5-fluorouracil and fish oil may be attributed to the incorporation of n-3 polyunsaturated fatty acids in membrane, which alters membrane fluidity in cancer cells. In conclusion, this study highlights that the induction of apoptotic pathway by fish oil may increase the susceptibility of tumors to chemotherapeutic regimens.
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Affiliation(s)
- Isha Rani
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - Bhoomika Sharma
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - Sandeep Kumar
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - Satinder Kaur
- Department of Biochemistry, Panjab University, Chandigarh, India
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Yan JK, Zhu J, Gong ZZ, Wen J, Xiao YT, Cai W, Zhang T. Olive Oil-Supplemented Lipid Emulsion Induces CELF1 Expression and Promotes Apoptosis in Caco-2 Cells. Cell Physiol Biochem 2017; 41:711-721. [DOI: 10.1159/000458430] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 01/08/2017] [Indexed: 12/15/2022] Open
Abstract
Background and Aims: Parenterally-administered lipid emulsion (LE) is a key cause of enterocyte apoptosis under total parenteral nutrition, yet the pathogenesis has not been fully understood. CUGBP, Elav-like family member 1 (CELF1) has been recently identified as a crucial modulator of apoptosis, and thus this study sought to investigate its role in the LE-induced apoptosis in vitro. Methods: Caco-2 cells were used as an in vitro model. The cells were treated with varying LEs derived from soybean oil, olive oil or fish oil, and changes in the apoptosis and CELF1 expression were assessed. Rescue study was performed using transient knockdown of CELF1 with specific siRNA prior to LE treatment. Regulation of CELF1 by LE treatment was studied using quantitative real-time PCR and Western blotting. Results: All the LEs up-regulated CELF1expression and induced apoptosis, but only olive oil-supplemented lipid emulsion (OOLE)-induced apoptosis was attenuated by depletion of CELF1. Up-regulation of apoptosis-inducing factor (AIF) was involved in OOLE-induced CELF1 dependent apoptosis. The protein expression of CELF1 was up-regulated by OOLE in a dose- and time-dependent manner, but the mRNA expression of CELF1 was unchanged. Analysis by polysomal profiling and nascent protein synthesis revealed that the regulation of CELF1 by OOLE treatment was mediated by directly accelerating its protein translation. Conclusion: OOLE-induces apoptosis in Caco-2 cells partially through up-regulation of CELF1.
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Michalak A, Mosińska P, Fichna J. Polyunsaturated Fatty Acids and Their Derivatives: Therapeutic Value for Inflammatory, Functional Gastrointestinal Disorders, and Colorectal Cancer. Front Pharmacol 2016; 7:459. [PMID: 27990120 PMCID: PMC5131004 DOI: 10.3389/fphar.2016.00459] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 11/14/2016] [Indexed: 12/12/2022] Open
Abstract
Polyunsaturated fatty acids (PUFAs) are bioactive lipids which modulate inflammation and immunity. They gained recognition in nutritional therapy and are recommended dietary supplements. There is a growing body of evidence suggesting the usefulness of PUFAs in active therapy of various gastrointestinal (GI) diseases. In this review we briefly cover the systematics of PUFAs and their metabolites, and elaborate on their possible use in inflammatory bowel disease (IBD), functional gastrointestinal disorders (FGIDs) with focus on irritable bowel syndrome (IBS), and colorectal cancer (CRC). Each section describes the latest findings from in vitro and in vivo studies, with reports of clinical interventions when available.
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Affiliation(s)
| | | | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of LodzLodz, Poland
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Abstract
Considerable debate exists regarding the potential antineoplastic effect of dietary long-chain n-3 PUFA contained in fatty fishes. Since the majority of published data has proven that their intake does not induce toxic or carcinogenic effects in humans, their possible preventive use against cancer has been suggested. On the other hand, it is unlikely that they could be effective in cancer patients as a single therapy. Nevertheless, a considerable effort has been put forth in recent years to evaluate the hypothesis that n-3 PUFA might improve the antineoplastic efficiency of currently used anticancer agents. The rationale for this therapeutic combinatory strategy is trying to increase cancer sensitivity to conventional therapies. This could allow the use of lower drug/radiation doses and, thereby, a reduction in the detrimental health effects associated with these treatments. We will here critically examine the studies that have investigated this possibility, by focusing particularly on the biological and molecular mechanisms underlying the antineoplastic effect of these combined treatments. A possible use of n-3 PUFA in combination with the innovative single-targeted anti-cancer therapies, that often are not completely devoid of dangerous side-effects, is also suggested.
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Gao K, Liang Q, Zhao ZH, Li YF, Wang SF. Synergistic anticancer properties of docosahexaenoic acid and 5-fluorouracil through interference with energy metabolism and cell cycle arrest in human gastric cancer cell line AGS cells. World J Gastroenterol 2016; 22:2971-2980. [PMID: 26973393 PMCID: PMC4779920 DOI: 10.3748/wjg.v22.i10.2971] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Revised: 11/22/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the synergistic effect of docosahexaenoic acid (DHA)/5-fluorouracil (5-FU) on the human gastric cancer cell line AGS and examine the underlying mechanism.
METHODS: AGS cells were cultured and treated with a series of concentrations of DHA and 5-FU alone or in combination for 24 and 48 h. To investigate the synergistic effect of DHA and 5-FU on AGS cells, the inhibition of cell proliferation was determined by MTT assay and cell morphology. Flow cytometric analysis was also used to assess cell cycle distribution, and the expression of mitochondrial electron transfer chain complexes (METCs) I, II and V in AGS cells was further determined by Western blot analysis.
RESULTS: DHA and 5-FU alone or in combination could markedly suppress the proliferation of AGS cells in a significant time and dose-dependent manner. DHA markedly strengthened the antiproliferative effect of 5-FU, decreasing the IC50 by 3.56-2.15-fold in an apparent synergy. The morphological changes of the cells were characterized by shrinkage, cell membrane blebbing and decreased adherence. Cell cycle analysis showed a shift of cells into the G0/G1 phase from the S phase following treatment with DHA or 5-FU (G0/G1 phase: 30.04% ± 1.54% vs 49.05% ± 6.41% and 63.39% ± 6.83%, respectively, P < 0.05; S phase: 56.76% ± 3.14% vs 34.75% ± 2.35% and 25.63% ± 2.21%, respectively, P < 0.05). Combination treatment of DHA and 5-FU resulted in a significantly larger shift toward the G0/G1 phase and subsequent reduction in S phase (G0/G1 phase: 69.06% ± 2.63% vs 49.05% ± 6.41% and 63.39% ± 6.83%, respectively, P < 0.05; S phase: 19.80% ± 4.30% vs 34.75% ± 2.35% and 25.63% ± 2.21%, respectively, P < 0.05). This synergy was also reflected in the significant downregulation of the expression of METCs in AGS cells.
CONCLUSION: Synergistic anticancer properties of DHA and 5-FU may involve interference with energy production of AGS cells via downregulation of METCs and cell cycle arrest.
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Eltweri AM, Thomas AL, Metcalfe M, Calder PC, Dennison AR, Bowrey DJ. Potential applications of fish oils rich in omega-3 polyunsaturated fatty acids in the management of gastrointestinal cancer. Clin Nutr 2016; 36:65-78. [PMID: 26833289 DOI: 10.1016/j.clnu.2016.01.007] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 12/01/2015] [Accepted: 01/09/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Despite advances in chemotherapeutic agents and surgical approaches for its management, gastrointestinal cancer still accounts for 27% of new cancer cases and 35% of cancer related mortality worldwide. Omega-3 polyunsaturated fatty acids (PUFAs) specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-inflammatory and anticancer activities and are used as immuno-nutrients. METHODS A literature search was conducted to identify primary research reporting on applications of the omega-3 PUFAs in gastrointestinal cancer. RESULTS Reported laboratory studies indicate a clear role for omega-3 PUFAs in preventing cancer development at various stages including cancer cell proliferation, survival, angiogenesis, inflammation and metastasis. In clinical settings, omega-3 PUFAs have been reported to improve the immune response, maintain lean body mass, improve quality of life and improve overall survival in patients with colorectal and pancreatic cancer. In contrast to other GI cancers, there is a strong connection between inflammation and oesophageal cancer. CONCLUSIONS Little work has been done exploring the role for omega-3 PUFAs in oesophageal cancer prevention and management. The authors are conducting a clinical trial investigating the use of parenteral omega-3 PUFAs supplementary to the standard of care (epirubicin, oxaliplatin and capecitabine palliative chemotherapy) in patients with advanced oesophagogastric cancer as a promising new therapeutic approach.
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Affiliation(s)
- A M Eltweri
- Department of Surgery, University Hospitals of Leicester, Leicester, LE1 5WW, United Kingdom.
| | - A L Thomas
- Department of Cancer Studies, University of Leicester, LE2 7LX, United Kingdom
| | - M Metcalfe
- Department of Surgery, University Hospitals of Leicester, Leicester, LE1 5WW, United Kingdom
| | - P C Calder
- Human Development & Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, United Kingdom
| | - A R Dennison
- Department of Surgery, University Hospitals of Leicester, Leicester, LE1 5WW, United Kingdom
| | - D J Bowrey
- Department of Surgery, University Hospitals of Leicester, Leicester, LE1 5WW, United Kingdom
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de Aguiar Pastore Silva J, Emilia de Souza Fabre M, Waitzberg DL. Omega-3 supplements for patients in chemotherapy and/or radiotherapy: A systematic review. Clin Nutr 2015; 34:359-66. [DOI: 10.1016/j.clnu.2014.11.005] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Revised: 11/03/2014] [Accepted: 11/05/2014] [Indexed: 12/29/2022]
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Maltese mushroom (Cynomorium coccineum L.) as source of oil with potential anticancer activity. Nutrients 2015; 7:849-64. [PMID: 25629557 PMCID: PMC4344564 DOI: 10.3390/nu7020849] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 01/14/2015] [Indexed: 01/05/2023] Open
Abstract
The present study aimed to examine the potential anticancer properties of fixed oil obtained from Maltese mushroom (Cynomorium coccineum L.), an edible, non-photosynthetic plant, used in traditional medicine of Mediterranean countries to treat various ailments and as an emergency food during the famine. We investigated the effect of the oil, obtained from dried stems by supercritical fractioned extraction with CO2, on B16F10 melanoma and colon cancer Caco-2 cell viability and lipid profile. The oil, rich in essential fatty acids (18:3n-3 and 18:2n-6), showed a significant growth inhibitory effect on melanoma and colon cancer cells. The incubation (24 h) with non-toxic oil concentrations (25 and 50 μg/mL) induced in both cancer cell lines a significant accumulation of the fatty acids 18:3n-3 and 18:2n-6 and an increase of the cellular levels of eicosapentaenoic acid (20:5n-3) with anticancer activity. Moreover, the oil exhibited the ability to potentiate the growth inhibitory effect of the antitumor drug 5-fluorouracil in Caco-2 cells and to influence the melanin content in B16F10 cells. The results qualify C. coccineum as a resource of oil, with potential benefits in cancer prevention, for nutraceutical and pharmaceutical applications.
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Rani I, Vaiphei K, Agnihotri N. Supplementation of fish oil augments efficacy and attenuates toxicity of 5-fluorouracil in 1,2-dimethylhydrazine dihydrochloride/dextran sulfate sodium-induced colon carcinogenesis. Cancer Chemother Pharmacol 2014; 74:309-22. [PMID: 24916547 DOI: 10.1007/s00280-014-2497-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Accepted: 05/22/2014] [Indexed: 12/20/2022]
Abstract
PURPOSE 5-Fluorouracil (5-FU) is used for the treatment of colorectal cancer, but has low therapeutic response rate and severe side effects. Recently, fish oil (FO) rich in n-3 polyunsaturated fatty acids has been preferred to chemosensitize tumor cells to anticancer drugs. Therefore, the current study is designed to evaluate chemotherapeutic efficacy and toxicity profile of 5-FU in combination with FO in 1,2-dimethylhydrazine dihydrochloride/dextran sulfate sodium (DMH/DSS)-induced colon cancer model. METHODS The therapeutic efficacy of 5-FU along with FO was analyzed through assessment of survival rate, tumor burden, volume, serum sialic acid levels, cytokeratin 19 (CK19) expression and index of cell proliferation such as cell cycle progression. Toxicological aspects were evaluated by standard functional and structural parameters related to spleen, gastrointestinal, liver and kidney. RESULTS In the present study, 5-FU in combination with FO increased the survival rate in carcinogen-treated animals. Synergism of 5-FU and FO was also reflected in significant inhibition in tumor growth and serum sialic acid levels in DMH/DSS model. Moreover, the combination dosage significantly augmented the inhibition of cell cycle progression, as shown by CK19 expression. Additionally, FO ameliorated hematologic depression, gastrointestinal, hepatic and renal toxicity caused by 5-FU as substantiated by a marked improvement in structural and functional alterations of these organs. CONCLUSION The supplementation of FO is potentially a promising option for increasing the therapeutic potential and mitigating the side effects of 5-FU.
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Affiliation(s)
- Isha Rani
- Department of Biochemistry, Panjab University, Chandigarh, 160014, India
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Effects of an oral nutritional supplement containing eicosapentaenoic acid on nutritional and clinical outcomes in patients with advanced non-small cell lung cancer: randomised trial. Clin Nutr 2014; 33:1017-23. [PMID: 24746976 DOI: 10.1016/j.clnu.2014.03.006] [Citation(s) in RCA: 166] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Revised: 01/29/2014] [Accepted: 03/18/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND Nutritional interventions have shown increased energy intake but not improvement in health-related quality of life (HRQL) or prognosis in non small cell lung cancer (NSCLC) patients. Eicosapentaenoic acid has been proposed to have anti-inflammatory, anticachectic and antitumoural effects. OBJECTIVE To compare the effect of an oral EPA enriched supplement with an isocaloric diet on nutritional, clinical and inflammatory parameters and HRQL in advanced NSCLC patients. DESIGN Patients with advanced NSCLC were randomized to receive diet plus oral nutritional supplement containing EPA (ONS-EPA) or only isocaloric diet (C). All patients received paclitaxel and cisplatin/carboplatin treatment. Weight, body composition, dietary intake, inflammatory parameters and HRQL were assessed at baseline and after the first and second cycles of chemotherapy. Response to chemotherapy and survival were evaluated. RESULTS Ninety two patients were analysed (46 ONS-EPA,46 C). ONS-EPA group had significantly greater energy (p < 0.001) and protein (p < 0.001) intake compared with control. Compared with baseline, patients receiving the ONS-EPA gained 1.6 ± 5 kg of lean body mass (LBM) compared with a loss of -2.0 ± 6 kg in the control (p = 0.01). Fatigue, loss of appetite and neuropathy decreased in the ONS-EPA group (p ≤ 0.05). There was no difference in response rate or overall survival between groups. CONCLUSION Patients with NSCLC receiving ONS-EPA significantly improves energy and protein intake, body composition. and decreased fatigue, loss of appetite and neuropathy. Registered with ClinicalTrials.gov (NCT01048970).
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Live and heat-killed Lactobacillus rhamnosus GG upregulate gene expression of pro-inflammatory cytokines in 5-fluorouracil-pretreated Caco-2 cells. Support Care Cancer 2014; 22:1647-54. [PMID: 24500789 DOI: 10.1007/s00520-014-2137-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2013] [Accepted: 01/13/2014] [Indexed: 01/16/2023]
Abstract
PURPOSE This study investigates whether post-chemotherapeutic use of live and heat-killed Lactobacillus rhamnosus GG can modulate the expression of three pro-inflammatory cytokines in 5-fluorouracil (5-FU)-induced intestinal mucositis in vitro. METHODS Live L. rhamnosus GG and heat-killed L. rhamnosus GG were observed using scanning electron microscopy. To establish the duration required for optimal expression of tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), and interleukin-12 (IL-12), 5 μM of 5-FU was selected to treat 10-day-old Caco-2 cells for 4, 6, 8, and 24 h. Caco-2 cells were treated with 5-FU (5 μM) for 4 h, followed by the administration of live L. rhamnosus GG (multiplicity of infection = 25), and heat-killed L. rhamnosus GG for 2 and 4 h. Finally, total cellular RNA was isolated to quantify mRNA expression of TNF-α, MCP-1, and IL-12 using real-time PCR. RESULTS The results demonstrated that heat-killed L. rhamnosus GG remained structurally intact with elongation. A biphasic upregulated expression of TNF-α, MCP-1, and IL-12 was observed in 5-FU-treated Caco-2 cells at 4 and 24 h. Compared to non-L. rhamnosus GG controls in 5-FU-pretreated Caco-2 cells, a 2-h treatment of heat-killed L. rhamnosus GG significantly upregulated the MCP-1 expression (p < 0.05), and both live and heat-killed L. rhamnosus GG treatments lasting 4 h upregulated the TNF-α and MCP-1 expression (p < 0.05). Only live L. rhamnosus GG upregulated the IL-12 expression (p < 0.05). CONCLUSIONS Post-chemotherapeutic use of live or heat-killed L. rhamnosus GG can upregulate the gene expression of 5-FU-induced pro-inflammatory cytokines in Caco-2 cells. Human intestinal epithelium may be vulnerable to the post-chemotherapeutic use of L. rhamnosus GG in 5-FU-induced mucositis that requires further in vivo studies for clarification.
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Cheah KY, Howarth GS, Bastian SEP. Grape seed extract dose-responsively decreases disease severity in a rat model of mucositis; concomitantly enhancing chemotherapeutic effectiveness in colon cancer cells. PLoS One 2014; 9:e85184. [PMID: 24465501 PMCID: PMC3897410 DOI: 10.1371/journal.pone.0085184] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 12/03/2013] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Mucositis is a serious disorder of the gastrointestinal tract that results from cancer chemotherapy. We investigated the effects of increasing grape seed extract doses on the severity of chemotherapy in a rat model and its coincident impact on chemotherapeutic effectiveness in colon cancer cells. DESIGN Female Dark Agouti rats were gavaged with grape seed extract (400-1000 mg/kg) or water (day 3-11) and were injected intraperitoneally with 5-Fluorouracil (150 mg/kg) or saline (control) on day 9 to induce mucositis. Daily metabolic data were collected and rats were sacrificed on day 12. Intestinal tissues were collected for histological and myeloperoxidase analyses. Caco-2 cell viability was examined in response to grape seed extract in combination with 5-Fluorouracil by 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide) assay. RESULTS Compared with 5-Fluorouracil controls, grape seed extract (400-1000 mg/kg) significantly decreased the histological damage score (P<0.05) in the jejunum. Grape seed extract (1000 mg/kg) increased jejunal crypt depth by 25% (P<0.05) in 5-Fluorouracil treated rats compared to 5-Fluorouracil controls, and attenuated the 5-Fluorouracil -induced reduction of mucosal thickness (25%, P<0.05). Grape seed extract (600 mg/kg) decreased myeloperoxidase activity by 55% (P<0.01) compared to 5-Fluorouracil controls. Grape seed extract was more effective at ameliorating 5-Fluorouracil induced intestinal injury, with effects most pronounced in the proximal jejunum. Grape seed extract (10-25 ug/mL) significantly enhanced the growth-inhibitory effects of 5-Fluorouracil by 26% (P<0.05) in Caco-2 cells and was more potent than 5-Fluorouracil at 50-100 µg/mL. CONCLUSION Grape seed extract may represent a new therapeutic option to decrease the symptoms of intestinal mucositis while concurrently impacting on the viability of colon cancer cells.
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Affiliation(s)
- Ker Yeaw Cheah
- School of Agriculture, Food and Wine, Waite Campus, University of Adelaide, South Australia, Australia
- Centre for Paediatric and Adolescent Gastroenterology, Children, Youth and Women's Health Service, North Adelaide, South Australia, Australia
| | - Gordon Stanley Howarth
- Centre for Paediatric and Adolescent Gastroenterology, Children, Youth and Women's Health Service, North Adelaide, South Australia, Australia
- School of Animal and Veterinary Sciences, Roseworthy Campus, University of Adelaide, South Australia, Australia
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Fauser JK, Matthews GM, Cummins AG, Howarth GS. Induction of apoptosis by the medium-chain length fatty acid lauric acid in colon cancer cells due to induction of oxidative stress. Chemotherapy 2013; 59:214-224. [PMID: 24356281 DOI: 10.1159/000356067] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 09/30/2013] [Indexed: 02/09/2025]
Abstract
BACKGROUND Fatty acids are classified as short-chain (SCFA), medium-chain (MCFA) or long-chain and hold promise as adjunctive chemotherapeutic agents for the treatment of colorectal cancer. The antineoplastic potential of MCFA remains underexplored; accordingly, we compared the MCFA lauric acid (C12:0) to the SCFA butyrate (C4:0) in terms of their capacity to induce apoptosis, modify glutathione (GSH) levels, generate reactive oxygen species (ROS), and modify phases of the cell cycle in Caco-2 and IEC-6 intestinal cell lines. METHODS Caco-2 and IEC-6 cells were treated with lauric acid, butyrate, or vehicle controls. Apoptosis, ROS, and cell cycle analysis were determined by flow cytometry. GSH availability was assessed by enzymology. RESULTS Lauric acid induced apoptosis in Caco-2 (p < 0.05) and IEC-6 cells (p < 0.05) compared to butyrate. In Caco-2 cells, lauric acid reduced GSH availability and generated ROS compared to butyrate (p < 0.05). Lauric acid reduced Caco-2 and IEC-6 cells in G0/G1and arrested cells in the S and G2/M phases. Lauric acid induced apoptosis in IEC-6 cells compared to butyrate (p < 0.05). Butyrate protected IEC-6 cells from ROS-induced damage, whereas lauric acid induced high levels of ROS compared to butyrate. CONCLUSION Compared to butyrate, lauric acid displayed preferential antineoplastic properties, including induction of apoptosis in a CRC cell line.
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Affiliation(s)
- J K Fauser
- School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Adelaide, S.A., Australia
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Tan YZ, Huang WG, Chen FY, Li J, Zhou JY, Wang LJ, Chen L, Zhu HL. n-3 Polyunsaturated fatty acids enhance the antitumor effect of 5-fluorouracil by inhibiting bcl-2 and mutant-p53. EUR J LIPID SCI TECH 2013. [DOI: 10.1002/ejlt.201300017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Yao-Zong Tan
- Guangdong Provincial Key Laboratory of Food; Nutrition and Health; School of Public Health; Sun Yat-Sen University; Guangzhou China
| | - Wen-Ge Huang
- Laboratory Animal Center of Sun Yat-Sen University; Guangzhou China
| | - Feng-Ying Chen
- Laboratory Animal Center of Sun Yat-Sen University; Guangzhou China
| | - Jie Li
- Laboratory Animal Center of Sun Yat-Sen University; Guangzhou China
| | - Jing-Ya Zhou
- Guangdong Provincial Key Laboratory of Food; Nutrition and Health; School of Public Health; Sun Yat-Sen University; Guangzhou China
| | - Li-Jun Wang
- Guangdong Provincial Key Laboratory of Food; Nutrition and Health; School of Public Health; Sun Yat-Sen University; Guangzhou China
| | - Li Chen
- Guangdong Provincial Key Laboratory of Food; Nutrition and Health; School of Public Health; Sun Yat-Sen University; Guangzhou China
| | - Hui-Lian Zhu
- Guangdong Provincial Key Laboratory of Food; Nutrition and Health; School of Public Health; Sun Yat-Sen University; Guangzhou China
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Rosa A, Scano P, Atzeri A, Deiana M, Falchi AM. Potential anti-tumor effects of Mugil cephalus processed roe extracts on colon cancer cells. Food Chem Toxicol 2013; 60:471-8. [DOI: 10.1016/j.fct.2013.08.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 08/02/2013] [Accepted: 08/04/2013] [Indexed: 01/03/2023]
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Mocellin MC, Pastore e Silva JDA, Camargo CDQ, Fabre MEDS, Gevaerd S, Naliwaiko K, Moreno YMF, Nunes EA, Trindade EBSDM. Fish oil decreases C-reactive protein/albumin ratio improving nutritional prognosis and plasma fatty acid profile in colorectal cancer patients. Lipids 2013; 48:879-88. [PMID: 23888317 DOI: 10.1007/s11745-013-3816-0] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Accepted: 07/08/2013] [Indexed: 11/25/2022]
Abstract
Previous studies have shown that n-3 polyunsaturated fatty acids n-3 (n-3 PUFA) have several anticancer effects, especially attributed to their ability to modulate a variety of genomic and immune responses. In this context, this randomized, prospective, controlled clinical trial was conducted in order to check whether supplementation of 2 g/day of fish oil for 9 weeks alters the production of inflammatory markers, the plasma fatty acid profile and the nutritional status in patients with colorectal cancer (CRC). Eleven adults with CRC in chemotherapy were randomized into two groups: (a) supplemented (SG) daily with 2 g/day of encapsulated fish oil [providing 600 mg/day of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] for 9 weeks (n = 6), and (b) control (CG) (n = 5). All outcomes were evaluated on the day before the first chemotherapy session and 9 weeks later. Plasma TNF-α, IL-1β, IL-10 and IL-17A, the pro/anti-inflammatory balance (ratio TNF-α/IL-10 and IL-1β/IL10) and serum albumin, showed no significant changes between times and study groups (p > 0.05). C-reactive protein (CRP) and the CRP/albumin ratio showed opposite behavior in groups, significantly reducing their values in SG (p < 0.05). Plasma proportions of EPA and DHA increased 1.8 and 1.4 times, respectively, while the ARA reduced approximately 0.6 times with the supplementation (9 weeks vs baseline, p < 0.05). Patients from SG gained 1.2 kg (median) while the CG lost -0.5 kg (median) during the 9 weeks of chemotherapy (p = 0.72). These results demonstrate that 2 g/day of fish oil for 9 weeks of chemotherapy improves CRP values, CRP/albumin status, plasma fatty acid profile and potentially prevents weight loss during treatment.
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Affiliation(s)
- Michel Carlos Mocellin
- Post-Graduate Program of Nutrition, Department of Nutrition, Federal University of Santa Catarina, Reitor João David Ferreira Lima Campus, Trindade, Florianópolis, SC, 88040-970, Brazil.
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Cai F, Granci V, Sorg O, Buchegger F, Pichard C, Dupertuis YM. Vitamin E content in fish oil emulsion does not prevent lipoperoxidative effects on human colorectal tumors. Nutrition 2012; 29:450-6. [PMID: 23085012 DOI: 10.1016/j.nut.2012.06.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Revised: 06/13/2012] [Accepted: 06/26/2012] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The anticancer action exerted by polyunsaturated fatty acid peroxidation may not be reproduced by commercially available lipid emulsions rich in vitamin E. Therefore, we evaluated the effects of fish oil (FO) emulsion containing α-tocopherol 0.19 g/L on human colorectal adenocarcinoma cells and tumors. METHODS HT-29 cell growth, survival, apoptosis, and lipid peroxidation were analyzed after a 24-h incubation with FO 18 to 80 mg/L. Soybean oil (SO) emulsion was used as an isocaloric and isolipidic control. In vivo, nude mice bearing HT-29 tumors were sacrificed 7 d after an 11-d treatment with intravenous injections of FO or SO 0.2 g ∙ kg(-1) ∙ d(-1) FO or SO to evaluate tumor growth, necrosis, and lipid peroxidation. RESULTS The FO inhibited cell viability and clonogenicity in a dose-dependent manner, whereas SO showed no significant effect compared with untreated controls. Lipid peroxidation and cell apoptosis after treatment with FO 45 mg/L were increased 2.0-fold (P < 0.01) and 1.6-fold (P = 0.04), respectively. In vivo, FO treatment did not significantly affect tumor growth. However, immunohistochemical analyses of tumor tissue sections showed a decrease of 0.6-fold (P < 0.01) in the cell proliferation marker Ki-67 and an increase of 2.3-fold (P = 0.03) in the necrotic area, whereas malondialdehyde and total peroxides were increased by 1.9-fold (P = 0.09) and 7.0-fold (P < 0.01), respectively, in tumors of FO-treated compared with untreated mice. CONCLUSION These results suggest that FO but not SO has an antitumor effect that can be correlated with lipid peroxidation, despite its vitamin E content.
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Affiliation(s)
- Fang Cai
- Nutrition, Geneva University Hospital, Geneva, Switzerland
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Skender B, Vaculova AH, Hofmanova J. Docosahexaenoic fatty acid (DHA) in the regulation of colon cell growth and cell death: a review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2012; 156:186-99. [PMID: 23069883 DOI: 10.5507/bp.2012.093] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 09/24/2012] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Experimental, epidemiological and clinical data substantiate the beneficial role of n-3 polyunsaturated fatty acids (PUFAs) in preventing inflammation and cancer of the colon. This review covers the unsaturated docosahexaenoic fatty acid (DHA), describes some of its important cellular and molecular mechanisms, its interaction with another dietary lipid, butyrate and with endogenous apoptotic regulators of the tumour necrosis factor (TNF) family. We also discuss the clinical impact of this knowledge and the use of these lipids in colon cancer prevention and treatment. RESULTS From the literature, DHA has been shown to suppress the growth, induce apoptosis in colon cancer cells in vitro and decrease the incidence and growth of experimental tumours in vivo. Based on these data and our own experimental results, we describe and discuss the possible mechanisms of DHA anticancer effects at various levels of cell organization. We show that DHA can sensitize colon cancer cells to other chemotherapeutic/chemopreventive agents and affect the action of physiological apoptotic regulators of the TNF family. CONCLUSION Use of n-3 PUFAs could be a relatively non-toxic form of supportive therapy for improving colon cancer treatment and slowing down or preventing its recurrence. However, it is necessary to use them with caution, based on solid scientific evidence of their mechanisms of action from the molecular to the cellular and organism levels.
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Affiliation(s)
- Belma Skender
- Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i. Brno, Czech Republic
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Hajjaji N, Bougnoux P. Selective sensitization of tumors to chemotherapy by marine-derived lipids: a review. Cancer Treat Rev 2012; 39:473-88. [PMID: 22850619 DOI: 10.1016/j.ctrv.2012.07.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2012] [Revised: 06/27/2012] [Accepted: 07/02/2012] [Indexed: 12/21/2022]
Abstract
Despite great improvements, a significant proportion of cancer patients still die, mainly because of the development of metastases. At this stage, current treatments still rely heavily on conventional chemotherapy for most cancers. The efficacy of chemotherapy is dose-dependent, which is limited by toxicity to non-tumor tissues, as a result of its poor tumor selectivity. To improve survival length and preserve quality of life, the challenge is to develop approaches aimed at increasing chemotherapy toxicity to tumor tissue while not affecting non-tumor tissues. Marine-derived lipids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have the potential to differentially sensitize tissues to chemotherapy. These lipids enhance the cytotoxicity of 15 anticancer drugs (antimetabolites, alkylating or intercalating agents, microtubule stabilizers, Abl tyrosine kinase inhibitor and arsenic trioxide) to a variety of cancer cell lines or tumors in animals, used as models for breast, prostate, colonic, lung, cervical, ovarian cancers, neuroblastomas, leukemia or lymphomas. However, DHA and EPA do not sensitize non-tumor tissues to anticancer drugs, which suggests that the effect of these lipids is tumor selective. Two phase II clinical trials already support these results, and randomized, phase III trials are ongoing. In this review, we discuss the double-faceted properties of these lipids, and then focus on their potential for transfer to the patient in the light of current therapeutic strategies. Should their beneficial effects be confirmed, the consequences could be considerable by opening up the prospect of systematic supplementation during cancer treatment, a significant shift in current cancer therapeutic paradigms.
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Affiliation(s)
- Nawale Hajjaji
- Cancer Research Laboratory, University Hospital of Tours, France.
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Omega-3 fatty acids and cancers: a systematic update review of epidemiological studies. Br J Nutr 2012; 107 Suppl 2:S228-39. [PMID: 22591896 DOI: 10.1017/s0007114512001614] [Citation(s) in RCA: 159] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Experimental models showed consistently a modulation of carcinogenesis by omega 3 polyunsaturated fatty acids (ω3 PUFA). Fish intake is often described as part of a beneficial dietary pattern. However, observational epidemiological studies on the relationship between ω3 PUFA reported conflicting results. The objective of this systematic review is to determine whether there exists any progress in the evaluation of the causal relationship between dietary ω3 PUFA and cancers since the previous FAO/OMS expert consultation and whether it is possible to propose preventive and/or adjuvant therapeutic recommendations. Prospective and case-control observational studies published since 2007 and meeting validity criteria were considered together with RCT. Experimental studies are mentioned to provide for biological plausibility. When evaluating the level of evidence, a portfolio approach was used, weighted by a hierarchy giving higher importance to prospective studies followed by RCT if any. There is a probable level of evidence that ALA per se is neither a risk factor nor a beneficial factor with regards to cancers. Observational studies on colorectal, prostate and breast cancers only provided limited evidence suggesting a possible role of LC-ω3PUFA in cancer prevention because insufficient homogeneity of the observations. Explanation for heterogeneity might be the inherent difficulties associated with epidemiology (confounding and dietary pattern context, measurement error, level of intake, genetic polymorphism). The role of LC-ω3PUFA as adjuvant, might be considered of possible use, in view of the latest RCT on lung cancers even if RCT on other cancers still need to be undertaken.
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Sala-Vila A, Calder PC. Update on the relationship of fish intake with prostate, breast, and colorectal cancers. Crit Rev Food Sci Nutr 2012; 51:855-71. [PMID: 21888535 DOI: 10.1080/10408398.2010.483527] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
A systematic review of prospective cohort and case-control studies investigating relationships between the intake of fish and incidence of prostate, breast, or colorectal cancers was conducted. A total of 106 studies fulfilled the requirements stated in the "Search strategy and selection criteria." Among 273 estimates of association reported by these studies, 53 indicated decreased risk while 12 indicated increased risk associated with fish intake. The hypothesis linking fish consumption and low cancer incidence appears to be supported by little epidemiological data. However, there are several factors that may mask potential protective associations with fish intake. The type and the amount of fish eaten, the cooking method, the stage of the cancer and, amongst women, menopausal status may all be important factors that relate to whether fish is protective or not. Future epidemiologic studies with a clearer assessment of these factors are needed to know more about the effects of fish consumption on cancer risk. Therefore, until there are better measures of dietary exposure or biomarkers to correlate self-report, no conclusion can be drawn regarding the recommendation for increasing fish consumption in general to reduce the risk of developing the most common cancers in Western societies.
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Affiliation(s)
- Aleix Sala-Vila
- Institute of Human Nutrition and Developmental Origins of Health and Disease, School of Medicine, University of Southampton , Southampton , SO16 6YD, United Kingdom
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Novel Anticancer Platinum(IV) Complexes with Adamantylamine: Their Efficiency and Innovative Chemotherapy Strategies Modifying Lipid Metabolism. Met Based Drugs 2011; 2008:417897. [PMID: 18414587 PMCID: PMC2291354 DOI: 10.1155/2008/417897] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2007] [Revised: 10/08/2007] [Accepted: 10/18/2007] [Indexed: 11/18/2022] Open
Abstract
The impressive impact of cisplatin on cancer on one side and severe side effects, as well as the development of drug resistance during treatment on the other side, were the factors motivating scientists to design and synthesize new more potent analogues lacking disadvantages of cisplatin. Platinum(IV) complexes represent one of the perspective groups of platinum-based drugs. In this review, we summarize recent findings on both in vitro and in vivo effects of platinum(IV) complexes with adamantylamine. Based on a literary overview of the mechanisms of activity of platinum-based cytostatics, we discuss opportunities for modulating the effects of novel platinum complexes through interactions with apoptotic signaling pathways and with cellular lipids, including modulations of the mitochondrial cell death pathway, oxidative stress, signaling of death ligands, lipid metabolism/signaling, or intercellular communication. These approaches might significantly enhance the efficacy of both novel and established platinum-based cytostatics.
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Abstract
The prevalence of malnutrition among critically ill patients, especially those with a protracted clinical course, has remained largely unchanged over the last two decades. The metabolic response to stress, injury, surgery, or inflammation cannot be accurately predicted and these metabolic alterations may change during the course of illness. Both underfeeding and overfeeding are common in intensive care units (ICU), resulting in large energy and other nutritional imbalances. Systematic research and clinical trials on various aspects of nutritional support in the ICU are limited and make it challenging to compile evidence-based practice guidelines.
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Murphy RA, Mourtzakis M, Chu QSC, Baracos VE, Reiman T, Mazurak VC. Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer. Cancer 2011; 117:3774-80. [DOI: 10.1002/cncr.25933] [Citation(s) in RCA: 158] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2010] [Revised: 12/06/2010] [Accepted: 12/21/2010] [Indexed: 01/05/2023]
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Sala-Vila A, Folkes J, Calder PC. The effect of three lipid emulsions differing in fatty acid composition on growth, apoptosis and cell cycle arrest in the HT-29 colorectal cancer cell line. Clin Nutr 2009; 29:519-24. [PMID: 19945772 DOI: 10.1016/j.clnu.2009.11.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2009] [Revised: 11/09/2009] [Accepted: 11/10/2009] [Indexed: 11/19/2022]
Abstract
BACKGROUND & AIMS An in vitro study showed that a lipid emulsion containing fish oil (FO) slows the growth of colon cancer cells and enhances their sensitivity to 5-fluorouracil (FU). The aim was to confirm this finding and to compare such an emulsion with an alternative to lowered n-6 fatty acid exposure. METHODS We determined the number of viable cells, apoptosis and cell cycle distribution of HT-29 cells after exposure to one of three lipid emulsions. Cell cycle distribution was also assessed after treatment with lipid emulsions and FU. RESULTS The lipid emulsion containing FO induced a significant growth inhibitory effect without changing the percentage of apoptotic cells. Exposure to the other lipid emulsions had no effect on growth and decreased apoptosis. Each lipid emulsion potentiated the S phase-halting effect of 1 and 10microM FU. This effect also occurred at 0.1microM FU when the cells were exposed to the FO containing lipid emulsion. CONCLUSIONS A lipid emulsion containing FO has a growth inhibitory effect on a human colon adenocarcinoma cell line, an effect not due to the induction of apoptosis, and potentiated the S phase-halting effect of FU. Thus, an FO lipid emulsion may be of benefit in colorectal cancer.
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Affiliation(s)
- Aleix Sala-Vila
- Institute of Human Nutrition and Developmental Origins of Health and Disease Division, School of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom
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Calviello G, Serini S, Piccioni E, Pessina G. Antineoplastic effects of n-3 polyunsaturated fatty acids in combination with drugs and radiotherapy: preventive and therapeutic strategies. Nutr Cancer 2009; 61:287-301. [PMID: 19373602 DOI: 10.1080/01635580802582777] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Many data support the beneficial effect of n-3 polyunsaturated fatty acids (PUFAs) as chemopreventive and chemotherapeutic agents in the treatment of several chronic pathologies including cancer. Different molecular mechanisms have been proposed to explain their effects, including alterations in arachidonic acid oxidative metabolism and metabolic conversion of n-3 PUFAs to novel discovered bioactive derivatives; modification of oxidative stress; changes in cell membrane fluidity and structure and altered metabolism and function of membrane proteins. Considerable knowledge has been recently gathered on the possible beneficial effects of n-3 PUFAs administered in combination with different antineoplastic drugs and radiotherapy against melanoma, leukemia, neuroblastoma, and colon, breast, prostate, and lung cancer. The efficacy of these combinations has been demonstrated both in vivo and in vitro, and clinical trials have also been conducted. The aim of this review is to analyze all the n-3 PUFA combinations investigated so far, their efficacy, and the possible molecular mechanisms involved. It would be highly auspicable that the detailed analysis of the literature in this field could further support the common use of n-3 PUFAs in combination with other chemopreventive agents and warrant more clinical investigations designed to test the effectiveness of n-3 PUFA treatments coupled with conventional antineoplastic therapies.
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Affiliation(s)
- G Calviello
- Institute of General Pathology, Catholic University, L.go F. Vito, 1, Rome 00168, Italy.
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Patten GS, Augustin MA, Sanguansri L, Head RJ, Abeywardena MY. Site specific delivery of microencapsulated fish oil to the gastrointestinal tract of the rat. Dig Dis Sci 2009; 54:511-21. [PMID: 18618251 DOI: 10.1007/s10620-008-0379-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2008] [Accepted: 06/03/2008] [Indexed: 12/09/2022]
Abstract
The aim of this study was to design food grade matrices to deliver microencapsulated fish oil to the large bowel of the rat where the potential exists to retard inflammation and cancer development. Digestion in simulated gastric fluid and intestinal fluid demonstrated that only 4-6% of oil was released from the following dried emulsion formulations: 50% fish oil encapsulated in heated casein-glucose-dried glucose syrup (1:1:1) (Cas-Glu-DGS-50); 25% fish oil in casein-modified resistant starch (Hylon VII) (1:1) (Cas-Hylon-25); or 25% fish oil in Cas-Glu-Hylon (1:1:1) (Cas-Glu-Hylon-25). A short-term gavage study (0-12 h) with fish oil and Cas-Glu-DGS-50 demonstrated the appearance of fish oil long chain (LC) n-3 polyunsaturated fatty acids (PUFA) into the plasma indicating specific small intestinal absorption with little LC n-3 PUFA reaching the large bowel. In a 2-week-long term, daily gavage study, the bioavailability of fish oil and fish oil in Cas-Glu-DGS-50 or Cas-Hylon-25 demonstrated that fish oil and Cas-Glu-DGS-50 LC n-3 PUFA were incorporated into the tissue of the small intestine and colon, whereas Cas-Hylon-25 was resistant to degradation in the small intestine. The use of modified Hylon VII for targeted colonic delivery was confirmed in the final short-term gavage study (0-14 h) using Cas-Glu-Hylon-25 with [(14)C]-trilinolenin as a marker incorporated into the microcapsules, where up to 60% of the labeled oil reached the large bowel. Depending on the microencapsulating matrix employed, fish oil can be delivered selectively to the small intestine or to a high degree to the large bowel.
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Affiliation(s)
- Glen S Patten
- CSIRO Human Nutrition, P.O. Box 10041, Adelaide BC, SA, 5000, Australia.
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Serini S, Piccioni E, Merendino N, Calviello G. Dietary polyunsaturated fatty acids as inducers of apoptosis: implications for cancer. Apoptosis 2009; 14:135-52. [DOI: 10.1007/s10495-008-0298-2] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Fukunaga K, Hossain Z, Takahashi K. Marine phosphatidylcholine suppresses 1,2-dimethylhydrazine-induced colon carcinogenesis in rats by inducing apoptosis. Nutr Res 2008; 28:635-40. [DOI: 10.1016/j.nutres.2008.05.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2007] [Revised: 04/03/2008] [Accepted: 05/09/2008] [Indexed: 11/30/2022]
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Biondo PD, Brindley DN, Sawyer MB, Field CJ. The potential for treatment with dietary long-chain polyunsaturated n-3 fatty acids during chemotherapy. J Nutr Biochem 2008; 19:787-96. [PMID: 18602809 DOI: 10.1016/j.jnutbio.2008.02.003] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2007] [Revised: 02/08/2008] [Accepted: 02/15/2008] [Indexed: 12/19/2022]
Abstract
Dietary intake of long-chain omega-3 (or n-3) polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) can affect numerous processes in the body, including cardiovascular, neurological and immune functions, as well as cancer. Studies on human cancer cell lines, animal models and preliminary trials with human subjects suggest that administration of EPA and DHA, found naturally in our diet in fatty fish, can alter toxicities and/or activity of many drugs used to treat cancer. Multiple mechanisms are proposed to explain how n-3 PUFA modulate the tumor cell response to chemotherapeutic drugs. n-3 PUFA are readily incorporated into cell membranes and lipid rafts, and their incorporation may affect membrane-associated signaling proteins such as Ras, Akt and Her-2/neu. Due to their high susceptibility to oxidation, it has also been proposed that n-3 PUFA may cause irreversible tumor cell damage through increased lipid peroxidation. n-3 PUFA may increase tumor cell susceptibility to apoptosis by altering expression or function of apoptotic proteins, or by modulating activity of survival-related transcription factors such as nuclear factor-kappaB. Some studies suggest n-3 PUFA may increase drug uptake or even enhance drug activation (e.g., in the case of some nucleoside analogue drugs). Further research is warranted to identify specific mechanisms by which n-3 PUFA increase chemotherapy efficacy and to determine the optimal cellular/membrane levels of n-3 PUFA required to promote these mechanisms, such that these fatty acids may be prescribed as adjuvants to chemotherapy.
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Affiliation(s)
- Patricia D Biondo
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5
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Fish oil infusion reverses 5-fluorouracil-induced impairments in mucosal immunity in mice. Clin Nutr 2008; 27:269-75. [PMID: 18249477 DOI: 10.1016/j.clnu.2007.12.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2007] [Revised: 10/27/2007] [Accepted: 12/06/2007] [Indexed: 02/02/2023]
Abstract
BACKGROUND & AIMS Anticancer drugs frequently have deleterious effects on host defense against infection, limiting their clinical application. We previously demonstrated continuous infusion of 5-fluorouracil (5FU) to reduce gut associated lymphoid tissue (GALT) mass and secretory IgA levels. This study was designed to examine the effects of concomitant infusion of fish oil on gut mucosal immunity in mice receiving 5FU. METHODS Male ICR mice were randomized to the control (n=12), 5FU (n=12), or 5FU+FO (n=10) group. The 5FU and 5FU+FO groups received continuous IV infusion of 5FU at 10 mg/kg for 5 days. The 5FU+FO group was given a simultaneous infusion of 10 ml/kg of a 10% fish oil emulsion. The controls received normal saline at 0.3 ml/h. During these treatments, all mice were allowed free access to chow and water ad libitum. Then, the mice were sacrificed and GALT lymphocytes were isolated from Peyer's patches (PPs), the intraepithelial space (IE), and the lamina propria (LP). Small intestinal, nasal and broncho-alveolar (BALF) washings were also obtained. Lymphocyte yields from each site and phenotypes (CD4, CD8, alphabetaTCR, gammadeltaTCR, B220) were determined. IgA levels in the washings were measured with ELISA. RESULTS The 5FU group had significantly lower IE and LP lymphocyte numbers and small intestinal and BALF IgA levels than the control group, with no differences in the percentages of any phenotypes. However, fish oil infusion restored IE and LP lymphocyte numbers and BALF IgA to control group levels. CONCLUSION Fish oil infusion along with 5FU preserves GALT lymphocyte numbers and respiratory IgA levels.
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Hering J, Garrean S, Dekoj TR, Razzak A, Saied A, Trevino J, Babcock TA, Espat NJ. Inhibition of Proliferation by Omega-3 Fatty Acids in Chemoresistant Pancreatic Cancer Cells. Ann Surg Oncol 2007; 14:3620-8. [PMID: 17896154 DOI: 10.1245/s10434-007-9556-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2007] [Revised: 07/06/2007] [Accepted: 07/07/2007] [Indexed: 02/03/2023]
Abstract
BACKGROUND Pancreatic cancer-gemcitabine (GEM) chemoresistance has been demonstrated to be associated with enhanced NF-kB activation and antiapoptotic protein synthesis. The well-known capacity of omega-3 fatty acids (n-3 FAs) to inhibit NF-kB activation and promote cellular apoptosis has the potential to restore or facilitate gemcitabine chemosensitivity. METHODS Four pancreatic cancer cell lines (MIA PaCa-2, BxPC-3, PANC-1, and L3.6), each with distinct basal NF-kB and differing GEM sensitivity profiles, were administered: 100 uM of (1) n-3FA, (2) n-6FA, (3) GEM, (4) n-3FA + GEM, or (5) n-6FA + GEM for 24 and 48 hours. Proliferation was assessed using the WST-1 assay. To define the mechanism(s) of altered proliferation, electron mobility shift assay for NF-kB activity, western blots of phoshoStat3, phosphoIkappaB, and poly(ADP-ribose) polymerase (PARP) cleavage were performed in the MIA PaCa-2 cell line. RESULTS All cell lines demonstrated a time/dose-dependent inhibition of proliferation in response to n-3FA. For MIA PaCa-2 cells, n-3FA and n-3FA + GEM treatment resulted in reduction of I-kB phosphorylation and NF-kB activation when compared with n-6FA control. n-3FA and combination treatment also significantly decreased Stat3 phosphorylation, whereas GEM alone had no effect. n-3FAs and n-3FA + GEM groups demonstrated increased PARP cleavage, mirroring NF-kB activity and Stat3 phosphorylation. CONCLUSIONS n-3 FA treatment is specifically associated with inhibition of proliferation in these four pancreatic cell lines irrespective of varied gemcitabine resistance. An experimental paradigm to screen for potential contributory mechanism(s) in altered pancreatic cancer cellular proliferation was defined, and using this approach the co-administration of n-3 FA with GEM inhibited GEM-induced NF-kB activation and restored apoptosis in the MIA PaCa-2 cell-line.
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Affiliation(s)
- Justin Hering
- Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, USA
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Dupertuis YM, Meguid MM, Pichard C. Colon cancer therapy: new perspectives of nutritional manipulations using polyunsaturated fatty acids. Curr Opin Clin Nutr Metab Care 2007; 10:427-32. [PMID: 17563460 DOI: 10.1097/mco.0b013e3281e2c9d4] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Recent advances in the development of new therapeutic strategies combining conventional adjuvant radio/chemotherapy with nutritional manipulations with n-3 polyunsaturated fatty acids (PUFAs) are presented. RECENT FINDINGS Studies in cell culture and tumour-bearing animals have reported the ability of long-chain n-3 PUFAs to enhance the cytotoxicity of several anticancer drugs. In colon cancer, combination of n-3 PUFAs with 5-fluorouracil resulted in an additive growth inhibitory effect on different cell lines. Moreover, recent findings suggest that eicosapentaenoic or docosahexaenoic acid may be used to enhance tumour radiosensitivity while reducing mucosal/epidermal radiotoxicity similar to radioprotective agents. The underlying mechanism is probably mediated through lipid peroxidation because the antitumour effect of n-3 PUFAs is shared with the n-6 PUFA, arachidonic acid, and abolished by vitamin E. In vivo, the use of n-3 PUFAs may provide an additional advantage compared with n-6 PUFAs. Downregulation of eicosanoid synthesis from cyclooxygenase II may reduce angiogenesis, inflammation and metastasis induction. SUMMARY New insights suggest that n-3 PUFAs may play an important role not only in cancer prevention but also in cancer management. They may act synergistically with radio/chemotherapy to kill tumour cells by increasing oxidative stress while reducing angiogenesis, inflammation and metastasis induction.
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