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Torres C, Mancinelli G, Chen JWE, Cordoba-Chacon J, Pins D, Saeed S, McKinney R, Castellanos K, Orsi G, Singhal M, Patel A, Acebedo J, Coleman A, Heneche J, Yalagala PCR, Subbaiah PV, Leal C, Grimaldo S, Ortuno FM, Bishehsari F, Grippo PJ. Cell Membrane Fatty Acids and PIPs Modulate the Etiology of Pancreatic Cancer by Regulating AKT. Nutrients 2024; 17:150. [PMID: 39796583 PMCID: PMC11722924 DOI: 10.3390/nu17010150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/17/2024] [Accepted: 12/20/2024] [Indexed: 01/13/2025] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the worst solid malignancies in regard to outcomes and metabolic dysfunction leading to cachexia. It is alarming that PDAC incidence rates continue to increase and warrant the need for innovative approaches to combat this disease. Due to its relatively slow progression (10-20 years), prevention strategies represent an effective means to improve outcomes. One of the risk factors for many cancers and for pancreatic cancer in particular is diet. Hence, our objective is to understand how a diet rich in ω3 and ω6 polyunsaturated fatty acids affects the progression of this disease. Methods: We investigated polyunsaturated fatty acid (PUFA) effects on disease progression employing both in vitro (PDAC cell lines) and in vivo (EL-Kras and KC mice) approaches. Also, we gathered data from the National Health and Nutrition Examination Survey (NHANES) and the National Cancer Institute (NCI) from 1999 to 2017 for a retrospective observational study. Results: The consumption of PUFAs in a patient population correlates with increased PDAC incidence, particularly when the ω3 intake increases to a lesser extent than ω6. Our data demonstrate dietary PUFAs can be incorporated into plasma membrane lipids affecting PI3K/AKT signaling and support the emergence of membrane-targeted therapies. Moreover, we show that the phospholipid composition of a lipid nanoparticle (LNP) can impact the cell membrane integrity and, ultimately, cell viability after administration of these LNPs. Conclusions: Cancer prevention is impactful particularly for those with very poor prognosis, including pancreatic cancer. Our results point to the importance of dietary intervention in this disease when detected early and the potential to improve the antiproliferative effect of drug efficacy when combined with these regimens in later stages of pancreatic cancer.
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Affiliation(s)
- Carolina Torres
- Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Instituto de Investigacion Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Georgina Mancinelli
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Jee-Wei Emily Chen
- Department of Materials Science & Engineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; (J.-W.E.C.)
| | - Jose Cordoba-Chacon
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Danielle Pins
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Sara Saeed
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Ronald McKinney
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Karla Castellanos
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | | | - Megha Singhal
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Akshar Patel
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Jose Acebedo
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Adonis Coleman
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Jorge Heneche
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Poorna Chandra Rao Yalagala
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Papasani V. Subbaiah
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Cecilia Leal
- Department of Materials Science & Engineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; (J.-W.E.C.)
| | - Sam Grimaldo
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
| | - Francisco M. Ortuno
- Department of Computer Architecture and Computer Technology, University of Granada, 18071 Granada, Spain
| | - Faraz Bishehsari
- Department of Medicine, Rush University Medical Center, Chicago, IL 60612, USA
| | - Paul J. Grippo
- Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (G.M.); (S.S.); (R.M.); (A.P.)
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois Chicago, 840 S. Wood Street, CSB 708, Chicago, IL 60612, USA
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Beton-Mysur K, Kopec M, Brozek-Pluska B. Raman Imaging-A Valuable Tool for Tracking Fatty Acid Metabolism-Normal and Cancer Human Colon Single-Cell Study. Int J Mol Sci 2024; 25:4508. [PMID: 38674093 PMCID: PMC11050638 DOI: 10.3390/ijms25084508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 04/14/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Altered metabolism of lipids is a key factor in many diseases including cancer. Therefore, investigations into the impact of unsaturated and saturated fatty acids (FAs) on human body homeostasis are crucial for understanding the development of lifestyle diseases. In this paper, we focus on the impact of palmitic (PA), linoleic (LA), and eicosapentaenoic (EPA) acids on human colon normal (CCD-18 Co) and cancer (Caco-2) single cells using Raman imaging and spectroscopy. The label-free nature of Raman imaging allowed us to evaluate FAs dynamics without modifying endogenous cellular metabolism. Thanks to the ability of Raman imaging to visualize single-cell substructures, we have analyzed the changes in chemical composition of endoplasmic reticulum (ER), mitochondria, lipid droplets (LDs), and nucleus upon FA supplementation. Analysis of Raman band intensity ratios typical for lipids, proteins, and nucleic acids (I1656/I1444, I1444/I1256, I1444/I750, I1304/I1256) proved that, using Raman mapping, we can observe the metabolic pathways of FAs in ER, which is responsible for the uptake of exogenous FAs, de novo synthesis, elongation, and desaturation of FAs, in mitochondria responsible for energy production via FA oxidation, in LDs specialized in cellular fat storage, and in the nucleus, where FAs are transported via fatty-acid-binding proteins, biomarkers of human colon cancerogenesis. Analysis for membranes showed that the uptake of FAs effectively changed the chemical composition of this organelle, and the strongest effect was noticed for LA. The spectroscopy studies have been completed using XTT tests, which showed that the addition of LA or EPA for Caco-2 cells decreases their viability with a stronger effect observed for LA and the opposite effect observed for PA. For normal cells, CCD-18 Co supplementation using LA or EPA stimulated cells for growing, while PA had the opposite impact.
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Affiliation(s)
| | | | - Beata Brozek-Pluska
- Laboratory of Laser Molecular Spectroscopy, Institute of Applied Radiation Chemistry, Faculty of Chemistry, Lodz University of Technology, Wroblewskiego 15, 93-590 Lodz, Poland; (K.B.-M.); (M.K.)
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3
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Lv H, Jia W, Dong P, Liu J, Wang S, Li X, Hu J, Zhao L, Shi Y. Improved Antitumor Efficacy of a Dextran-based Docetaxel-coupled Conjugate against Triple-Negative Breast Cancer. Curr Drug Deliv 2024; 21:775-784. [PMID: 37349996 DOI: 10.2174/1567201820666230622105503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 04/10/2023] [Accepted: 04/19/2023] [Indexed: 06/24/2023]
Abstract
BACKGROUND Most chemotherapeutic agents are characterized by poor water solubility and non-specific distribution. Polymer-based conjugates are promising strategies for overcoming these limitations. OBJECTIVE This study aims to fabricate a polysaccharide, dextran-based, dual-drug conjugate by covalently grafting docetaxel (DTX) and docosahexaenoic acid (DHA) onto the bifunctionalized dextran through a long linker, and to investigate the antitumor efficacy of this conjugate against breast cancer. METHODS DTX was firstly coupled with DHA and covalently bounded with the bifunctionalized dextran (100 kDa) through a long linker to produce a conjugate dextran-DHA-DTX (termed C-DDD). Cytotoxicity and cellular uptake of this conjugate were measured in vitro. Drug biodistribution and pharmacokinetics were investigated through liquid chromatography/mass spectrometry analysis. The inhibitory effects on tumor growth were evaluated in MCF-7- and 4T1-tumor-bearing mice. RESULTS The loading capacity of the C-DDD for DTX was 15.90 (weight/weight). The C-DDD possessed good water solubility and was able to self-assemble into nanoparticles measuring 76.8 ± 5.5 nm. The maximum plasma concentration and area under the curve (0-∞) for the released DTX and total DTX from the C-DDD were significantly enhanced compared with the conventional DTX formulation. The C-DDD selectively accumulated in the tumor, with limited distribution was observed in normal tissues. The C-DDD exhibited greater antitumor activity than the conventional DTX in the triplenegative breast cancer model. Furthermore, the C-DDD nearly eliminated all MCF-7 tumors in nude mice without leading to systemic adverse effects. CONCLUSION This dual-drug C-DDD has the potential to become a candidate for clinical application through the optimization of the linker.
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Affiliation(s)
- Hongshuai Lv
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate Based Medicine, Shandong University, Qingdao, Shandong 266237, China
| | - Weiping Jia
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate Based Medicine, Shandong University, Qingdao, Shandong 266237, China
| | - Peng Dong
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate Based Medicine, Shandong University, Qingdao, Shandong 266237, China
| | - Jiaojiao Liu
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate Based Medicine, Shandong University, Qingdao, Shandong 266237, China
| | - Si Wang
- Santolecan Pharmaceuticals LLC, Jupiter, Florida 33458, USA
| | - Xiaohai Li
- Santolecan Pharmaceuticals LLC, Jupiter, Florida 33458, USA
| | - Jinghua Hu
- Santolecan Pharmaceuticals LLC, Jupiter, Florida 33458, USA
| | - Ling Zhao
- Santolecan Pharmaceuticals LLC, Jupiter, Florida 33458, USA
| | - Yikang Shi
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate Based Medicine, Shandong University, Qingdao, Shandong 266237, China
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Theinel MH, Nucci MP, Alves AH, Dias OFM, Mamani JB, Garrigós MM, Oliveira FA, Rego GNA, Valle NME, Cianciarullo G, Gamarra LF. The Effects of Omega-3 Polyunsaturated Fatty Acids on Breast Cancer as a Preventive Measure or as an Adjunct to Conventional Treatments. Nutrients 2023; 15:nu15061310. [PMID: 36986040 PMCID: PMC10052714 DOI: 10.3390/nu15061310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/10/2023] Open
Abstract
In order to understand how omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplements affect breast cancer prevention and treatment, a systematic review of articles published in the last 5 years in two databases was performed. Of the 679 articles identified, only 27 were included and examined based on five topics, taking into account: the induction type of the breast cancer used in animal models; the characteristics of the induction model by cell transplantation; the experimental design of the ω-3 supplementation—combined or not with a treatment antitumor drug; the fatty acids (FAs) composition used; the analysis of the studies’ outcomes. There are diverse and well-established animal models of breast cancer in the literature, with very relevant histological and molecular similarities depending on the specific objective of the study, such as whether the method of tumor induction was transgenic, by cell transplantation, or by oncogenic drugs. The analyses of outcomes were mainly focused on monitoring tumor growth, body/tumor weight, and molecular, genetic, or histological analyses, and few studies evaluated latency, survival, or metastases. The best results occurred when supplementation with ω-3 PUFA was associated with antitumor drugs, especially in the analysis of metastases and volume/weight of tumors or when the supplementation was started early and maintained for a long time. However, the beneficial effect of ω-3 PUFA supplementation when not associated with an antitumor agent remains unclear.
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Affiliation(s)
| | - Mariana P. Nucci
- LIM44–Hospital das Clínicas da Faculdade Medicina da Universidade de São Paulo, São Paulo 05403-000, Brazil
| | | | | | | | | | | | | | | | | | - Lionel F. Gamarra
- Hospital Israelita Albert Einstein, São Paulo 05652-000, Brazil
- Correspondence: ; Tel.: +55-11-2151-0243
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Beteta-Göbel R, Miralles M, Fernández-Díaz J, Rodríguez-Lorca R, Torres M, Fernández-García P, Escribá PV, Lladó V. HCA (2-Hydroxy-Docosahexaenoic Acid) Induces Apoptosis and Endoplasmic Reticulum Stress in Pancreatic Cancer Cells. Int J Mol Sci 2022; 23:9902. [PMID: 36077299 PMCID: PMC9456069 DOI: 10.3390/ijms23179902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/24/2022] [Accepted: 08/27/2022] [Indexed: 12/09/2022] Open
Abstract
Pancreatic cancer has a high mortality rate due to its aggressive nature and high metastatic rate. When coupled to the difficulties in detecting this type of tumor early and the lack of effective treatments, this cancer is currently one of the most important clinical challenges in the field of oncology. Melitherapy is an innovative therapeutic approach that is based on modifying the composition and structure of cell membranes to treat different diseases, including cancers. In this context, 2-hydroxycervonic acid (HCA) is a melitherapeutic agent developed to combat pancreatic cancer cells, provoking the programmed cell death by apoptosis of these cells by inducing ER stress and triggering the production of ROS species. The efficacy of HCA was demonstrated in vivo, alone and in combination with gemcitabine, using a MIA PaCa-2 cell xenograft model of pancreatic cancer in which no apparent toxicity was evident. HCA is metabolized by α-oxidation to C21:5n-3 (heneicosapentaenoic acid), which in turn also showed anti-proliferative effect in these cells. Given the unmet clinical needs associated with pancreatic cancer, the data presented here suggest that the use of HCA merits further study as a potential therapy for this condition.
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Affiliation(s)
- Roberto Beteta-Göbel
- Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, 07122 Palma de Mallorca, Spain
- R&D Department, Laminar Pharmaceuticals, C/Isaac Newton, 07121 Palma de Mallorca, Spain
| | - Marc Miralles
- Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, 07122 Palma de Mallorca, Spain
- R&D Department, Laminar Pharmaceuticals, C/Isaac Newton, 07121 Palma de Mallorca, Spain
| | - Javier Fernández-Díaz
- Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, 07122 Palma de Mallorca, Spain
- R&D Department, Laminar Pharmaceuticals, C/Isaac Newton, 07121 Palma de Mallorca, Spain
| | - Raquel Rodríguez-Lorca
- Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, 07122 Palma de Mallorca, Spain
- R&D Department, Laminar Pharmaceuticals, C/Isaac Newton, 07121 Palma de Mallorca, Spain
| | - Manuel Torres
- Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, 07122 Palma de Mallorca, Spain
| | - Paula Fernández-García
- Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, 07122 Palma de Mallorca, Spain
- R&D Department, Laminar Pharmaceuticals, C/Isaac Newton, 07121 Palma de Mallorca, Spain
| | - Pablo V. Escribá
- Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, 07122 Palma de Mallorca, Spain
| | - Victoria Lladó
- Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, 07122 Palma de Mallorca, Spain
- R&D Department, Laminar Pharmaceuticals, C/Isaac Newton, 07121 Palma de Mallorca, Spain
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Ferreri C, Sansone A, Chatgilialoglu C, Ferreri R, Amézaga J, Burgos MC, Arranz S, Tueros I. Critical Review on Fatty Acid-Based Food and Nutraceuticals as Supporting Therapy in Cancer. Int J Mol Sci 2022; 23:ijms23116030. [PMID: 35682708 PMCID: PMC9181022 DOI: 10.3390/ijms23116030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/17/2022] [Accepted: 05/24/2022] [Indexed: 02/02/2023] Open
Abstract
Fatty acids have an important place in both biological and nutritional contexts and, from a clinical point of view, they have known consequences for diseases’ onset and development, including cancer. The use of fatty acid-based food and nutraceuticals to support cancer therapy is a multidisciplinary subject, involving molecular and clinical research. Knowledge regarding polyunsaturated fatty acids essentiality/oxidizability and the role of lipogenesis-desaturase pathways for cell growth, as well as oxidative reactivity in cancer cells, are discussed, since they can drive the choice of fatty acids using their multiple roles to support antitumoral drug activity. The central role of membrane fatty acid composition is highlighted for the application of membrane lipid therapy. As fatty acids are also known as biomarkers of cancer onset and progression, the personalization of the fatty acid-based therapy is also possible, taking into account other important factors such as formulation, bioavailability and the distribution of the supplementation. A holistic approach emerges combining nutra- and pharma-strategies in an appropriate manner, to develop further knowledge and applications in cancer therapy.
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Affiliation(s)
- Carla Ferreri
- Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via Piero Gobetti 101, 40129 Bologna, Italy; (A.S.); (C.C.)
- Correspondence:
| | - Anna Sansone
- Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via Piero Gobetti 101, 40129 Bologna, Italy; (A.S.); (C.C.)
| | - Chryssostomos Chatgilialoglu
- Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via Piero Gobetti 101, 40129 Bologna, Italy; (A.S.); (C.C.)
| | - Rosaria Ferreri
- Department of Integrated Medicine, Tuscany Reference Centre for Integrated Medicine in the Hospital Pathway, Pitigliano Hospital, ASL Sudest Toscana, 58017 Pitigliano, Italy;
| | - Javier Amézaga
- AZTI, Food Research, Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio, Spain; (J.A.); (M.C.B.); (S.A.); (I.T.)
| | - Mercedes Caro Burgos
- AZTI, Food Research, Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio, Spain; (J.A.); (M.C.B.); (S.A.); (I.T.)
| | - Sara Arranz
- AZTI, Food Research, Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio, Spain; (J.A.); (M.C.B.); (S.A.); (I.T.)
| | - Itziar Tueros
- AZTI, Food Research, Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio, Spain; (J.A.); (M.C.B.); (S.A.); (I.T.)
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Dong P, Liu J, Lv H, Wu J, Zhang N, Wang S, Li X, Hu J, Wang A, Li DJ, Wang D, Cao S, Xie L, Shi YK. The enhanced antitumor activity of the polymeric conjugate covalently coupled with docetaxel and docosahexaenoic acid. Biomater Sci 2022; 10:3454-3465. [DOI: 10.1039/d2bm00337f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Docetaxel (DTX) has been widely used for treatment of many types of cancer. However, DTX is poor water soluble and commercial DTX is formulated in nonionic surfactant polysorbate 80 and...
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Docosahexaenoic Acid Inhibits Cell Proliferation through a Suppression of c-Myc Protein in Pancreatic Ductal Adenocarcinoma Cells. Antioxidants (Basel) 2021; 10:antiox10111721. [PMID: 34829591 PMCID: PMC8614909 DOI: 10.3390/antiox10111721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 11/17/2022] Open
Abstract
Treatment of pancreatic cancer by inhibiting the aberrant activation of the survival signaling pathways has received considerable attention. We investigated the probable action of DHA on the suppression of cell proliferation in human pancreatic ductal adenocarcinoma (PDAC) cells. Our results demonstrated that DHA dose-dependently inhibited cell proliferation through an induction of cell cycle arrest in human PDAC cells. DHA suppressed the expression of phosphorylated-Rb (p-Rb), cyclin D1, cyclin E, cyclin A, E2F1 and c-Myc proteins. Blocking the activation of STAT3 signaling pathway led to an inactivation of CAMKII and increased phosphorylation of c-Myc (T58) protein accompanied with decreased expression of c-Myc protein. Treatment of DHA effectively inhibited cell survival through decreased phosphorylation levels of EGFR, STAT3 and CAMKII proteins. The mechanisms of action were associated with increased phosphorylation levels of c-Myc (T58) and instability of c-Myc proteins. DHA inhibited cell survival through an increased GSSG/GSH ratio and oxidative stress level in HPAF-II cells. DHA induced cell apoptosis through increased expression of Bax, c-caspase 3 and c-PARP proteins in HPAF-II cells. Moreover, treatment of DHA significantly inhibited nucleotide synthesis. In conclusion, DHA might significantly suppress the proliferation of PDAC cells and therefore have potential as an anti-cancer therapeutic agent.
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9
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Trestini I, Cintoni M, Rinninella E, Grassi F, Paiella S, Salvia R, Bria E, Pozzo C, Alfieri S, Gasbarrini A, Tortora G, Milella M, Mele MC. Neoadjuvant treatment: A window of opportunity for nutritional prehabilitation in patients with pancreatic ductal adenocarcinoma. World J Gastrointest Surg 2021; 13:885-903. [PMID: 34621468 PMCID: PMC8462076 DOI: 10.4240/wjgs.v13.i9.885] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 05/28/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
Patients affected by pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced disease at the time of diagnosis, limiting an upfront surgical approach. Neoadjuvant treatment (NAT) has become the standard of care to downstage non-metastatic locally advanced PDAC. However, this treatment increases the risk of a nutritional status decline, which in turn, may impact therapeutic tolerance, postoperative outcomes, or even prevent the possibility of surgery. Literature on prehabilitation programs on surgical PDAC patients show a reduction of postoperative complications, length of hospital stay, and readmission rate, while data on prehabilitation in NAT patients are scarce and randomized controlled trials are still missing. Particularly, appropriate nutritional management represents an important therapeutic strategy to promote tissue healing and to enhance patient recovery after surgical trauma. In this regard, NAT may represent a new interesting window of opportunity to implement a nutritional prehabilitation program, aiming to increase the PDAC patient's capacity to complete the planned therapy and potentially improve clinical and survival outcomes. Given these perspectives, this review attempts to provide an in-depth view of the nutritional derangements during NAT and nutritional prehabilitation program as well as their impact on PDAC patient outcomes.
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Affiliation(s)
- Ilaria Trestini
- Section of Oncology, Department of Medicine, Pancreas Institute, University of Verona Hospital Trust, Verona 37126, Italy
| | - Marco Cintoni
- Scuola di Specializzazione in Scienza dell’Alimentazione, Università di Roma Tor Vergata, Roma 00133, Italy
| | - Emanuele Rinninella
- UOC Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico A. Gemelli IRCCS, Roma 00168, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Futura Grassi
- UOC Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico A. Gemelli IRCCS, Roma 00168, Italy
| | - Salvatore Paiella
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona 37126, Italy
| | - Roberto Salvia
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona 37126, Italy
| | - Emilio Bria
- Oncologia Medica Unit, Comprehensive Cancer Center, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00167, Italy
- Oncologia Medica Unit, Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Carmelo Pozzo
- Oncologia Medica Unit, Comprehensive Cancer Center, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00167, Italy
- Oncologia Medica Unit, Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Sergio Alfieri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma 00168, Italy
- Digestive Surgery Unit and Pancreatic Surgery Gemelli Center Director, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00167, Italy
| | - Antonio Gasbarrini
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00167, Italy
| | - Giampaolo Tortora
- Oncologia Medica Unit, Comprehensive Cancer Center, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00167, Italy
- Oncologia Medica Unit, Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Michele Milella
- Section of Oncology, Department of Medicine, Pancreas Institute, University of Verona Hospital Trust, Verona 37126, Italy
| | - Maria Cristina Mele
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma 00168, Italy
- UOSD Nutrizione Avanzata in Oncologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00167, Italy
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Prevention and Nursing Research of PICC Catheter-Related Complications in Patients with Digestive System Malignant Tumor Based on Smart Medical Block Chain. JOURNAL OF HEALTHCARE ENGINEERING 2021; 2021:5519722. [PMID: 33953896 PMCID: PMC8057877 DOI: 10.1155/2021/5519722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/12/2021] [Accepted: 03/29/2021] [Indexed: 01/30/2023]
Abstract
Malignant tumors of digestive system mainly include gastric cancer, colorectal cancer, and esophageal cancer, which generally need chemotherapy. PICC refers to peripherally inserted central venous catheter, which plays an important role in the treatment of malignant tumor patients with chemotherapy, and it has the characteristics of high success rate of puncture and reducing the pain of patients. Its principle is to use PICC catheter for drug delivery, which can effectively reduce the pain of tumor patients for multiple puncture, and also can avoid drug extravasation or local stimulation of drugs. However, PICC catheter-related complications cannot be ignored, to some extent, directly affect the treatment effect of patients, and increase the pain and burden of patients. Therefore, this paper proposes a study of PICC catheter-related complications and protective nursing for patients with digestive system cancer based on smart medical block chain. First of all, using the method of literature, this paper deeply studied the combination of smart medicine and block chain and further strengthened the research on PICC catheter-related complications. Based on this, we designed a study on the prevention and nursing of PICC catheter-related complications in patients with digestive system cancer. Before the implementation of nursing, the incidence of complications in patients with digestive system cancer was 17.35%; after the implementation of nursing, the incidence of complications decreased to 4.08%. The purpose of this study is to analyze the causes through clinical research and put forward the protective nursing measures of related diseases, so as to reduce the incidence of PICC-related complications.
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Jin H, Kim HS, Yu ST, Shin SR, Lee SH, Seo GS. Synergistic anticancer effect of docosahexaenoic acid and isoliquiritigenin on human colorectal cancer cells through ROS-mediated regulation of the JNK and cytochrome c release. Mol Biol Rep 2021; 48:1171-1180. [PMID: 33502699 DOI: 10.1007/s11033-021-06159-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 01/12/2021] [Indexed: 11/25/2022]
Abstract
A large body of research has demonstrated a synergistic anticancer effect between docosahexaenoic acid (DHA) and standard chemotherapy regimens against colorectal cancer (CRC). In this study, we investigated the chemotherapeutic potential of cotreatment with DHA and isoliquiritigenin (ISL) against CRC HCT-116 cells. Apoptosis was confirmed by Annexin V/PI staining and expression of apoptosis-associated proteins. The synergistic effect of DHA and ISL combination on apoptosis was detected using combination index approaches. Flow cytometry was carried out using fluorescent probes to measure the production of reactive oxygen species (ROS). DHA and ISL in combination synergistically enhanced the decrease in cell viability versus the compounds used alone. Moreover, we demonstrated that the synergistic anti-CRC activity of cotreatment with these two compounds was achieved by inducing the apoptosis caspase-dependently mediated through augmented ROS generation followed by increased Fas ligand mRNA expression and cytochrome c release. Our data also demonstrated that cotreating with DHA and ISL strongly upregulated the phosphorylation of ERK and JNK, which are functionally associated with ROS induced by the two compounds in combination. Interestingly, further study revealed that inhibiting ERK phosphorylation strongly enhanced Fas ligand mRNA expression and the combination of the two compounds induced stronger cytotoxicity, whereas inhibiting JNK phosphorylation significantly reduced the apoptotic signals mediated by cotreatment with these two compounds. Excessive ROS-induced JNK activation and cytochrome c release from mitochondria played a key role in the synergistic anticancer activity of CRC cells by cotreating with DHA and ISL.
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Affiliation(s)
- Hao Jin
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, 54538, Republic of Korea
| | - Hak Sung Kim
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, 54538, Republic of Korea
| | - Seung Taek Yu
- Department of Pediatrics, Digestive Disease Research Institute, Wonkwang University School of Medicine, Iksan, Jeonbuk, 54538, Republic of Korea
| | - Sae Ron Shin
- Department of Family Medicine, Digestive Disease Research Institute, Wonkwang University School of Medicine, Iksan, Jeonbuk, 54538, Republic of Korea
| | - Sung Hee Lee
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, 54538, Republic of Korea.
| | - Geom Seog Seo
- Department of Internal Medicine, Digestive Disease Research Institute, Wonkwang University School of Medicine, Iksan, Jeonbuk, 54538, Republic of Korea.
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12
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Wirkus J, Ead AS, Mackenzie GG. Impact of dietary fat composition and quantity in pancreatic carcinogenesis: Recent advances and controversies. Nutr Res 2020; 88:1-18. [PMID: 33607535 DOI: 10.1016/j.nutres.2020.12.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/11/2020] [Accepted: 12/20/2020] [Indexed: 12/11/2022]
Abstract
A significant number of pancreatic cancer cases are due to modifiable risk factors, with many being attributed to increased body fatness. This has sparked investigators to examine the role played by high dietary fat intake in pancreatic cancer development and the mechanisms driving this connection. However, there is currently no consensus on how dietary fat quantity and composition specifically affect pancreatic carcinogenesis. The objective of this narrative review is to discuss the link between high total fat consumption and fatty acid composition (saturated, mono-, or poly-unsaturated fats) with pancreatic cancer incidence and progression. Following our detailed analysis of the strengths and weaknesses of recent preclinical and human studies, we discuss existing research gaps and opportunities, and provide recommendations for future studies. Numerous studies suggest that diets high in omega-3 polyunsaturated fatty acids are associated with reduced pancreatic cancer risk. However, the current evidence appears insufficient for a general conclusion regarding the impact of other types of fat in pancreatic carcinogenesis, with many studies providing inconclusive findings due to study limitations. Thus, we recommend future studies to include detailed methodology of the animal experiments, not limited to the diet composition, type of ingredients, formulations, and administration of the diets. Moreover, human studies should include a diverse population and well-characterized biomarkers for accurate determination of dietary fat intake. Ultimately, this will aid the study rigor, and improve our understanding of the impact of fat quantity and composition in pancreatic carcinogenesis.
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Affiliation(s)
- Joanna Wirkus
- Department of Nutrition, University of California, Davis. One Shields Ave, Davis, CA 95616, USA
| | - Aya S Ead
- Department of Nutrition, University of California, Davis. One Shields Ave, Davis, CA 95616, USA
| | - Gerardo G Mackenzie
- Department of Nutrition, University of California, Davis. One Shields Ave, Davis, CA 95616, USA.
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13
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Chen J, Garssen J, Redegeld F. The efficacy of bortezomib in human multiple myeloma cells is enhanced by combination with omega-3 fatty acids DHA and EPA: Timing is essential. Clin Nutr 2020; 40:1942-1953. [PMID: 32977994 DOI: 10.1016/j.clnu.2020.09.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 08/22/2020] [Accepted: 09/04/2020] [Indexed: 02/01/2023]
Abstract
BACKGROUND & AIMS Although bortezomib as one of the first line medicines that has greatly improved the overall survival of patients with multiple myeloma (MM), undesired drug resistance is frequently observed. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been shown to be able to enhance the efficacy of chemotherapeutic drugs in many cancer types. The aim of the present study was to further evaluate the anticancer activity of DHA and EPA in relation to bortezomib chemosensitivity in human MM cells. The potential involvement of NF-κB signaling pathway was studied. METHODS MM cells were treated with DHA/EPA with or without bortezomib. Cell viability was estimated by WST-1 assay. Apoptotic cells were determined through flow cytometry using annexin V and propidium iodide (PI) staining. Protein expression and phosphorylation was investigated by western blotting. RESULTS Cell type dependent anticancer potential of DHA and EPA was observed in the cell viability assay. DHA and EPA induced apoptosis in L363, OPM2, MM.1S and U266 cell lines through both mitochondrial and death receptor pathways. Treating MM cells with DHA and EPA significantly downregulated IκBα and upregulated phosphorylation of p65, indicating that they triggered NF-κB activation in MM cells. Treating cells with DHA or EPA prior to bortezomib enhanced the induced cell death. However, concomitant use of bortezomib in combination with either of DHA or EPA decreased the cell death induced by bortezomib, indicating that timing of coincubation is important for the effects on chemosensitivity. CONCLUSIONS The present study provides novel evidence for the anticancer effects of DHA and EPA, and highlights their rational utilization in combination with bortezomib to achieve improved therapeutic outcome for MM.
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Affiliation(s)
- Jing Chen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, 3508, TB, the Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, 3508, TB, the Netherlands; Nutricia Research, Utrecht, 3508, TC, the Netherlands
| | - Frank Redegeld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, 3508, TB, the Netherlands.
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14
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Muhammad I, Rahman N, Nayab GE, Niaz S, Shah M, Afridi SG, Khan H, Daglia M, Capanoglu E. The Molecular Docking of Flavonoids Isolated from Daucus carota as a Dual Inhibitor of MDM2 and MDMX. Recent Pat Anticancer Drug Discov 2020; 15:154-164. [PMID: 32101134 DOI: 10.2174/1574892815666200226112506] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/22/2020] [Accepted: 02/23/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cancer is characterized by overexpression of p53 associated proteins, which down-regulate P53 signaling pathway. In cancer therapy, p53 activity can be restored by inhibiting the interaction of MDMX (2N0W) and MDM2 (4JGR) proteins with P53 protein. OBJECTIVE In the current, study in silico approaches were adapted to use a natural product as a source of cancer therapy. METHODS In the current study in silico approaches were adapted to use a natural product as a source of cancer therapy. For in silico studies, Chemdraw and Molecular Operating Environment were used for structure drawing and molecular docking, respectively. Flavonoids isolated from D. carota were docked with cancerous proteins. RESULT Based on the docking score analysis, we found that compound 7 was the potent inhibitor of both cancerous proteins and can be used as a potent molecule for inhibition of 2N0W and 4JGR interaction with p53. CONCLUSION Thus the compound 7 can be used for the revival of p53 signaling pathway function however, intensive in vitro and in vivo experiments are required to prove the in silico analysis.
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Affiliation(s)
- Ijaz Muhammad
- Department of Zoology, Abdul Wali Khan University Mardan, Mardan-23200, KP, Pakistan
| | - Noor Rahman
- Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan-23200, KP, Pakistan
| | - Gul E Nayab
- Department of Zoology, Abdul Wali Khan University Mardan, Mardan-23200, KP, Pakistan
| | - Sadaf Niaz
- Department of Zoology, Abdul Wali Khan University Mardan, Mardan-23200, KP, Pakistan
| | - Mohibullah Shah
- Department of Biochemistry, Bahauddin Zakariya University, Multan-66000, Pakistan
| | - Sahib G Afridi
- Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan-23200, KP, Pakistan
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan-23200, KP, Pakistan
| | - Maria Daglia
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
| | - Esra Capanoglu
- Department of Food Engineering, Faculty of Chemical and Metallurgical Engineering, Istanbul Technical University, 34469 Maslak, Istanbul, Turkey
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15
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Lee S, Jeong YK, Lim JW, Kim H. Docosahexaenoic Acid Inhibits Expression of Fibrotic Mediators in Mice With Chronic Pancreatitis. J Cancer Prev 2020; 24:233-239. [PMID: 31950023 PMCID: PMC6951317 DOI: 10.15430/jcp.2019.24.4.233] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 12/19/2019] [Accepted: 12/19/2019] [Indexed: 12/19/2022] Open
Abstract
Background Chronic pancreatitis (CP) is an irreversible progressive disease that destroys exocrine parenchyma, which are replaced by fibrous tissue. As pancreatic fibrosis is a key feature of CP, reducing fibrotic protein content in the pancreas is crucial for preventing CP. Studies suggest that NF-κB facilitates the expression of fibrotic mediators in pancreas and protein kinase C-δ (PKC-δ) regulates NF-κB activation in stimulated pancreatic acinar cells. Docosahexaenoic acid (DHA) is an omega-3 fatty acid having anti-inflammatory and anti-fibrotic effects. It has been shown to inhibit NF-κB activity in cerulein-stimulated pancreatic acinar cells which is a cellular model of CP. In the present study, we investigated if DHA inhibits expression of fibrotic mediators by reducing PKC-δ and NF-κB expression in mouse pancreatic tissues with CP. Methods For six weeks, mice were weekly induced for acute pancreatitis to develop CP. Furthermore, acute pancreatitis was induced by hourly intraperitoneal injections of cerulein (50 μg/kg × 7). Mice were administered DHA (10 μM) via drinking water before and after CP induction. Results Cerulein-induced pancreatic damages like decreased pancreatic weight/total body weight, leukocyte infiltration, necrosis of acinar cells, and vacuolization were found to be inhibited by DHA. Additionally, DHA inhibited cerulein-induced fibrotic mediators like alpha-smooth muscle actin and fibronectin in pancreas. DHA reduced expression of PKC-δ and NF-κB p65 in pancreatic tissues of cerulein-treated mice. Conclusions DHA may be beneficial in preventing CP by suppressing pancreatic expression of fibrotic mediators.
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Affiliation(s)
- Sle Lee
- Department of Food and Nutrition, Brian Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
| | - Yoo Kyung Jeong
- Department of Food and Nutrition, Brian Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
| | - Joo Weon Lim
- Department of Food and Nutrition, Brian Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
| | - Hyeyoung Kim
- Department of Food and Nutrition, Brian Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
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16
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Ashfaq W, Rehman K, Siddique MI, Khan QAA. Eicosapentaenoic Acid and Docosahexaenoic Acid from Fish Oil and Their Role in Cancer Research. FOOD REVIEWS INTERNATIONAL 2019. [DOI: 10.1080/87559129.2019.1686761] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Wardah Ashfaq
- Department of Medicine, Ameer ud Din Medical College, Lahore, Pakistan
| | - Khurram Rehman
- Department of Pharmacy, Forman Christan College (A Chartered University), Lahore, Pakistan
| | - Muhammad Irfan Siddique
- Institute of Pharmaceutical Sciences, University of Veterinary & Animal Sciences, Lahore, Pakistan
| | - Qurrat-Al-Ain Khan
- Institute of Pharmaceutical Sciences, University of Veterinary & Animal Sciences, Lahore, Pakistan
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17
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Fanconi Anemia complementation group C protein in metabolic disorders. Aging (Albany NY) 2019; 10:1506-1522. [PMID: 29930218 PMCID: PMC6046246 DOI: 10.18632/aging.101487] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 06/16/2018] [Indexed: 01/01/2023]
Abstract
Given importance of 22-Fanconi Anemia (FA) proteins together to act in a signaling pathway in preventing deleterious clinical symptoms, e.g. severe bone marrow failure, congenital defects, an early onset of aging and cancer, studies on each FA protein become increasingly attractive. However, an unbiased and systematic investigation of cellular effects resulting from each FA protein is missing. Here, we report roles of FA complementation C group protein (FANCC) in the protection from metabolic disorders. This study was prompted by the diabetes-prone feature displayed in FANCC knockout mice, which is not typically shown in patients with FA. We found that in cells expressing FANCC at different levels, there are representative alterations in metabolites associated with aging (glycine, citrulline, ornithine, L-asparagine, L-tyrosine, L-arginine, L-glutamine, L-leucine, L-isoleucine, L-valine, L-proline and L-alanine), Diabetes Mellitus (DM) (carbon monoxide, collagens, fatty acids, D-glucose, fumaric acid, 2-oxoglutaric acid, C3), inflammation (inosine, L-arginine, L-isoleucine, L-leucine, L-lysine, L-phenylalanine, hypoxanthine, L-methionine), and cancer ( L-methionine, sphingomyelin, acetyl-L-carnitine, L-aspartic acid, L-glutamic acid, niacinamide, phospho-rylethanolamine). We also found that FANCC can act in an FA-pathway-independent manner in tumor suppression. Collectively, featured-metabolic alterations are readouts of functional mechanisms underlying reduced tumorigenicity driven by FANCC, demonstrating close links among cancer, aging, inflammation and DM.
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18
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Hanikoglu A, Kucuksayan E, Hanikoglu F, Ozben T, Menounou G, Sansone A, Chatgilialoglu C, Di Bella G, Ferreri C. Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes. Can J Physiol Pharmacol 2019; 98:131-138. [PMID: 31545905 DOI: 10.1139/cjpp-2019-0352] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Breast cancer is a worldwide commonly found malignancy in women and effective treatment is regarded as a huge clinical challenge even in the presence of several treatment options. Extensive literature is available demonstrating polyphenols as phytopharmaceutical anticancer agents. Among the polyphenols, quercetin and curcumin have been reported to have a strong potential against breast cancer. However, so far, no comprehensive study has been performed to demonstrate the anticarcinogenic effects of curcumin, quercetin, and their combinations with somatostatin on the fatty acid profile of breast cancer cell membranes. We used MCF-7 and MDA-MB231 breast cancer cells incubated with curcumin and quercetin for 24 h, in the absence and presence of somatostatin, at their EC50 concentrations to evaluate membrane fatty acid based functional lipidomics together with the followup of EGFR and MAPK signaling pathways. The two cell lines gave different membrane free fatty acid reorganization. In MCF-7 cells, the following changes were observed: an increase of ω6 linoleic acid in the cells incubated with somatostatin + quercetin and quercetin and a decrease of ω3 acids in the cells incubated with somatostatin + curcumin compared to somatostatin and significant increases of monounsaturated fatty acid (MUFA), mono-trans arachidonic acid levels and docosapentaenoic acid for the cells incubated with somatostatin + quercetin compared to the control cells. In MDA-MB231 cells, incubations with curcumin, quercetin, and somatostatin + quercetin induced the most significant membrane remodeling with the increase of stearic acid, diminution of ω6 linoleic, arachidonic acids, and ω3 (docosapentaenoic and docosahexaenoic acids). Distinct signaling pathway changes were found for these cell lines. In MCF-7 cells, separate or combined incubations with somatostatin and quercetin, significantly decreased EGFR and incubation with curcumin decreased MAPK signaling. In MDA-MB231 cells, incubation with curcumin decreased AKT1 and p-AKT1 (Thr308) levels. Incubation with curcumin and quercetin decreased the EGFR levels. Our results showed that cytostatic and antioxidant treatments can be combined to induce membrane fatty acid changes, including lipid isomerization as specific free radical driven process, and to influence signaling pathways. This study aimed to contribute to the literature on these antioxidants in the treatment of breast cancer to clarify the effects and mechanisms in combination with somatostatin.
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Affiliation(s)
- Aysegul Hanikoglu
- Department of Biochemistry, Faculty of Pharmacy, Biruni University, Istanbul, Turkey
| | - Ertan Kucuksayan
- Department of Biochemistry, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Ferhat Hanikoglu
- Department of Biochemistry, Faculty of Medicine, Biruni University, Istanbul, Turkey
| | - Tomris Ozben
- Department of Biochemistry, Faculty of Medicine, Akdeniz University, 07070 Antalya, Turkey
| | - Georgia Menounou
- Consiglio Nazionale delle Ricerche, ISOF, Via Piero Gobetti 101, 40129 Bologna, Italy
| | - Anna Sansone
- Consiglio Nazionale delle Ricerche, ISOF, Via Piero Gobetti 101, 40129 Bologna, Italy
| | - Chrys Chatgilialoglu
- Consiglio Nazionale delle Ricerche, ISOF, Via Piero Gobetti 101, 40129 Bologna, Italy
| | | | - Carla Ferreri
- Consiglio Nazionale delle Ricerche, ISOF, Via Piero Gobetti 101, 40129 Bologna, Italy
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19
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Yamada H, Hakozaki M, Uemura A, Yamashita T. Effect of fatty acids on melanogenesis and tumor cell growth in melanoma cells. J Lipid Res 2019; 60:1491-1502. [PMID: 31345992 PMCID: PMC6718436 DOI: 10.1194/jlr.m090712] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 07/12/2019] [Indexed: 11/20/2022] Open
Abstract
Fatty acids have various physiological effects on melanoma. For example, palmitic acid (PA) increases melanin levels; linoleic acid and DHA decrease melanin levels; and DHA suppresses tumor growth. In this study, we focused on the relationship between the structure of fatty acids and their physiological effects in melanoma to examine the likely mechanisms of action. We showed that saturated fatty acids and PUFAs display opposing effects on melanin content in melanoma cells. Likewise, PA and EPA have opposing effects in terms of actin polymerization. Our findings suggest that PA and EPA change melanin content in melanoma to alter melanosome trafficking by modulating actin polymerization. Here, we also examined the mechanism of the anti-tumor effect of DHA. We found that DHA interacts with receptor for activated C kinase 1 and represses melanoma cell proliferation by suppressing protein kinase C signaling. Our results suggest a new mechanism to explain the physiological effects of fatty acids.
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Affiliation(s)
- Hidetoshi Yamada
- Iwate Biotechnology Research Center, Kitakami, Iwate 024-0003, Japan.
| | - Mayuka Hakozaki
- Iwate Biotechnology Research Center, Kitakami, Iwate 024-0003, Japan
| | - Aiko Uemura
- Iwate Biotechnology Research Center, Kitakami, Iwate 024-0003, Japan
| | - Tetsuro Yamashita
- Department of Biological Chemistry and Food Sciences Faculty of Agriculture, Iwate University, Morioka, Iwate 020-8550, Japan
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Docosahexaenoic Acid Enhances Oxaliplatin-Induced Autophagic Cell Death via the ER Stress/Sesn2 Pathway in Colorectal Cancer. Cancers (Basel) 2019; 11:cancers11070982. [PMID: 31337142 PMCID: PMC6678695 DOI: 10.3390/cancers11070982] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 07/06/2019] [Accepted: 07/08/2019] [Indexed: 01/14/2023] Open
Abstract
Oxaliplatin is an anticancer drug administered to colorectal cancer (CRC) patients in combination with 5-fluorouracil and antibodies (bevacizumab and cetuximab), thereby significantly improving the survival rate of CRC. However, due to various side effects associated with the above treatment strategy, the need for combinatorial therapeutic strategies has emerged. Based on the demand for new combinatorial therapies and the known antitumor effects of the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), we investigated the Oxaliplatin and DHA combination for its effect. Our results indicated that DHA further enhanced Oxaliplatin-induced cell viability and autophagic cell death, in vitro and in vivo. Oxaliplatin and DHA also increased the expression of Sestrin 2 (SESN2) and endoplasmic reticulum (ER) stress related C/EBP homologous protein (CHOP). Additionally, treatment with Oxaliplatin and DHA enhanced the binding of CHOP to the promotor region of SESN2, increasing SESN2 expression. These results suggested that DHA enhanced Oxaliplatin-induced reduction in cell viability and increase in autophagy via activating SESN2 and increasing ER stress. Thus, SESN2 may be an effective preclinical target for CRC treatment.
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21
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Xu F, Song Y, Guo A. Anti-Apoptotic Effects of Docosahexaenoic Acid in IL-1β-Induced Human Chondrosarcoma Cell Death through Involvement of the MAPK Signaling Pathway. Cytogenet Genome Res 2019; 158:17-24. [PMID: 31261155 DOI: 10.1159/000500290] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2018] [Indexed: 12/12/2022] Open
Abstract
Osteoarthritis (OA) is a degenerative disease characterized by progressive articular cartilage destruction and joint marginal osteophyte formation with different degrees of synovitis. Docosahexaenoic acid (DHA) is an unsaturated fatty acid with anti-inflammatory, antioxidant, and antiapoptotic functions. In this study, the human chondrosarcoma cell line SW1353 was cultured in vitro, and an OA cell model was constructed with inflammatory factor IL-1β stimulation. After cells were treated with DHA, cell apoptosis was measured. Western blot assay was used to detect protein expression of apoptosis-related factors (Bax, Bcl-2, and cleaved caspase-3) and mitogen-activated protein kinase (MAPK) signaling pathway family members, including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38 MAPK. Our results show that IL-1β promotes the apoptosis of SW1353 cells, increases the expression of Bax and cleaved caspase-3, and activates the MAPK signaling pathway. In contrast, DHA inhibits the expression of IL-1β, inhibits IL-1β-induced cell apoptosis, and has a certain inhibitory effect on the activation of the MAPK signaling pathway. When the MAPK signaling pathway is inhibited by its inhibitors, the effects of DHA on SW1353 cells are weakened. Thus, DHA enhances the apoptosis of SW1353 cells through the MAPK signaling pathway.
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Ahmed S, Khan H, Fratantonio D, Hasan MM, Sharifi S, Fathi N, Ullah H, Rastrelli L. Apoptosis induced by luteolin in breast cancer: Mechanistic and therapeutic perspectives. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 59:152883. [PMID: 30986716 DOI: 10.1016/j.phymed.2019.152883] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 03/06/2019] [Accepted: 03/09/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Breast cancer is worldwide commonly found malignancy in women and effective treatment is regarded as a huge clinical challenge even in the presence of several options. Extensive literature is available that demonstrating polyphenols, the richly introduce phytopharmaceuticals as anticancer agents. Among these polyphenols, resveratrol, silibinin, quercetin, genistein, curcumin reported to have an awesome potential against breast cancer. However, till now no comprehensive survey found about the anticarcinogenic properties of luteolin against breast cancer. SCOPE AND APPROACH This review targeted the available literature on luteolin in the treatment of breast cancer, effects in combination with other anticancer drugs with possible mechanisms. KEY FINDINGS AND CONCLUSION An outstanding therapeutic potential of luteolin in the treatment of breast cancer has been recorded not just as a chemopreventive and chemotherapeutic agent yet complemented by its synergistic effects with other anticancer therapies such as cyclophosphamide, doxorubicin, and NSAID such as celecoxib, and possible underlying mechanisms. Ideally, this review will open new dimensions for luteolin as an effective and safe therapeutic agent in diminishing breast cancer.
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Affiliation(s)
- Salman Ahmed
- Department of Pharmacognosy, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali khan University Mardan 23200, Pakistan.
| | - Deborah Fratantonio
- "Bambino Gesù" Children's Hospital-IRCCS, Research Laboratories, V.le di San Paolo 15, 00146, Rome, Italy.
| | - Muhammad Mohtasheemul Hasan
- Department of Pharmacognosy, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Simin Sharifi
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nazanin Fathi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hammad Ullah
- Department of Pharmacy, Abdul Wali khan University Mardan 23200, Pakistan
| | - Luca Rastrelli
- Dipartimento di Farmacia, University of Salerno, Via Giovanni Paolo II, 84084, Fisciano, Italy
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Ali M, Haque R, Khan SA. Docosahexaenoic Acid (DHA). THE MOLECULAR NUTRITION OF FATS 2019:389-400. [DOI: 10.1016/b978-0-12-811297-7.00030-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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24
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Yakovenko A, Cameron M, Trevino JG. Molecular therapeutic strategies targeting pancreatic cancer induced cachexia. World J Gastrointest Surg 2018; 10:95-106. [PMID: 30622678 PMCID: PMC6314860 DOI: 10.4240/wjgs.v10.i9.95] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/01/2018] [Accepted: 11/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) induced cachexia is a complex metabolic syndrome associated with significantly increased morbidity and mortality and reduced quality of life. The pathophysiology of cachexia is complex and poorly understood. Many molecular signaling pathways are involved in PC and cachexia. Though our understanding of cancer cachexia is growing, therapeutic options remain limited. Thus, further discovery and investigation of the molecular signaling pathways involved in the pathophysiology of cachexia can be applied to development of targeted therapies. This review focuses on three main pathophysiologic processes implicated in the development and progression of cachexia in PC, as well as their utility in the discovery of novel targeted therapies.
Skeletal muscle wasting is the most prominent pathophysiologic anomaly in cachectic patients and driven by multiple regulatory pathways. Several known molecular pathways that mediate muscle wasting and cachexia include transforming growth factor-beta (TGF-β), myostatin and activin, IGF-1/PI3K/AKT, and JAK-STAT signaling. TGF-β antagonism in cachectic mice reduces skeletal muscle catabolism and weight loss, while improving overall survival. Myostatin/activin inhibition has a great therapeutic potential since it plays an essential role in skeletal muscle regulation. Overexpression of insulin-like growth factor binding protein-3 (IGFBP-3) leads to increased ubiquitination associated proteolysis, inhibition of myogenesis, and decreased muscle mass in PC induced cachexia. IGFBP-3 antagonism alleviates muscle cell wasting.
Another component of cachexia is profound systemic inflammation driven by pro-cachectic cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon gamma (INF-γ). IL-6 antagonism has been shown to reduce inflammation, reduce skeletal muscle loss, and ameliorate cachexia. While TNF-α inhibitors are clinically available, blocking TNF-α signaling is not effective in the treatment of cancer cachexia. Blocking the synthesis or action of acute phase reactants and cytokines is a feasible therapeutic strategy, but no anti-cytokine therapies are currently approved for use in PC. Metabolic alterations such as increased energy expenditure and gluconeogenesis, insulin resistance, fat tissue browning, excessive oxidative stress, and proteolysis with amino acid mobilization support tumor growth and the development of cachexia. Current innovative nutritional strategies for cachexia management include ketogenic diet, utilization of natural compounds such as silibinin, and supplementation with ω3-polyunsaturated fatty acids. Elevated ketone bodies exhibit an anticancer and anticachectic effect. Silibinin has been shown to inhibit growth of PC cells, induce metabolic alterations, and reduce myofiber degradation. Consumption of ω3-polyunsaturated fatty acids has been shown to significantly decrease resting energy expenditure and regulate metabolic dysfunction.
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Affiliation(s)
- Anastasiya Yakovenko
- University of Florida College of Medicine, Gainesville, Florida 32610, United States
| | - Miles Cameron
- University of Florida College of Medicine, Gainesville, Florida 32610, United States
| | - Jose Gilberto Trevino
- Department of Surgery, University of Florida Health Sciences Center, Gainesville, Florida 32610, United States
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25
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Ruan M, Liu J, Ren X, Li C, Zhao AZ, Li L, Yang H, Dai Y, Wang Y. Whole transcriptome sequencing analyses of DHA treated glioblastoma cells. J Neurol Sci 2018; 396:247-253. [PMID: 30529802 DOI: 10.1016/j.jns.2018.11.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/05/2018] [Accepted: 11/21/2018] [Indexed: 01/06/2023]
Abstract
Glioblastoma (GBM) is a typical malignant tumor, and there are no effective drugs capable of improving patient survival. Docosahexaenoic acid (DHA), a nutrient essential to animal health and neurodevelopment, exerts an anticancer effect in several types of cancer. However, the function of DHA in GBM is still unclear. Here, we showed that DHA could repress the migration and invasion of GBM U251 cells and promote their apoptosis in a dose- and time-dependent manner, indicating that DHA has an anticancer effect on GBM cells. Whole-transcriptome analysis indicated that DHA treatment mainly regulates the genes associated with receptor binding, oxidoreductase activity, organic acid transmembrane transporter activity, and carboxylic acid transmembrane transporter activity. Long non-coding RNAs (LncRNAs) involved in the regulation network of DHA were also identified, and their targets were assigned to the Gene Ontology (GO) categories. In silico analysis was conducted to predict the pathways related to the differentially expressed genes by DHA treatment. Our findings suggest that DHA acts as an antitumor agent in GBM, which may provide a suitable means of improving the efficacy of GBM treatment in the future.
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Affiliation(s)
- Miaomiao Ruan
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China; Jiangsu Center for Safety Evaluation of Drugs, School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, China
| | - Jiying Liu
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China
| | - Xueyang Ren
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China
| | - Chu Li
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China
| | - Allan Z Zhao
- Collaborative Innovation Center for Cancer Medicine, Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong Province 510643, China
| | - Lin Li
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Haiyuan Yang
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Yifan Dai
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China; Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, China
| | - Ying Wang
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China.
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26
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Park M, Lim JW, Kim H. Docoxahexaenoic Acid Induces Apoptosis of Pancreatic Cancer Cells by Suppressing Activation of STAT3 and NF-κB. Nutrients 2018; 10:nu10111621. [PMID: 30400136 PMCID: PMC6267441 DOI: 10.3390/nu10111621] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 10/22/2018] [Accepted: 10/24/2018] [Indexed: 12/16/2022] Open
Abstract
The ω3-polyunsaturated fatty acid docosahexenoic acid (DHA) is known to induce apoptosis of cancer cells. In this study, DHA was shown to reduce viability of pancreatic cancer cells (PANC-1) by inducing DNA fragmentation, activating caspase-3, and increasing the ratio of Bax/Bcl-2. To determine the DHA mechanism of action, the impact of DHA on the activation of the key signaling proteins epidermal growth factor receptor (EGFR), signal transducer and activator of transcription factor 3 (STAT3), nuclear transcription factor-κB (NF-κB), and IκBα in PANC-1 cells was probed. The observed DHA suppression of NF-κB DNA-binding activity was found to result from reduced IκBα phosphorylation. The observed DHA-induced suppression of STAT3 activation was found to be the result of suppressed EGFR activation, which derives from the inhibitory effect of DHA on the integrity of localization of EGFR to cell membrane lipid rafts. Since the activation of STAT3 and NF-κB mediates the expression of survival genes cyclin D1 and survivin, DHA induced apoptosis by suppressing the STAT3/NF-κB-cyclin D1/survivin axis. These results support the proposal that DHA-induced apoptosis of pancreatic cells occurs via disruption of key pro-cell survival signaling pathways. We suggest that the consumption of DHA-enriched foods could decrease the incidence of pancreatic cancer.
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Affiliation(s)
- Mirae Park
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Joo Weon Lim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Hyeyoung Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
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Shirooie S, Nabavi SF, Dehpour AR, Belwal T, Habtemariam S, Argüelles S, Sureda A, Daglia M, Tomczyk M, Sobarzo-Sanchez E, Xu S, Nabavi SM. Targeting mTORs by omega-3 fatty acids: A possible novel therapeutic strategy for neurodegeneration? Pharmacol Res 2018; 135:37-48. [PMID: 29990625 DOI: 10.1016/j.phrs.2018.07.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 07/03/2018] [Accepted: 07/05/2018] [Indexed: 12/26/2022]
Abstract
Neurodegenerative diseases (NDs) such as Parkinson's (PD), Alzheimer's (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) cause significant world-wide morbidity and mortality. To date, there is no drug of cure for these, mostly age-related diseases, although approaches in delaying the pathology and/or giving patients some symptomatic relief have been adopted for the last few decades. Various studies in recent years have shown the beneficial effects of omega-3 poly unsaturated fatty acids (PUFAs) through diverse mechanisms including anti-inflammatory effects. This review now assesses the potential of this class of compounds in NDs therapy through specific action against the mammalian target of rapamycin (mTOR) signaling pathway. The role of mTOR in neurodegenerative diseases and targeted therapies by PUFAs are discussed.
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Affiliation(s)
- Samira Shirooie
- Department of Pharmacology, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed Fazel Nabavi
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran; Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 14359-16471, Iran
| | - Ahmad R Dehpour
- Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Tarun Belwal
- G.B. Pant National Institute of Himalayan Environment and Sustainable Development, Kosi Katarmal, Almora, Uttarakhand, India
| | - Solomon Habtemariam
- Pharmacognosy Research Laboratories & Herbal Analysis Services UK, University of Greenwich, Chatham-Maritime, Kent ME4 4TB, UK
| | - Sandro Argüelles
- Department of Physiology, Faculty of Pharmacy, University of Seville, Seville, Spain
| | - Antoni Sureda
- Research Group on Community Nutrition and Oxidative Stress (NUCOX) and CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), University of Balearic Islands, Palma de Mallorca E-07122, Balearic Islands, Spain
| | - Maria Daglia
- Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Italy
| | - Michał Tomczyk
- Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Białystok, ul. Mickiewicza 2a, 15-230 Białystok, Poland
| | - Eduardo Sobarzo-Sanchez
- Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782, Spain; Instituto de Investigación en Innovación en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago, Chile
| | - Suowen Xu
- Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY 14623, United States
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 14359-16471, Iran.
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Mathew SA, Bhonde RR. Omega-3 polyunsaturated fatty acids promote angiogenesis in placenta derived mesenchymal stromal cells. Pharmacol Res 2018; 132:90-98. [PMID: 29665425 DOI: 10.1016/j.phrs.2018.04.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Revised: 03/23/2018] [Accepted: 04/03/2018] [Indexed: 02/07/2023]
Abstract
Enhancement of angiogenesis is solicited in wound repair and regeneration. Mesenchymal stromal cells derived from the placenta (P-MSCs) have an inherent angiogenic potential. Polyunsaturated fatty acids (PUFAs) in turn, specifically the omega-3 (N-3) are essential for growth and development. They are also recommended as dietary supplements during pregnancy. We therefore hypothesized that addition of N-3 PUFAs in P-MSC culture media may enhance their angiogenic potential. Hence, we treated P-MSCs with omega-3 (N-3) fatty acids -Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) at different concentrations and tested their angiogenic potential. We saw an upregulation of both bFGF and VEGFA. We also found enhanced in vitro tube formation ability of P-MSCs treated with DHA: EPA. We then looked at the influence of the conditioned medium (CM) collected from P-MSCs exposed to DHA: EPA on the key effector cells -HUVECs (Human Umbilical Vein derived endothelial cells and their functionality was further confirmed on chick yolk sac membrane. We found that the CM of P-MSCs exposed to DHA: EPA could enhance angiogenesis in both cases. These result were finally validated in an in vivo matrigel plug assay which revealed enhanced migration and vessel formation in CM treated with DHA: EPA. Our data thus reveals for the first time that supplementation with lower concentration of PUFA enhances the angiogenic potential of P-MSCs making them suitable for chronic wound healing applications.
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Affiliation(s)
- Suja Ann Mathew
- School of Regenerative Medicine, Manipal University, MAHE, GKVK Post, Bellary Road, Allalasandra, Near Royal Orchid, Yelahanka, Bangalore, 560 065, India.
| | - Ramesh R Bhonde
- Dr. D.Y. Patil Vidyapeeth - (DPU), Pimpri, Pune, 411018, India.
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Synergetic effects of essential oils mixture improved egg quality traits, oxidative stability and liver health indices in laying hens fed fish oil. Anim Feed Sci Technol 2017. [DOI: 10.1016/j.anifeedsci.2017.10.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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