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Valivand N, Aravand S, Lotfi H, Esfahani AJ, Ahmadpour-Yazdi H, Gheibi N. Propolis: a natural compound with potential as an adjuvant in cancer therapy - a review of signaling pathways. Mol Biol Rep 2024; 51:931. [PMID: 39177837 DOI: 10.1007/s11033-024-09807-9] [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: 12/10/2023] [Accepted: 07/18/2024] [Indexed: 08/24/2024]
Abstract
Propolis is a natural product used in cancer treatment, which is produced by bees via different sources. The chemical composition of Propolis is determined based on the climatic and geographical conditions, as well as harvesting time and method. This compound has been the subject of numerous investigational endeavors due to its expansive therapeutic capacity which includes antibacterial, anti-fungal, anti-inflammatory, anti-oxidant, anti-viral, and anti-cancer effects. The growing incidence rate of different cancers necessitates the need for developing novel preventive and therapeutic strategies. Chemotherapy, radiotherapy, and stem cell therapy have proved effective in cancer treatment, regardless of the adverse events associated with these modalities. Clinical application of natural compounds such as Propolis may confer promise as an adjuvant therapeutic intervention, particularly in certain subpopulations of patients that develop adverse events associated with anticancer regimens. The diverse biologically active compounds of propolis are believed to confer anti-cancer potential by modulation of critical signaling cascades such as caffeic acid phenethyl ester, Galangin, Artepillin C, Chrysin, Quercetin, Caffeic acid, Nymphaeols A and C, Frondoside A, Genistein, p-coumaric acid, and Propolin C. This review article aims to deliver a mechanistic account of anti-cancer effects of propolis and its components. Propolis can prevent angiogenesis by downregulating pathways involving Jun-N terminal kinase, ERK1/2, Akt and NF-ƘB, while counteracting metastatic progression of cancer by inhibiting Wtn2 and FAK, and MAPK and PI3K/AKT signaling pathways. Moreover, propolis or its main components show regulatory effects on cyclin D, CDK2/4/6, and their inhibitors. Additionally, propolis-induced up-regulation of p21 and p27 may result in cell cycle arrest at G2/M or G0/G1. The broad anti-apoptotic effects of propolis are mediated through upregulation of TRAIL, Bax, p53, and downregulation of the ERK1/2 signaling pathway. Considering the growing body of evidence regarding different anti-cancers effects of propolis and its active components, this natural compound could be considered an effective adjuvant therapy aimed at reducing related side effects associated with chemotherapy and radiotherapy.
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Affiliation(s)
- Nassim Valivand
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Sara Aravand
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Hajie Lotfi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Azam Janati Esfahani
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Hossein Ahmadpour-Yazdi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Nematollah Gheibi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.
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Bava R, Castagna F, Lupia C, Poerio G, Liguori G, Lombardi R, Naturale MD, Bulotta RM, Biondi V, Passantino A, Britti D, Statti G, Palma E. Hive Products: Composition, Pharmacological Properties, and Therapeutic Applications. Pharmaceuticals (Basel) 2024; 17:646. [PMID: 38794216 PMCID: PMC11124102 DOI: 10.3390/ph17050646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 05/03/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Beekeeping provides products with nutraceutical and pharmaceutical characteristics. These products are characterized by abundance of bioactive compounds. For different reasons, honey, royal jelly, propolis, venom, and pollen are beneficial to humans and animals and could be used as therapeutics. The pharmacological action of these products is related to many of their constituents. The main bioactive components of honey include oligosaccharides, methylglyoxal, royal jelly proteins (MRJPs), and phenolics compounds. Royal jelly contains jelleins, royalisin peptides, MRJPs, and derivatives of hydroxy-decenoic acid, particularly 10-hydroxy-2-decenoic acid (10-HDA), which possess antibacterial, anti-inflammatory, immunomodulatory, neuromodulatory, metabolic syndrome-preventing, and anti-aging properties. Propolis has a plethora of activities that are referable to compounds such as caffeic acid phenethyl ester. Peptides found in bee venom include phospholipase A2, apamin, and melittin. In addition to being vitamin-rich, bee pollen also includes unsaturated fatty acids, sterols, and phenolics compounds that express antiatherosclerotic, antidiabetic, and anti-inflammatory properties. Therefore, the constituents of hive products are particular and different. All of these constituents have been investigated for their properties in numerous research studies. This review aims to provide a thorough screening of the bioactive chemicals found in honeybee products and their beneficial biological effects. The manuscript may provide impetus to the branch of unconventional medicine that goes by the name of apitherapy.
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Affiliation(s)
- Roberto Bava
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (R.B.); (C.L.); (R.M.B.); (D.B.); (E.P.)
| | - Fabio Castagna
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (R.B.); (C.L.); (R.M.B.); (D.B.); (E.P.)
- Mediterranean Ethnobotanical Conservatory, Sersale (CZ), 88054 Catanzaro, Italy
| | - Carmine Lupia
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (R.B.); (C.L.); (R.M.B.); (D.B.); (E.P.)
- Mediterranean Ethnobotanical Conservatory, Sersale (CZ), 88054 Catanzaro, Italy
| | - Giusi Poerio
- ATS Val Padana, Via dei Toscani, 46100 Mantova, Italy;
| | | | - Renato Lombardi
- IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), 71013 Foggia, Italy;
| | - Maria Diana Naturale
- Ministry of Health, Directorate General for Health Programming, 00144 Rome, Italy;
| | - Rosa Maria Bulotta
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (R.B.); (C.L.); (R.M.B.); (D.B.); (E.P.)
| | - Vito Biondi
- Department of Veterinary Sciences, University of Messina, 98168 Messina, Italy; (V.B.); (A.P.)
| | - Annamaria Passantino
- Department of Veterinary Sciences, University of Messina, 98168 Messina, Italy; (V.B.); (A.P.)
| | - Domenico Britti
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (R.B.); (C.L.); (R.M.B.); (D.B.); (E.P.)
| | - Giancarlo Statti
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 87036 Cosenza, Italy;
| | - Ernesto Palma
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (R.B.); (C.L.); (R.M.B.); (D.B.); (E.P.)
- Center for Pharmacological Research, Food Safety, High Tech and Health (IRC-FSH), University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy
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Pérez R, Burgos V, Marín V, Camins A, Olloquequi J, González-Chavarría I, Ulrich H, Wyneke U, Luarte A, Ortiz L, Paz C. Caffeic Acid Phenethyl Ester (CAPE): Biosynthesis, Derivatives and Formulations with Neuroprotective Activities. Antioxidants (Basel) 2023; 12:1500. [PMID: 37627495 PMCID: PMC10451560 DOI: 10.3390/antiox12081500] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/21/2023] [Accepted: 06/27/2023] [Indexed: 08/27/2023] Open
Abstract
Neurodegenerative disorders are characterized by a progressive process of degeneration and neuronal death, where oxidative stress and neuroinflammation are key factors that contribute to the progression of these diseases. Therefore, two major pathways involved in these pathologies have been proposed as relevant therapeutic targets: The nuclear transcription factor erythroid 2 (Nrf2), which responds to oxidative stress with cytoprotecting activity; and the nuclear factor NF-κB pathway, which is highly related to the neuroinflammatory process by promoting cytokine expression. Caffeic acid phenethyl ester (CAPE) is a phenylpropanoid naturally found in propolis that shows important biological activities, including neuroprotective activity by modulating the Nrf2 and NF-κB pathways, promoting antioxidant enzyme expression and inhibition of proinflammatory cytokine expression. Its simple chemical structure has inspired the synthesis of many derivatives, with aliphatic and/or aromatic moieties, some of which have improved the biological properties. Moreover, new drug delivery systems increase the bioavailability of these compounds in vivo, allowing its transcytosis through the blood-brain barrier, thus protecting brain cells from the increased inflammatory status associated to neurodegenerative and psychiatric disorders. This review summarizes the biosynthesis and chemical synthesis of CAPE derivatives, their miscellaneous activities, and relevant studies (from 2010 to 2023), addressing their neuroprotective activity in vitro and in vivo.
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Affiliation(s)
- Rebeca Pérez
- Laboratory of Natural Products & Drug Discovery, Center CEBIM, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4780000, Chile; (R.P.); (V.M.)
| | - Viviana Burgos
- Departamento de Ciencias Biológicas y Químicas, Facultad de Recursos Naturales, Universidad Católica de Temuco, Rudecindo Ortega, Temuco 4780000, Chile;
| | - Víctor Marín
- Laboratory of Natural Products & Drug Discovery, Center CEBIM, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4780000, Chile; (R.P.); (V.M.)
| | - Antoni Camins
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, 08028 Barcelona, Spain;
- Institut de Neurociències (UBNeuro), Universitat de Barcelona, 08028 Barcelona, Spain
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain
| | - Jordi Olloquequi
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, 08028 Barcelona, Spain;
- Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Talca 3460000, Chile
| | - Iván González-Chavarría
- Departamento de Fisiopatología, Facultad de Ciencias Biológicas Universidad de Concepción, Concepción 4030000, Chile;
| | - Henning Ulrich
- Department of Biochemistry, Instituto de Química, Universidad de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo 05508-000, SP, Brazil;
| | - Ursula Wyneke
- Facultad de Medicina, Universidad de Los Andes, Santiago 111711, Chile; (U.W.)
- Center of Interventional Medicine for Precision and Advanced Cellular Therapy (IMPACT), Santiago 7620001, Chile
| | - Alejandro Luarte
- Facultad de Medicina, Universidad de Los Andes, Santiago 111711, Chile; (U.W.)
- Center of Interventional Medicine for Precision and Advanced Cellular Therapy (IMPACT), Santiago 7620001, Chile
| | - Leandro Ortiz
- Instituto de Ciencias Químicas, Facultad de Ciencias, Universidad Austral de Chile, Casilla 567, Valdivia 5110566, Chile;
| | - Cristian Paz
- Laboratory of Natural Products & Drug Discovery, Center CEBIM, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4780000, Chile; (R.P.); (V.M.)
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Pandey P, Khan F, Upadhyay TK, Giri PP. Therapeutic efficacy of caffeic acid phenethyl ester in cancer therapy: An updated review. Chem Biol Drug Des 2023; 102:201-216. [PMID: 36929632 DOI: 10.1111/cbdd.14233] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/31/2023] [Accepted: 02/28/2023] [Indexed: 03/18/2023]
Abstract
Nowadays, there is a lot of public and scientific interest in using phytochemicals to treat human ailments. Existing cancer medicines still run across obstacles, despite significant advancements in the field. For instance, chemotherapy may result in severe adverse effects, increased drug resistance, and treatment failure. Natural substances that are phytochemically derived provide innovative approaches as potent therapeutic molecules for the treatment of cancer. Bioactive natural compounds may enhance chemotherapy for cancer by increasing the sensitivity of cancer cells to medicines. Propolis has been found to interfere with the viability of cancer cells, among other phytochemicals. Of all the components that make up propolis, caffeic acid phenethyl ester (CAPE) (a flavonoid) has been the subject of the most research. It demonstrates a broad spectrum of therapeutic uses, including antitumor, antimicrobial, antiviral, anti-inflammatory, immunomodulatory, hepatoprotective, neuroprotective, and cardioprotective effects. Studies conducted in vitro and in vivo have demonstrated that CAPE specifically targets genes involved in cell death, cell cycle regulation, angiogenesis, and metastasis. By altering specific signaling cascades, such as the NF-κB signaling pathway, CAPE can limit the proliferation of human cancer cells. This review highlights the research findings demonstrating the anticancer potential of CAPE with a focus on multitargeted molecular and biological implications in various cancer models.
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Affiliation(s)
- Pratibha Pandey
- Department of Biotechnology, Noida Institute of Engineering & Technology, Greater Noida, India
| | - Fahad Khan
- Department of Biotechnology, Noida Institute of Engineering & Technology, Greater Noida, India
| | - Tarun Kumar Upadhyay
- Department of Biotechnology, Parul Institute of Applied Sciences and Centre of Research for Development, Parul University, Vadodara, India
| | - Pavan Prakash Giri
- Department of Chemistry, Noida Institute of Engineering & Technology, Greater Noida, India
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Tseng JC, Wang BJ, Wang YP, Kuo YY, Chen JK, Hour TC, Kuo LK, Hsiao PJ, Yeh CC, Kao CL, Shih LJ, Chuu CP. Caffeic acid phenethyl ester suppresses EGFR/FAK/Akt signaling, migration, and tumor growth of prostate cancer cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 116:154860. [PMID: 37201366 DOI: 10.1016/j.phymed.2023.154860] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/26/2023] [Accepted: 05/03/2023] [Indexed: 05/20/2023]
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) is upregulated in prostate cancer (PCa). However, suppression of EGFR did not improve the patient outcome, possibly due to the activation of PI3K/Akt signaling in PCa. Compounds able to suppress both PI3K/Akt and EGFR signaling may be effective for treating advanced PCa. PURPOSE We examined if caffeic acid phenethyl ester (CAPE) simultaneously suppresses the EGFR and Akt signaling, migration and tumor growth in PCa cells. METHODS Wound healing assay, transwell migration assay and xenograft mice model were used to determine the effects of CAPE on migration and proliferation of PCa cells. Western blot, immunoprecipitation, and immunohistochemistry staining were performed to determine the effects of CAPE on EGFR and Akt signaling. RESULTS CAPE treatment decreased the gene expression of HRAS, RAF1, AKT2, GSK3A, and EGF and the protein expression of phospho-EGFR (Y845, Y1069, Y1148, Y1173), phospho-FAK, Akt, and ERK1/2 in PCa cells. CAPE treatment inhibited the EGF-induced migration of PCa cells. Combined treatment of CAPE with EGFR inhibitor gefitinib showed additive inhibition on migration and proliferation of PCa cells. Injection of CAPE (15 mg/kg/3 days) for 14 days suppressed the tumor growth of prostate xenografts in nude mice as well as suppressed the levels of Ki67, phospho-EGFR Y845, MMP-9, phospho-Akt S473, phospho-Akt T308, Ras, and Raf-1 in prostate xenografts. CONCLUSIONS Our study suggested that CAPE can simultaneously suppress the EGFR and Akt signaling in PCa cells and is a potential therapeutic agent for advanced PCa.
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Affiliation(s)
- Jen-Chih Tseng
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan; Immunology Research Center, National Health Research Institutes, Miaoli County 35053, Taiwan
| | - Bi-Juan Wang
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan
| | - Ya-Pei Wang
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan
| | - Ying-Yu Kuo
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan
| | - Jen-Kun Chen
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County 35053, Taiwan
| | - Tzyh-Chyuan Hour
- Neuroscience Research Center, Kaohsiung Medical University, Kaohsiung 80737, Taiwan; Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung 80737, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80737, Taiwan
| | - Li-Kuo Kuo
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mackay Memorial Hospital, Taipei City 104217, Taiwan; Department of Nursing, Mackay Medical College, Taipei City, Taiwan
| | - Po-Jen Hsiao
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan; Division of Nephrology, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan 325, Taiwan; Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Chien-Chih Yeh
- Department of Education and Medical Research, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan; Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Cheng-Li Kao
- Division of Urology, Departments of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Division of Urology, Department of Surgery, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - Li-Jane Shih
- Department of Education and Medical Research, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan; Graduate Institute of Medical Science, National Defense Medical Center, Taipei 114, Taiwan
| | - Chih-Pin Chuu
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan; Department of Life Sciences, National Central University, Taoyuan 32031, Taiwan; PhD Program for Aging and Graduate Institute of Basic Medical Science, China Medical University, Taichung City 40402, Taiwan; Biotechnology Center, National Chung Hsing University, Taichung City 40227, Taiwan.
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Propolis: A Detailed Insight of Its Anticancer Molecular Mechanisms. Pharmaceuticals (Basel) 2023; 16:ph16030450. [PMID: 36986549 PMCID: PMC10059947 DOI: 10.3390/ph16030450] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/10/2023] [Accepted: 03/12/2023] [Indexed: 03/19/2023] Open
Abstract
Cancer is the second most life-threatening disease and has become a global health and economic problem worldwide. Due to the multifactorial nature of cancer, its pathophysiology is not completely understood so far, which makes it hard to treat. The current therapeutic strategies for cancer lack the efficacy due to the emergence of drug resistance and the toxic side effects associated with the treatment. Therefore, the search for more efficient and less toxic cancer treatment strategies is still at the forefront of current research. Propolis is a mixture of resinous compounds containing beeswax and partially digested exudates from plants leaves and buds. Its chemical composition varies widely depending on the bee species, geographic location, plant species, and weather conditions. Since ancient times, propolis has been used in many conditions and aliments for its healing properties. Propolis has well-known therapeutic actions including antioxidative, antimicrobial, anti-inflammatory, and anticancer properties. In recent years, extensive in vitro and in vivo studies have suggested that propolis possesses properties against several types of cancers. The present review highlights the recent progress made on the molecular targets and signaling pathways involved in the anticancer activities of propolis. Propolis exerts anticancer effects primarily by inhibiting cancer cell proliferation, inducing apoptosis through regulating various signaling pathways and arresting the tumor cell cycle, inducing autophagy, epigenetic modulations, and further inhibiting the invasion and metastasis of tumors. Propolis targets numerous signaling pathways associated with cancer therapy, including pathways mediated by p53, β-catenin, ERK1/2, MAPK, and NF-κB. Possible synergistic actions of a combination therapy of propolis with existing chemotherapies are also discussed in this review. Overall, propolis, by acting on diverse mechanisms simultaneously, can be considered to be a promising, multi-targeting, multi-pathways anticancer agent for the treatment of various types of cancers.
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Chavda VP, Chaudhari AZ, Teli D, Balar P, Vora L. Propolis and Their Active Constituents for Chronic Diseases. Biomedicines 2023; 11:biomedicines11020259. [PMID: 36830794 PMCID: PMC9953602 DOI: 10.3390/biomedicines11020259] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 01/11/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Propolis is a mass of chemically diverse phytoconstituents with gummy textures that are naturally produced by honeybees upon collection of plant resins for utilization in various life processes in beehives. Since ancient times, propolis has been a unique traditional remedy globally utilized for several purposes, and it has secured value in pharmaceutical and nutraceutical areas in recent years. The chemical composition of propolis comprises diverse constituents and deviations in the precise composition of the honeybee species, plant source used for propolis production by bees, climate conditions and harvesting season. Over 300 molecular structures have been discovered from propolis, and important classes include phenolic acids, flavonoids, terpenoids, benzofurans, benzopyrene and chalcones. Propolis has also been reported to have diverse pharmacological activities, such as antidiabetic, anti-inflammatory, antioxidant, anticancer, immunomodulatory, antibacterial, antiviral, antifungal, and anticaries. As chronic diseases have risen as a global health threat, abundant research has been conducted to track propolis and its constituents as alternative therapies for chronic diseases. Several clinical trials have also revealed the potency of propolis and its constituents for preventing and curing some chronic diseases. This review explores the beneficial effect of propolis and its active constituents with credible mechanisms and computational studies on chronic diseases.
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Affiliation(s)
- Vivek P. Chavda
- Department of Pharmaceutics and Pharmaceutical Technology, L. M. College of Pharmacy, Ahmedabad 380008, India
- Correspondence: (V.P.C.); (L.V.)
| | - Amit Z. Chaudhari
- Department of Pharmaceutical Chemistry, L. M. College of Pharmacy, Ahmedabad 380009, India
| | - Divya Teli
- Department of Pharmaceutical Chemistry, L. M. College of Pharmacy, Ahmedabad 380009, India
| | - Pankti Balar
- Pharmacy Section, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380009, India
| | - Lalitkumar Vora
- School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
- Correspondence: (V.P.C.); (L.V.)
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Eser N, Cicek M, Yoldas A, Demir M, Deresoy FA. Caffeic acid phenethyl ester ameliorates imidacloprid-induced acute toxicity in the rat cerebral cortex. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 96:103980. [PMID: 36191819 DOI: 10.1016/j.etap.2022.103980] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 09/13/2022] [Accepted: 09/26/2022] [Indexed: 06/16/2023]
Abstract
This study aimed to investigate the role of caffeic acid phenethyl ester (CAPE), a compound found in propolis, on imidacloprid (IMI), a nicotinic acetylcholine receptor agonist that causes cerebral toxicity. 60 adult rats were randomly divided into five groups: control, IMI (100 mg/kg), and IMI+CAPE (1, 5, 10 mg/kg). Cerebral cortex tissue was examined histopathologically, biochemically, spectrophotometrically and immunohistochemically. The results showed that IMI caused toxicity in the cerebral cortex. However, CAPE (5 and 10 mg/kg) attenuated the deteriorated histopathological score and normalized the apoptotic markers (Bax and Caspase-3). Additionally, CAPE dose-dependently normalized the levels of TNF-α, dopamin, GFAP and NGF, and at the highest dose (10 mg/kg) also normalized the balance of oxidative parameters (MDA, SOD, CAT, and GSH). In conclusion, the antioxidant, anti-inflammatory, and anti-apoptotic effects of CAPE may be a promising treatment for acute IMI-induced cerebral cortex toxicity.
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Affiliation(s)
- Nadire Eser
- Department of Pharmacology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey.
| | - Mustafa Cicek
- Department of Medical Biology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey
| | - Atila Yoldas
- Department of Anatomy, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey
| | - Mehmet Demir
- Department of Anatomy, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey
| | - Faik Alev Deresoy
- Department of Pathology, Faculty of Medicine, Gaziosmanpasa University, Tokat, Turkey
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Amalia E, Diantini A, Endang Prabandari E, Waluyo D, Subarnas A. Caffeic Acid Phenethyl Ester as a DHODH Inhibitor and Its Synergistic Anticancer Properties in Combination with 5-Fluorouracil in a Breast Cancer Cell Line. J Exp Pharmacol 2022; 14:243-253. [PMID: 35910085 PMCID: PMC9329448 DOI: 10.2147/jep.s365159] [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: 03/05/2022] [Accepted: 07/11/2022] [Indexed: 11/23/2022] Open
Abstract
Introduction A combination of chemotherapy agents is the best choice in breast cancer treatment to increase the patient survival rate. 5-fluorouracil (5-FU) is one of the drugs applied in combination with other drugs to control and delay development of cancer cells. Nevertheless, the occurrence of multidrug resistance and dose-limiting cytotoxicity have limited the efficacy of 5-FU treatment. Therefore, the discovery of new anti-breast cancer drugs should be pursued. Objective To study potency of a promising naturally derived compound, caffeic acid phenethyl ester (CAPE), for breast cancer treatment in single and combination with 5-FU. Methods Cytotoxicity of CAPE, 5-FU, and 5-FU+CAPE was studied by in vitro MTT experiment in MCF-7 cell line, and RT-PCR analysis was used to evaluate the change in gene expression due to the treatment. Moreover, an enzymatic assay and molecular docking analysis were applied to evaluate the possible mechanism of substance-induced apoptosis. Results The study revealed that a single treatment of CAPE showed cytotoxicity with IC50 6.6 ± 1.0 µM and 6.5 ± 2.9 µM at 24 h and 48 h, respectively. Meanwhile, 5-FU showed cytostatic activity. The 5-FU + CAPE has a synergistic effect at 24 h treatment with a CI = 0.5 and an additive effect at 48 h treatment with CI = 1.0. CAPE was also found to enhances the mRNA expression of caspase-8 and BAX within 6 hours in combination with 5-FU compared to 5-FU treatment alone. Our study reveals a new mechanism of CAPE which is related to the inhibition of human dihydroorotate dehydrogenase (HsDHODH) with an IC50 of 120.7 ± 6.8 µM, by bound to the ubiquinone-binding site of the enzyme and could be responsible for inducing extrinsic and intrinsic apoptosis. Conclusion This study demonstrated the cytotoxicity of CAPE potential to induce apoptosis of breast cancer MCF-7 cell line single and cytotoxic-cytostatic combination with 5-FU. Therefore, further studies to develop CAPE and its derivatives will be required to discover new candidates for breast cancer agents.
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Affiliation(s)
- Eri Amalia
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia.,Department of Pharmacology, Faculty of Science and Technology, Department of Pharmacy, Muhammadiyah University, Bandung, Indonesia.,Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Ajeng Diantini
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | | | - Danang Waluyo
- Research Center for Vaccine and Drug, National Research and Innovation Agency, Bogor, Indonesia
| | - Anas Subarnas
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
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10
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Hussain A, Bourguet-Kondracki ML, Hussain F, Rauf A, Ibrahim M, Khalid M, Hussain H, Hussain J, Ali I, Khalil AA, Alhumaydhi FA, Khan M, Hussain R, Rengasamy KRR. The potential role of dietary plant ingredients against mammary cancer: a comprehensive review. Crit Rev Food Sci Nutr 2022; 62:2580-2605. [DOI: 10.1080/10408398.2020.1855413] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Amjad Hussain
- Department of Chemistry, University of Okara, Okara, Pakistan
- Laboratoire Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 MNHN-CNRS, Muséum National d’Histoire Naturelle, Paris, France
- Department of Applied Chemistry, Government College University, Faisalabad, Pakistan
| | - Marie-Lise Bourguet-Kondracki
- Laboratoire Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 MNHN-CNRS, Muséum National d’Histoire Naturelle, Paris, France
| | - Farhad Hussain
- Department of Applied Chemistry, Government College University, Faisalabad, Pakistan
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Swabi, Anbar, Khyber Pukhtanuk (KP), Pakistan
| | - Muhammad Ibrahim
- Department of Applied Chemistry, Government College University, Faisalabad, Pakistan
| | - Muhammad Khalid
- Department of Chemistry, Khwaja Fareed University of Engineering & Information Technology, Punjab, Pakistan
| | - Hidayat Hussain
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Halle (Salle), Germany
| | - Javid Hussain
- Department of Biological Sciences & Chemistry, College of Arts and Sciences, University of Nizwa, Nizwa, Sultanate of Oman
| | - Iftikhar Ali
- Department of Chemistry, Karakoram International University, Gilgit, Pakistan
| | - Anees Ahmed Khalil
- University Institute of Diet and Nutritional Sciences, Faculty of Allied Health Sciences, The University of Lahore, Lahore, Pakistan
| | - Fahad A. Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Muhammad Khan
- Department of Chemistry, University of Okara, Okara, Pakistan
| | - Riaz Hussain
- Department of Chemistry, University of Okara, Okara, Pakistan
| | - Kannan R. R. Rengasamy
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam
- Faculty of Environment and Chemical Engineering, Duy Tan University, Da Nang, Vietnam
- Indigenous Knowledge Systems Centre, Faculty of Natural and Agricultural Sciences, North-West University, Mmabatho, South Africa
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11
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Hachem K, Bokov D, Mahdavian L. Antioxidant Capacity of Caffeic Acid Phenethyl Ester in Scavenging Free Radicals by a Computational Insight. Polycycl Aromat Compd 2022. [DOI: 10.1080/10406638.2022.2053174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Kadda Hachem
- Laboratory of Biotoxicology, Pharmacognosy and Biological Valorization of Plants (LBPVBP), Faculty of Sciences, University of Saida - Dr Moulay Tahar, Saida, Algeria
| | - Dmitry Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Leila Mahdavian
- Department of Chemistry, Doroud Branch, Islamic Azad University, Doroud, Iran
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12
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Hernández-Melchor D, Ramírez-Martínez L, Cid L, Palafox-Gómez C, López-Bayghen E, Ortega A. EAAT1-dependent slc1a3 Transcriptional Control depends on the Substrate Translocation Process. ASN Neuro 2022; 14:17590914221116574. [PMID: 35903937 PMCID: PMC9340397 DOI: 10.1177/17590914221116574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Glutamate, the major excitatory neurotransmitter in the vertebrate brain, is removed from the synaptic cleft by a family of sodium-dependent transporters expressed in neurons and glial cells. The bulk of glutamate uptake activity occurs in glial cells through the sodium-dependent glutamate/aspartate transporter (EAAT1/GLAST) and glutamate transporter 1 (EAAT2/GLT-1). EAAT1/GLAST is the predominant transporter within the cerebellum. It is highly enriched in Bergmann glial cells that span the cerebellar cortex and wrap the most abundant glutamatergic synapses in the central nervous system, the synapse formed by the parallel fibers and the Purkinje cells. In the past years, it has become evident that Bergmann glial cells are involved in glutamatergic transmission. Glutamate transporters are tightly regulated due to their essential role in tripartite synapses. Glutamate regulates EAAT1/GLAST function and gene expression in a receptor-dependent and receptor-independent manner. Through the use of the non-metabolizable EAAT1/GLAST ligand, D-Aspartate, and the well-established chick cerebellar Bergmann glia primary culture, in this contribution, we demonstrate that EAAT1/GLAST down-regulates its expression and function at the transcriptional level through the activation of a signaling pathway that includes the phosphatidyl inositol 3 kinase (PI3K), the Ca2+/diacylglycerol dependent protein kinase PKC and the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB). These results favor the notion of an activity-dependent fine-tuning of glutamate recycling and its synaptic transactions through glial cells. Summary statement EAAT1/GLAST down-regulates its expression and function at the transcriptional level by activating a signaling pathway that includes PI3K, PKC and NF-κB, favoring the notion of an activity-dependent fine-tuning of glutamate recycling and its synaptic transactions through glial cells.
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Affiliation(s)
- Dinorah Hernández-Melchor
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
- Science, Technology and Society Program. Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
| | - Leticia Ramírez-Martínez
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
| | - Luis Cid
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
| | - Cecilia Palafox-Gómez
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
| | - Esther López-Bayghen
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
| | - Arturo Ortega
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
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13
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Lipovka Y, Alday E, Hernandez J, Velazquez C. Molecular Mechanisms of Biologically Active Compounds from Propolis in Breast Cancer: State of the Art and Future Directions. FOOD REVIEWS INTERNATIONAL 2021. [DOI: 10.1080/87559129.2021.2003380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- Yulia Lipovka
- Department of Chemistry-Biology, University of Sonora, Hermosillo, Mexico
| | - Efrain Alday
- Department of Chemistry-Biology, University of Sonora, Hermosillo, Mexico
| | - Javier Hernandez
- Unidad de Servicios de Apoyo en Resolución Analítica, Universidad Veracruzana, Xalapa, Mexico
| | - Carlos Velazquez
- Department of Chemistry-Biology, University of Sonora, Hermosillo, Mexico
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14
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Chaudhry GES, Jan R, Akim A, Zafar MN, Sung YY, Muhammad TST. Breast Cancer: A Global Concern, Diagnostic and Therapeutic Perspectives, Mechanistic Targets in Drug Development. Adv Pharm Bull 2021; 11:580-594. [PMID: 34888205 PMCID: PMC8642807 DOI: 10.34172/apb.2021.068] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 08/10/2020] [Accepted: 10/14/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer is a complex multifactorial process, unchecked and abrupt division, and cell growth—conventional chemotherapy, along with radiotherapy, is used to treat breast cancer. Due to reduce efficacy and less survival rate, there is a particular need for the discovery of new active anticancer agents. Natural resources such as terrestrial/marine plants or organisms are a promising source for the generation of new therapeutics with improving efficacy. The screening of natural plant extracts and fractions, isolations of phytochemicals, and mechanistic study of those potential compounds play a remarkable role in the development of new therapeutic drugs with increased efficacy. Cancer is a multistage disease with complex signaling cascades. The initial study of screening whole extracts or fractions and later the isolation of secondary compounds and their mechanism of action study gives a clue of potential therapeutic agents for future drug development. The phytochemicals present in extracts/fractions produce remarkable effects due to synergistically targeting multiple signals. In this review, the molecular targets of extracts/ fractions and isolated compounds highlighted. The therapeutic agent's mechanistic targets in drug development focused involves; i) Induction of Apoptosis, ii) modulating cell cycle arrest, iii) Inhibition or suppression of invasion and metastasis and iv) various other pro-survival signaling pathways. The phytochemicals and their modified analogs identified as future potential candidates for anticancer chemotherapy.
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Affiliation(s)
- Gul-E-Saba Chaudhry
- Institute of Marine Biotechnology, University Malaysia Terengganu, 21030 Kuala Terengganu, Malaysia
| | - Rehmat Jan
- Department of Environmental Sciences, Fatima Jinnah University, Rawalpindi, Pakistan
| | - Abdah Akim
- Department of Biomedical Sciences, Universiti Putra Malaysia, Seri Kembangan, Selangor, Malaysia
| | | | - Yeong Yik Sung
- Institute of Marine Biotechnology, University Malaysia Terengganu, 21030 Kuala Terengganu, Malaysia
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15
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Sun X, Zhang T, Cai Y, Yang K, Peng T, Liu R, Li XN. Tonkinensine B induces apoptosis through mitochondrial dysfunction and inactivation of the PI3K/AKT pathway in triple-negative breast cancer cells. J Pharm Pharmacol 2021; 73:1397-1404. [PMID: 34313786 DOI: 10.1093/jpp/rgab108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 07/05/2021] [Indexed: 11/14/2022]
Abstract
OBJECTIVES Tonkinensine B, a novel compound with cytisine-pterocarpan skeleton isolated from the root of Sophora tonkinensis Gagnep, was reported to have a significant antitumor effect. The effect and intrinsic mechanism of tonkinensine B on tumour need to be further investigated. METHODS With the help of cell cytotoxicity, the effect of tonkinensine B on MDA-MB-231 cells was investigated. By observing mitochondrial function changes, the intrinsic mechanism was further studied. The levels of key apoptosis-associated proteins Bcl-2, Bax, caspase-9, caspase-3 and AKT in MDA-MB-231 cells were analysed to determine whether tonkinensine B caused apoptosis via the mitochondrial pathway. KEY FINDINGS After treated with tonkinensine B, MDA-MB-231 cells multiplication was repressed, and the decreased mitochondrial membrane potential, loss of ATP synthesis and elevated ROS generation were detected. Furthermore, the proportions of Bax/Bcl-2, cleaved caspase-3 and caspase-9 proteins production were up-regulated, indicating that tonkinensine B acted on intrinsic mitochondrial-mediated apoptosis pathway. In addition, tonkinensine B also reduced phosphorylation levels of AKT, and thus the activation of apoptosis might likewise be correlated with the inhibition of the PI3K/AKT pathway. CONCLUSIONS Tonkinensine B may be a hopeful candidate for human triple-negative breast cancer, and further structural optimization is expected to improve its anti-tumour activity.
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Affiliation(s)
- Xuanrong Sun
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China
| | - Tianwei Zhang
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China
| | - Yue Cai
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China
| | - Ke Yang
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China
| | - Tingting Peng
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China
| | - Renhao Liu
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China
| | - Xing-Nuo Li
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China
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Mirzaei S, Gholami MH, Zabolian A, Saleki H, Farahani MV, Hamzehlou S, Far FB, Sharifzadeh SO, Samarghandian S, Khan H, Aref AR, Ashrafizadeh M, Zarrabi A, Sethi G. Caffeic acid and its derivatives as potential modulators of oncogenic molecular pathways: New hope in the fight against cancer. Pharmacol Res 2021; 171:105759. [PMID: 34245864 DOI: 10.1016/j.phrs.2021.105759] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/18/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023]
Abstract
As a phenolic acid compound, caffeic acid (CA) can be isolated from different sources such as tea, wine and coffee. Caffeic acid phenethyl ester (CAPE) is naturally occurring derivative of CA isolated from propolis. This medicinal plant is well-known due to its significant therapeutic impact including its effectiveness as hepatoprotective, neuroprotective and anti-diabetic agent. Among them, anti-tumor activity of CA has attracted much attention, and this potential has been confirmed both in vitro and in vivo. CA can induce apoptosis in cancer cells via enhancing ROS levels and impairing mitochondrial function. Molecular pathways such as PI3K/Akt and AMPK with role in cancer progression, are affected by CA and its derivatives in cancer therapy. CA is advantageous in reducing aggressive behavior of tumors via suppressing metastasis by inhibiting epithelial-to-mesenchymal transition mechanism. Noteworthy, CA and CAPE can promote response of cancer cells to chemotherapy, and sensitize them to chemotherapy-mediated cell death. In order to improve capacity of CA and CAPE in cancer suppression, it has been co-administered with other anti-tumor compounds such as gallic acid and p-coumaric acid. Due to its poor bioavailability, nanocarriers have been developed for enhancing its ability in cancer suppression. These issues have been discussed in the present review with a focus on molecular pathways to pave the way for rapid translation of CA for clinical use.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | | | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hossein Saleki
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | | | - Fatemeh Bakhtiari Far
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Seyed Omid Sharifzadeh
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Vice President at Translational Sciences, Xsphera Biosciences Inc. 6 Tide Street, Boston, MA, 02210, USA
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, 34956 Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey.
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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17
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Gastaldello GH, Cazeloto ACV, Ferreira JC, Rodrigues DM, Bastos JK, Campo VL, Zoccal KF, Tefé-Silva C. Green Propolis Compounds (Baccarin and p-Coumaric Acid) Show Beneficial Effects in Mice for Melanoma Induced by B16f10. MEDICINES 2021; 8:medicines8050020. [PMID: 33946188 PMCID: PMC8146786 DOI: 10.3390/medicines8050020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/19/2021] [Accepted: 04/23/2021] [Indexed: 12/12/2022]
Abstract
Background: Cutaneous melanoma is the most aggressive form of skin cancer, with the worst prognosis, and it affects a younger population than most cancers. The high metastatic index, in more advanced stages, and the high aggressiveness decrease the effectiveness of currently used therapies, such as surgical removal, radiotherapy, cryotherapy, and chemotherapy, used alone or in combination. Based on these disadvantages, research focused on alternative medicine offers great potential for therapeutic innovation. Medicinal plants represent a remarkable source of compounds for the treatment of various diseases. Methods: In this study, we investigated the tumoral behavior of melanoma under treatment with the compounds baccharin and p-coumaric acid, extracted from green propolis, in mice inoculated with B16F10 cells for 26 days. Results: A significant modulation in the number of inflammatory cells recruited to the tumor region and blood in the groups treated with the compounds was observed. In addition, a significant reduction in the amount of blood vessels and mitosis in the neoplastic area was noticed. Conclusions: Through our research, we confirmed that baccharin and coumaric acid, isolated substances from Brazilian green propolis, have a promising anticarcinogenic potential to be explored for the development of new antitumor agents, adhering to the trend of drugs with greater tolerance and biological effectiveness.
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Affiliation(s)
- Gabriel H. Gastaldello
- Centro Universitário Barão de Mauá (CBM), Rua Ramos de Azevedo, n 423, Ribeirão Preto, SP 14090-180, Brazil; (G.H.G.); (A.C.V.C.); (J.C.F.); (V.L.C.); (K.F.Z.)
| | - Ana Caroline V. Cazeloto
- Centro Universitário Barão de Mauá (CBM), Rua Ramos de Azevedo, n 423, Ribeirão Preto, SP 14090-180, Brazil; (G.H.G.); (A.C.V.C.); (J.C.F.); (V.L.C.); (K.F.Z.)
| | - Juliana C. Ferreira
- Centro Universitário Barão de Mauá (CBM), Rua Ramos de Azevedo, n 423, Ribeirão Preto, SP 14090-180, Brazil; (G.H.G.); (A.C.V.C.); (J.C.F.); (V.L.C.); (K.F.Z.)
| | - Débora Munhoz Rodrigues
- Departamento de Ciências Farmacêuticas. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, SP 14040-903, Brazil; (D.M.R.); (J.K.B.)
| | - Jairo Kennup Bastos
- Departamento de Ciências Farmacêuticas. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, SP 14040-903, Brazil; (D.M.R.); (J.K.B.)
| | - Vanessa L. Campo
- Centro Universitário Barão de Mauá (CBM), Rua Ramos de Azevedo, n 423, Ribeirão Preto, SP 14090-180, Brazil; (G.H.G.); (A.C.V.C.); (J.C.F.); (V.L.C.); (K.F.Z.)
- Departamento de Ciências Farmacêuticas. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, SP 14040-903, Brazil; (D.M.R.); (J.K.B.)
| | - Karina F. Zoccal
- Centro Universitário Barão de Mauá (CBM), Rua Ramos de Azevedo, n 423, Ribeirão Preto, SP 14090-180, Brazil; (G.H.G.); (A.C.V.C.); (J.C.F.); (V.L.C.); (K.F.Z.)
| | - Cristiane Tefé-Silva
- Centro Universitário Barão de Mauá (CBM), Rua Ramos de Azevedo, n 423, Ribeirão Preto, SP 14090-180, Brazil; (G.H.G.); (A.C.V.C.); (J.C.F.); (V.L.C.); (K.F.Z.)
- Correspondence:
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Klein S, Distel LVR, Neuhuber W. X-ray Dose-Enhancing Impact of Functionalized Au–Fe 3O 4 Nanoheterodimers on MCF-7 and A549 Multicellular Tumor Spheroids. ACS APPLIED BIO MATERIALS 2021; 4:3113-3123. [DOI: 10.1021/acsabm.0c01494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Stefanie Klein
- Department of Chemistry and Pharmacy, Physical Chemistry I and ICMM, Friedrich-Alexander University of Erlangen-Nuremberg, Egerlandstr.3, D-91058 Erlangen, Germany
| | - Luitpold V. R. Distel
- Department of Radiation Oncology, Friedrich-Alexander University of Erlangen-Nuremberg, Universitaetsstr. 27, D-91054 Erlangen, Germany
| | - Winfried Neuhuber
- Institute of Anatomy and Cell Biology, Chair of Anatomy I, Friedrich-Alexander University of Erlangen-Nuremberg, Krankenhausstr. 9, D-91054 Erlangen, Germany
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Malik V, Kumar V, Kaul SC, Wadhwa R, Sundar D. Computational Insights into the Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl Ester for Treatment of Aberrant-EGFR Driven Lung Cancers. Biomolecules 2021; 11:biom11020160. [PMID: 33530424 PMCID: PMC7911128 DOI: 10.3390/biom11020160] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/12/2021] [Accepted: 01/16/2021] [Indexed: 12/15/2022] Open
Abstract
The anticancer activities of Withaferin-A (Wi-A) and Withanone (Wi-N) from Ashwagandha and Caffeic Acid Phenethyl Ester (CAPE) from honeybee propolis have been well documented. Here, we examined the binding potential of these natural compounds to inhibit the constitutive phosphorylation of epidermal growth factor receptors (EGFRs). Exon 20 insertion mutants of EGFR, which show resistance to various FDA approved drugs and are linked to poor prognosis of lung cancer patients, were the primary focus of this study. Apart from exon 20 insertion mutants, the potential of natural compounds to serve as ATP competitive inhibitors of wildtype protein and other common mutants of EGFR, namely L858R and exon19del, were also examined. The potential of natural compounds was compared to the positive controls such as erlotinib, TAS6417 and poziotinib. Similar to known inhibitors, Wi-A and Wi-N could displace and binds at the ATP orthosteric site of exon19del, L858R and exon20, while CAPE was limited to wildtype EGFR and exon 20 insertion mutants only. Moreover, the binding free energy of the natural drugs against EGFRs was also comparable to the positive controls. This computational study suggests that Wi-A and Wi-N have potential against multiple mutated EGFRs, warranting further in vitro and in vivo experiments.
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Affiliation(s)
- Vidhi Malik
- DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biochemical Engineering & Biotechnology, Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi 110 016, India; (V.M.); (V.K.)
| | - Vipul Kumar
- DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biochemical Engineering & Biotechnology, Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi 110 016, India; (V.M.); (V.K.)
| | - Sunil C. Kaul
- AIST-INDIA DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba 305-8565, Japan;
| | - Renu Wadhwa
- AIST-INDIA DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba 305-8565, Japan;
- Correspondence: (R.W.); (D.S.); Tel.: +81-29-861-9464 (R.W.); +91-11-2659-1066 (D.S.)
| | - Durai Sundar
- DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biochemical Engineering & Biotechnology, Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi 110 016, India; (V.M.); (V.K.)
- Correspondence: (R.W.); (D.S.); Tel.: +81-29-861-9464 (R.W.); +91-11-2659-1066 (D.S.)
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20
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Lyu ZJ, Wang Y, Huang JL, Chen M, Wu SY, Yan Q, Zhang Y, Tang Y, Jiang C, Li L, Jia YZ, Liu YC, Mei HB, Wang F, Li RH, Chen YC, Lin X, Cai ZM, Guan XY. Recurrent ZNF83-E293V Mutation Promotes Bladder Cancer Progression through the NF-κB Pathway via Transcriptional Dysregulation of S100A8. Mol Ther 2021; 29:275-290. [PMID: 33002420 PMCID: PMC7791007 DOI: 10.1016/j.ymthe.2020.09.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 08/07/2020] [Accepted: 09/01/2020] [Indexed: 02/05/2023] Open
Abstract
Urothelial carcinoma (UC) is the predominant form of bladder cancer. Significant molecular heterogeneity caused by diverse molecular alterations brings about large variations in the response to treatment in UC. An improved understanding of the genetic mechanisms underlying the development and progression of UC is essential. Through deep analysis of next-generation sequencing data of 99 UC patients, we found that 18% of cases had recurrent somatic mutations in zinc finger protein gene zinc finger protein 83 (ZNF83). ZNF83 mutations were correlated with poor prognosis of UC. We also found a hotspot mutation, p.E293V, in the evolutionarily well-conserved region of ZNF83. ZNF83-E293V increased tumor growth and reduced the apoptosis of UC cells compared to wild-type ZNF83 both in vitro and in mice xenografted tumors. ZNF83-E293V activated nuclear factor κB (NF-κB) more potently than did the wild-type protein owing to its decreased transcriptional repression for S100A8. The NF-κB inhibitors could pharmacologically block the tumor growth in mice engrafted with ZNF83-E293V-transfected UC cells. These findings provide a mechanistic insight and a potential therapeutic strategy for UC, which established a foundation for using the ZNF83-E293V mutation as a predictive biomarker of therapeutic response from NF-κB inhibitors.
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Affiliation(s)
- Zhao J Lyu
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518029, China; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Ying Wang
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518029, China; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China; Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510030, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510030, China
| | - Jin L Huang
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou 510030, China
| | - Miao Chen
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Sha Y Wu
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Qian Yan
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Yu Zhang
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Ying Tang
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Chen Jiang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510030, China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou 510030, China
| | - Lei Li
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510030, China
| | - Yi Z Jia
- Core Laboratory, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518029, China
| | - Yu C Liu
- Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518029, China
| | - Hong B Mei
- Department of Urology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518029, China
| | - Feng Wang
- Department of Urology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518029, China
| | - Ren H Li
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Ya C Chen
- Department of Pathology, Shenzhen University General Hospital, Shenzhen 518055, China
| | - Xiang Lin
- School of Chinese Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Zhi M Cai
- Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518029, China; Department of Urology, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, China; Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen 518061, China; BGI-Medicine, BGI, Shenzhen 518083, China.
| | - Xin Y Guan
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518029, China; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510030, China.
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Masadah R, Ikram D, Rauf S. Effects of propolis and its bioactive components on breast cancer cell pathways and the molecular mechanisms involved. Breast Dis 2021; 40:S15-S25. [PMID: 34057114 DOI: 10.3233/bd-219003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Breast cancer is a female malignancy that is a significant cause of mortality worldwide. Currently, investigations on natural ingredients as new candidates for chemopreventive agents and breast cancer chemotherapies are increasing. Propolis is a natural resinous material produced by honeybees that exhibit anticancer potential. Several studies have mentioned the major bioactive compounds of propolis, but their mechanism of action is not clearly understood. OBJECTIVES The purpose of this review is to collect and summarize the evidence related to the effectiveness of propolis and its bioactive contents as candidates for breast cancer therapy and analyze the molecular mechanisms involved in their therapeutic pathways. METHODS We reviewed 94 articles from journals and databases, extracted the results, and produced summaries and conclusions. RESULTS Propolis and its bioactive ingredients show cytotoxic, anti-proliferative, pro-autophagic, anti-metastatic, and antioxidant activities, as well as synergistic effects with chemotherapy or radiotherapy in breast cancer. Its therapeutic activity involves various target molecules, including NF-κβ, Fas receptors, p53, TLR4, ANXA7, and voltage-gated Na+ channel (VGSC). CONCLUSION The bioactive components of propolis and the target molecules involved need to be explored further to develop new breast cancer therapies and overcome the problem of chemoradiation resistance.
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Affiliation(s)
- Rina Masadah
- Department of Pathology Anatomy, Hasanuddin University, Makassar, Indonesia
| | - Dzul Ikram
- Department of Pathology Anatomy, Hasanuddin University, Makassar, Indonesia
- Department of Histology, Muslim University of Indonesia, Makassar, Indonesia
| | - Syahrul Rauf
- Department of Obstetric and Gynecology, Hasanuddin University, Makassar, Indonesia
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22
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Shao B, Mao L, Shao J, Huang CH, Qin L, Huang R, Sheng ZG, Cao D, Zhang ZQ, Lin L, Zhang CZ, Zhu BZ. Mechanism of synergistic DNA damage induced by caffeic acid phenethyl ester (CAPE) and Cu(II): Competitive binding between CAPE and DNA with Cu(II)/Cu(I). Free Radic Biol Med 2020; 159:107-118. [PMID: 32755670 DOI: 10.1016/j.freeradbiomed.2020.06.033] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 06/13/2020] [Accepted: 06/21/2020] [Indexed: 12/26/2022]
Abstract
Caffeic acid phenethyl ester (CAPE) is an active polyphenol of propolis from honeybee hives, and exhibits antioxidant and interesting pharmacological activities. However, in this study, we found that in the presence of Cu(II), CAPE exhibited pro-oxidative rather than antioxidant effect: synergistic DNA damage was induced by the combination of CAPE and Cu(II) together as measured by strand breakage in plasmid DNA and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation, which is dependent on the molar ratio of CAPE:Cu(II). Production of Cu(I) and H2O2 from the redox reaction between CAPE and Cu(II), and subsequent OH formation was found to be responsible for the synergistic DNA damage. DNA sequencing investigations provided more direct evidence that CAPE/Cu(II) caused preferential cleavage at guanine, thymine and cytosine residues. Interestingly, we found there are competitive binding between CAPE and DNA with Cu(II)/Cu(I), which changed the redox activity of Cu(II)/Cu(I), via complementary applications of different analytical methods. The observed DNA damage was mainly attributed to the formation of DNA-Cu(II)/Cu(I) complexes, which is still redox active and initiated the redox reaction near the binding site between copper and DNA. Based on these data, we proposed that the synergistic DNA damage induced by CAPE/Cu(II) might be due to the competitive binding between CAPE and DNA with Cu, and site-specific production of OH near the binding site of copper with DNA. Our findings may have broad biological implications for future research on the pro-oxidative effects of phenolic compounds in the presence of transition metals.
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Affiliation(s)
- Bo Shao
- School of Public Health, Jining Medical University, Jining, Shandong, 272067, PR China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing, 100085, PR China
| | - Li Mao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing, 100085, PR China
| | - Jie Shao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing, 100085, PR China
| | - Chun-Hua Huang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing, 100085, PR China
| | - Li Qin
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing, 100085, PR China
| | - Rong Huang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing, 100085, PR China
| | - Zhi-Guo Sheng
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing, 100085, PR China
| | - Dong Cao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing, 100085, PR China
| | - Zhao-Qiang Zhang
- School of Public Health, Jining Medical University, Jining, Shandong, 272067, PR China
| | - Li Lin
- School of Public Health, Jining Medical University, Jining, Shandong, 272067, PR China
| | - Chun-Zhi Zhang
- School of Public Health, Jining Medical University, Jining, Shandong, 272067, PR China
| | - Ben-Zhan Zhu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing, 100085, PR China; Joint Institute for Environmental Science, Research Center for Eco-Environmental Sciences and Hong Kong Baptist University, Beijing, PR China.
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23
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Wang J, Bhargava P, Yu Y, Sari AN, Zhang H, Ishii N, Yan K, Zhang Z, Ishida Y, Terao K, Kaul SC, Miyako E, Wadhwa R. Novel Caffeic Acid Phenethyl Ester-Mortalin Antibody Nanoparticles Offer Enhanced Selective Cytotoxicity to Cancer Cells. Cancers (Basel) 2020; 12:cancers12092370. [PMID: 32825706 PMCID: PMC7564736 DOI: 10.3390/cancers12092370] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/01/2020] [Accepted: 08/13/2020] [Indexed: 12/12/2022] Open
Abstract
Caffeic acid phenethyl ester (CAPE) is a key bioactive ingredient of honeybee propolis and is claimed to have anticancer activity. Since mortalin, a hsp70 chaperone, is enriched in a cancerous cell surface, we recruited a unique cell internalizing anti-mortalin antibody (MotAb) to generate mortalin-targeting CAPE nanoparticles (CAPE-MotAb). Biophysical and biomolecular analyses revealed enhanced anticancer activity of CAPE-MotAb both in in vitro and in vivo assays. We demonstrate that CAPE-MotAb cause a stronger dose-dependent growth arrest/apoptosis of cancer cells through the downregulation of Cyclin D1-CDK4, phospho-Rb, PARP-1, and anti-apoptotic protein Bcl2. Concomitantly, a significant increase in the expression of p53, p21WAF1, and caspase cleavage was obtained only in CAPE-MotAb treated cells. We also demonstrate that CAPE-MotAb caused a remarkably enhanced downregulation of proteins critically involved in cell migration. In vivo tumor growth assays for subcutaneous xenografts in nude mice also revealed a significantly enhanced suppression of tumor growth in the treated group suggesting that these novel CAPE-MotAb nanoparticles may serve as a potent anticancer nanomedicine.
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Affiliation(s)
- Jia Wang
- AIST-INDIA DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan; (J.W.); (P.B.); (Y.Y.); (A.N.S.); (H.Z.); (N.I.); (K.Y.); (S.C.K.)
- Graduate School of Life & Environmental Sciences, University of Tsukuba, Ibaraki 305-8575, Japan;
| | - Priyanshu Bhargava
- AIST-INDIA DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan; (J.W.); (P.B.); (Y.Y.); (A.N.S.); (H.Z.); (N.I.); (K.Y.); (S.C.K.)
| | - Yue Yu
- AIST-INDIA DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan; (J.W.); (P.B.); (Y.Y.); (A.N.S.); (H.Z.); (N.I.); (K.Y.); (S.C.K.)
- Biomedical Research Institute (BMRI), National Institute of Advanced Industrial Science & Technology (AIST), Ikeda 563-8577, Japan
| | - Anissa Nofita Sari
- AIST-INDIA DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan; (J.W.); (P.B.); (Y.Y.); (A.N.S.); (H.Z.); (N.I.); (K.Y.); (S.C.K.)
| | - Huayue Zhang
- AIST-INDIA DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan; (J.W.); (P.B.); (Y.Y.); (A.N.S.); (H.Z.); (N.I.); (K.Y.); (S.C.K.)
| | - Noriyuki Ishii
- AIST-INDIA DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan; (J.W.); (P.B.); (Y.Y.); (A.N.S.); (H.Z.); (N.I.); (K.Y.); (S.C.K.)
| | - Kangmin Yan
- AIST-INDIA DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan; (J.W.); (P.B.); (Y.Y.); (A.N.S.); (H.Z.); (N.I.); (K.Y.); (S.C.K.)
| | - Zhenya Zhang
- Graduate School of Life & Environmental Sciences, University of Tsukuba, Ibaraki 305-8575, Japan;
| | - Yoshiyuki Ishida
- CycloChem Co., Ltd., 7-4-5 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan; (Y.I.); (K.T.)
| | - Keiji Terao
- CycloChem Co., Ltd., 7-4-5 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan; (Y.I.); (K.T.)
| | - Sunil C. Kaul
- AIST-INDIA DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan; (J.W.); (P.B.); (Y.Y.); (A.N.S.); (H.Z.); (N.I.); (K.Y.); (S.C.K.)
- KAUL-Tech Co. Ltd., 3-24 Nagakunidai, Tsuchiura City, Ibaraki 300-0810, Japan
| | - Eijiro Miyako
- School of Materials Science, Japan Advanced Institute of Science & Technology, 1-1 Asahidai, Nomi, Ishikawa 923-1292, Japan;
| | - Renu Wadhwa
- AIST-INDIA DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan; (J.W.); (P.B.); (Y.Y.); (A.N.S.); (H.Z.); (N.I.); (K.Y.); (S.C.K.)
- Correspondence: ; Tel.: +81-29-8-61-9464
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Effects of Propolis and Phenolic Acids on Triple-Negative Breast Cancer Cell Lines: Potential Involvement of Epigenetic Mechanisms. Molecules 2020; 25:molecules25061289. [PMID: 32178333 PMCID: PMC7143942 DOI: 10.3390/molecules25061289] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/03/2020] [Accepted: 03/06/2020] [Indexed: 12/23/2022] Open
Abstract
Triple-negative breast cancer is an aggressive disease frequently associated with resistance to chemotherapy. Evidence supports that small molecules showing DNA methyltransferase inhibitory activity (DNMTi) are important to sensitize cancer cells to cytotoxic agents, in part, by reverting the acquired epigenetic changes associated with the resistance to therapy. The present study aimed to evaluate if chemical compounds derived from propolis could act as epigenetic drugs (epi-drugs). We selected three phenolic acids (caffeic, dihydrocinnamic, and p-coumaric) commonly detected in propolis and the (−)-epigallocatechin-3-gallate (EGCG) from green tea, which is a well-known DNA demethylating agent, for further analysis. The treatment with p-coumaric acid and EGCG significantly reduced the cell viability of four triple-negative breast cancer cell lines (BT-20, BT-549, MDA-MB-231, and MDA-MB-436). Computational predictions by molecular docking indicated that both chemicals could interact with the MTAse domain of the human DNMT1 and directly compete with its intrinsic inhibitor S-Adenosyl-l-homocysteine (SAH). Although the ethanolic extract of propolis (EEP) did not change the global DNA methylation content, by using MS-PCR (Methylation-Specific Polymerase Chain Reaction) we demonstrated that EEP and EGCG were able to partly demethylate the promoter region of RASSF1A in BT-549 cells. Also, in vitro treatment with EEP altered the RASSF1 protein expression levels. Our data indicated that some chemical compound present in the EEP has DNMTi activity and can revert the epigenetic silencing of the tumor suppressor RASSF1A. These findings suggest that propolis are a promising source for epi-drugs discovery.
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Shao B, Wang M, Chen A, Zhang C, Lin L, Zhang Z, Chen A. Protective effect of caffeic acid phenethyl ester against imidacloprid-induced hepatotoxicity by attenuating oxidative stress, endoplasmic reticulum stress, inflammation and apoptosis. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2020; 164:122-129. [PMID: 32284117 DOI: 10.1016/j.pestbp.2020.01.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Revised: 01/03/2020] [Accepted: 01/03/2020] [Indexed: 06/11/2023]
Abstract
Imidacloprid (IMI) is a widely used neonicotinoid pesticide in the world, its environmental and human health risk has particularly attracted the attention of researchers. Caffeic acid phenethyl ester (CAPE), an active polyphenol of propolis, has many pharmacological activities including free radical scavenger, anti-inflammatory, and anti-oxidant. In this study, protective effect of CAPE against IMI induced liver injury in mice was performed. Administration of 1 and 2.5 mg/kg CAPE markedly prevented serum AST and ALT increase in 5 mg/kg IMI-induced mice. CAPE significantly downregulated liver NO generation and lipid peroxidation, and upregulated glutathione, catalase, superoxide dismutase and glutathione peroxidase in a dose-dependent manner in liver of IMI-induced mice. Endoplasmic reticulum stress represented by the swelling of endoplasmic reticulum was observed by transmission electron microscope in IMI group. Pretreatment of 2.5 mg/kg CAPE significantly attenuated the endoplasmic reticulum stress induced by IMI in liver. Western blot analysis illustrated that pretreatment of CAPE downregulated the upregulation of TNF-α and IFN-γ induced by IMI in liver of mice. Moreover, the increase of positive apoptotic hepatocytes further suggested apoptosis might be involved in IMI-induced hepatotoxicity. Pretreatment of 1 and 2.5 mg/kg CAPE significantly decreased positive apoptotic hepatocytes, suggested that CAPE prevented apoptosis in liver of IMI-induced mice. In conclusion, CAPE prevented liver injury in IMI-induced mice via attenuation of oxidative stress, endoplasmic reticulum stress, inflammation and apoptosis. Our findings may have broad biological and environmental implications for future research on the therapeutic strategy to prevent liver injury induced by pesticides.
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Affiliation(s)
- Bo Shao
- Department of Public Health, Jining Medical University, Jining, Shandong 272067, PR China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China.
| | - Meixia Wang
- Department of pharmacy, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272067, PR China
| | - Anran Chen
- Department of Mental Health, Jining Medical University, Jining, Shandong 272067, PR China
| | - Chunzhi Zhang
- Department of Public Health, Jining Medical University, Jining, Shandong 272067, PR China
| | - Li Lin
- Department of Public Health, Jining Medical University, Jining, Shandong 272067, PR China
| | - Zhaoqiang Zhang
- Department of Public Health, Jining Medical University, Jining, Shandong 272067, PR China
| | - Anlan Chen
- Department of Public Health, Jining Medical University, Jining, Shandong 272067, PR China
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26
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Chemopreventive Effects of Propolis in the MNU-Induced Rat Mammary Tumor Model. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:4014838. [PMID: 32184916 PMCID: PMC7063188 DOI: 10.1155/2020/4014838] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/27/2019] [Accepted: 02/10/2020] [Indexed: 02/03/2023]
Abstract
Currently, one of the central problems in cancer management is the relapse of disease following conventional treatments, yet few therapeutic agents targeting resistance and tolerance exist. Propolis is known as a healing agent since ancient times. Therefore, over time, its curative properties have kept the interest of scientists, thus leading permanently to investigations of its other possible undiscovered effects. In this context, current experiments were performed to establish the chemopreventive potential of propolis extract (PE) (1.05 mg/kg BW/day) in N-methyl-N-nitrosourea- (MNU-) induced rat mammary tumors. MNU-inoculated/PE-treated rats had tumors of different physical attributes compared with control rats MNU-inoculated. The number of developed tumors (mean 49% versus 100%), incidence (mean 49% versus 100%), multiplicity (1.8 versus 3.7 (p < 0.001)), tumor volume (mean 10 cm3 versus 16 cm3 (p < 0.001)), and weight of the tumor mass (mean 7.42 g versus 9.00 g (p < 0.05)) were noted. The numbers of grade I tumors recorded for MNU-inoculated rats were 24 (Group 1) and 7 (Group 2) for MNU-induced/PE-treated rats. In the serum of rats MNU-inoculated/PE-treated were found higher levels of antioxidative enzymes (SOD, CAT, and GPx) than in MNU-induced. Taken together, these data indicate that propolis could be a chemopreventive agent against MNU-induced mammary carcinogenesis.
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Gajek G, Marciniak B, Lewkowski J, Kontek R. Antagonistic Effects of CAPE (a Component of Propolis) on the Cytotoxicity and Genotoxicity of Irinotecan and SN38 in Human Gastrointestinal Cancer Cells In Vitro. Molecules 2020; 25:molecules25030658. [PMID: 32033066 PMCID: PMC7038052 DOI: 10.3390/molecules25030658] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/1970] [Revised: 01/31/2020] [Accepted: 02/01/2020] [Indexed: 12/20/2022] Open
Abstract
The incidence of gastrointestinal cancers is increasing every year. Irinotecan (CPT-11), a drug used in the treatment of colorectal cancer and gastric cancer, is metabolized by carboxylesterases to an active metabolite, SN-38, which is more cytotoxic. CAPE (caffeic acid phenethyl ester) is an active component of propolis, which has a high antibacterial, antiviral, and antineoplastic potential. This study analyses the impact of CAPE on the cytotoxic (MTT assay), genotoxic (comet assay) and proapoptotic (caspase-3/7 activity) potential of irinotecan and its metabolite SN-38 in cultures of gastrointestinal neoplastic cells (HCT116, HT29, AGS). Cytotoxicity and genotoxicity activities of these compounds were carried out in comparison with human peripheral blood lymphocytes (PBLs) in vitro. The antioxidant potential of CAPE was investigated in relation H2O2-induced oxidative stress in the both neoplastic cells and PBLs. CAPE expressed cytotoxic, genotoxic, and pro-apoptotic activity against AGS, HCT116, and HT29 tumor cells. CAPE, in the presence of different concentrations of irinotecan or SN38, decreased the cytotoxicity, genotoxicity, and pro-apoptotic activity in these cell lines, but it has no such action on normal human peripheral blood lymphocytes.
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Affiliation(s)
- Gabriela Gajek
- Laboratory of Cytogenetics, Institute of Experimental Biology, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland; (B.M.); (R.K.)
- Correspondence: ; Tel.: +48-42-635-44-26
| | - Beata Marciniak
- Laboratory of Cytogenetics, Institute of Experimental Biology, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland; (B.M.); (R.K.)
| | - Jarosław Lewkowski
- Department of Organic Chemistry, Faculty of Chemistry, University of Lodz, 12 Tamka St., 91-403 Lodz, Poland;
| | - Renata Kontek
- Laboratory of Cytogenetics, Institute of Experimental Biology, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland; (B.M.); (R.K.)
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Tanriseven D, Kadiroglu P, Selli S, Kelebek H. LC-DAD-ESI-MS/MS-assisted elucidation of the phenolic compounds in shalgams: Comparison of traditional and direct methods. Food Chem 2020; 305:125505. [DOI: 10.1016/j.foodchem.2019.125505] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 09/07/2019] [Accepted: 09/08/2019] [Indexed: 12/17/2022]
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Desamero MJ, Kakuta S, Tang Y, Chambers JK, Uchida K, Estacio MA, Cervancia C, Kominami Y, Ushio H, Nakayama J, Nakayama H, Kyuwa S. Tumor-suppressing potential of stingless bee propolis in in vitro and in vivo models of differentiated-type gastric adenocarcinoma. Sci Rep 2019; 9:19635. [PMID: 31873082 PMCID: PMC6928070 DOI: 10.1038/s41598-019-55465-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 11/11/2019] [Indexed: 01/19/2023] Open
Abstract
The protective property of propolis across a wide spectrum of diseases has long been realized, yet the anti-tumor efficacy of this bioactive substance from Philippine stingless bees has remained poorly understood. Here, we showed the tumor-suppressing potential of crude ethanolic extract of Philippine stingless bee propolis (EEP) in in vitro models of gastric cancer highlighting the first indication of remarkable subtype specificity towards differentiated-type human gastric cancer cell lines but not the diffuse-type. Mechanistically, this involved the profound modulation of several cell cycle related gene transcripts, which correlated with the prominent cell cycle arrest at the G0/G1 phase. To reinforce our data, a unique differentiated-type gastric cancer model, A4gnt KO mice, together with age-matched 60 week-old C57BL/6 J mice were randomly assigned to treatment groups receiving distilled water or EEP for 30 consecutive days. EEP treatment induced significant regression of gross and histological lesions of gastric pyloric tumors that consistently corresponded with specific transcriptional regulation of cell cycle components. Also, the considerable p21 protein expression coupled with a marked reduction in rapidly dividing BrdU-labeled S-phase cells unequivocally supported our observation. Altogether, these findings support the role of Philippine stingless bee propolis as a promising adjunct treatment option in differentiated-type gastric cancer.
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Affiliation(s)
- Mark Joseph Desamero
- Laboratory of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan.,Department of Basic Veterinary Sciences, College of Veterinary Medicine, University of the Philippines Los Baños, Laguna, 4031, Philippines.,UPLB Bee Program, University of the Philippines Los Baños, Laguna, 4031, Philippines
| | - Shigeru Kakuta
- Laboratory of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan.
| | - Yulan Tang
- Laboratory of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - James Kenn Chambers
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Kazuyuki Uchida
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Maria Amelita Estacio
- Department of Basic Veterinary Sciences, College of Veterinary Medicine, University of the Philippines Los Baños, Laguna, 4031, Philippines.,UPLB Bee Program, University of the Philippines Los Baños, Laguna, 4031, Philippines
| | - Cleofas Cervancia
- UPLB Bee Program, University of the Philippines Los Baños, Laguna, 4031, Philippines.,Institute of Biological Sciences, College of Arts and Sciences, University of the Philippines Los Baños, Laguna, 4031, Philippines
| | - Yuri Kominami
- Laboratory of Marine Biochemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Hideki Ushio
- Laboratory of Marine Biochemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Jun Nakayama
- Department of Molecular Pathology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 3908621, Japan
| | - Hiroyuki Nakayama
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Shigeru Kyuwa
- Laboratory of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan
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Yordanov Y. Caffeic acid phenethyl ester (CAPE): pharmacodynamics and potential for therapeutic application. PHARMACIA 2019. [DOI: 10.3897/pharmacia.66.e38573] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Caffeic acid phenethyl ester (CAPE) is the major pharmacologically-active component of some propolis types, rich in polyphenols, such as poplar propolis types. CAPE has the potential to be applied as a pharmaceutical as it possesses most of the pharmacological activities of propolis, such as anti-proliferative, antioxidant, immunomodulatory, antidiabetic, anti-inflammatory and antimicrobial. Its advantage is that it lacks some of the downsides of total propolis extracts, such as inability for unified standardization, which is cornerstone for implementing its therapeutic potential as a drug. The current paper provides an overview on the pharmacodynamic principles of CAPE. We present literature search outcomes form ClinicalTrials.gov database and from scientific publications, available on Scopus and Crossref databases. We take a round view of CAPE’s potential therapeutic implications in light of approved drugs with related modes of action.
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31
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Raselli T, Wyss A, Gonzalez Alvarado MN, Weder B, Mamie C, Spalinger MR, Van Haaften WT, Dijkstra G, Sailer AW, Imenez Silva PH, Wagner CA, Tosevski V, Leibl S, Scharl M, Rogler G, Hausmann M, Misselwitz B. The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis. J Crohns Colitis 2019; 13:1186-1200. [PMID: 31220227 PMCID: PMC6751338 DOI: 10.1093/ecco-jcc/jjz039] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Intestinal fibrosis and stenosis are common complications of Crohn's disease [CD], frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidised cholesterol derivatives with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase [CH25H] converts cholesterol to 25-hydroxycholesterol [25-HC], which modulates immune responses and oxidative stress. In human intestinal samples from CD patients, we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme, using the sodium dextran sulphate [DSS]-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis.
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Affiliation(s)
- T Raselli
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich University, Zurich, Switzerland
| | - A Wyss
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich University, Zurich, Switzerland
| | - M N Gonzalez Alvarado
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich University, Zurich, Switzerland
| | - B Weder
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich University, Zurich, Switzerland
| | - C Mamie
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich University, Zurich, Switzerland
| | - M R Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich University, Zurich, Switzerland
| | - W T Van Haaften
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich University, Zurich, Switzerland
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - G Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - A W Sailer
- Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | | | - C A Wagner
- Institute of Physiology, Zurich University, Zurich, Switzerland
| | - V Tosevski
- Mass Cytometry Facility, Zurich University, Zurich, Switzerland
| | - Sebastian Leibl
- Institute of Pathology and Molecular Pathology, University Hospital Zurich and Zurich University, Zurich, Switzerland
| | - M Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich University, Zurich, Switzerland
| | - G Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich University, Zurich, Switzerland
| | - M Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich University, Zurich, Switzerland
| | - B Misselwitz
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich University, Zurich, Switzerland
- Corresponding author: Dr. Benjamin Misselwitz, Dept. of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Freiburgstr 18, 3010 Bern, Switzerland.
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Tajbakhsh A, Rivandi M, Abedini S, Pasdar A, Sahebkar A. Regulators and mechanisms of anoikis in triple-negative breast cancer (TNBC): A review. Crit Rev Oncol Hematol 2019; 140:17-27. [DOI: 10.1016/j.critrevonc.2019.05.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 12/13/2018] [Accepted: 05/14/2019] [Indexed: 12/17/2022] Open
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Karakuş F, Yılmaz K, Eyol E, Ünüvar S. Combination of 2 Bioactive Compounds for Treatment of Breast Cancer: Triterpenoid Cucurbitacin I and Phenolic CAPE. Nat Prod Commun 2019. [DOI: 10.1177/1934578x19857492] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
It has been demonstrated that both cucurbitacin I (Cu I) and caffeic acid phenethyl ester (CAPE) have anticancer activities. The current study aimed to examine the proliferation, migration, and colony formation actions of Cu I and CAPE on MCF-7 and MDA-MB-231 human breast cancer cells. The antimigration, antiproliferative, and colony inhibition effects of different dosages of Cu I, CAPE, and Cu I + CAPE on cells were determined by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) cell viability assay, wound healing, and colony formation assays, respectively. Compared with single treatment, combination of 2 bioactive compounds enhanced the anticancer activity. When Cu I and CAPE were combined, a strong inhibitor effect was shown on cell growth, colony formation, and cell migration compared with the compounds used singly. The concomitant treatment with Cu I and CAPE showed stronger antiproliferative activities on both MCF-7 and MDA-MB-231 cells compared with individual treatment with either Cu I or CAPE. Caffeic acid phenethyl ester is a specific inhibitor of Nuclear factor-kappa B (NF-κB). It shows anticancer activity depending on this inhibition. It is a bioactive phenolic compound that is derived from propolis. Cucurbitacin I is a selective Januskinase/signal transducer and a transcription-3 signal pathway inhibitor. Combination of these 2 natural anticancer compounds is beneficial in the treatment of cancer, as well as the side effects associated with classical chemotherapeutics not being observed with the use of these compounds.
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Affiliation(s)
- Fuat Karakuş
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ege University, İzmir, Turkey
| | - Kadir Yılmaz
- Department of Chemistry, Faculty of Art and Science, İnönü University, Malatya, Turkey
| | - Ergül Eyol
- Chemotherapy and Toxicology Unit, German Cancer Research Center, Heidelberg, Germany
| | - Songül Ünüvar
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, İnönü University, Malatya, Turkey
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34
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Karapetsas A, Voulgaridou GP, Konialis M, Tsochantaridis I, Kynigopoulos S, Lambropoulou M, Stavropoulou MI, Stathopoulou K, Aligiannis N, Bozidis P, Goussia A, Gardikis K, Panayiotidis MI, Pappa A. Propolis Extracts Inhibit UV-Induced Photodamage in Human Experimental In Vitro Skin Models. Antioxidants (Basel) 2019; 8:antiox8050125. [PMID: 31075866 PMCID: PMC6562595 DOI: 10.3390/antiox8050125] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/01/2019] [Accepted: 05/05/2019] [Indexed: 02/07/2023] Open
Abstract
The aim of this study was to assess the antioxidant, photoprotective, and antiaging effects of Greek propolis. Propolis was subjected to n-heptane or methanol extraction. Total phenolic/flavonoid content and antioxidant potential were determined in the extracts. Promising extracts were evaluated for their cytoprotective properties using human immortalized keratinocyte (HaCaT) or reconstituted human skin tissue following exposure to UVB. Assessment of cytotoxicity, DNA damage, oxidative status, and gene/protein expression levels of various matrix metalloproteinases (MMPs) were performed. The propolis methanolic fractions exhibited higher total phenolic and flavonoid contents and significant in vitro antioxidant activity. Incubation of HaCaT cells with certain methanolic extracts significantly decreased the formation of DNA strand breaks following exposure to UVB and attenuated UVB-induced decrease in cell viability. The extracts had no remarkable effect on the total antioxidant status, but significantly lowered total protein carbonyl content used as a marker for protein oxidation in HaCaT cells. MMP-1, -3, -7, and -9, monitored as endpoints of antiaging efficacy, were significantly reduced by propolis following UVB exposure in a model of reconstituted skin tissue. In conclusion, propolis protects against the oxidative and photodamaging effects of UVB and could be further explored as a promising agent for developing natural antiaging strategies.
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Affiliation(s)
- Athanasios Karapetsas
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
| | | | - Manolis Konialis
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
| | - Ilias Tsochantaridis
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
| | - Spyridon Kynigopoulos
- Laboratory of Histology & Embryology, School of Medicine, Faculty of Health Sciences, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
| | - Maria Lambropoulou
- Laboratory of Histology & Embryology, School of Medicine, Faculty of Health Sciences, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
| | - Maria-Ioanna Stavropoulou
- Department of Pharmacy, Division of Pharmocognosy & Natural Products Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece.
| | - Konstantina Stathopoulou
- Department of Pharmacy, Division of Pharmocognosy & Natural Products Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece.
| | - Nektarios Aligiannis
- Department of Pharmacy, Division of Pharmocognosy & Natural Products Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece.
| | - Petros Bozidis
- Department of Pathology, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece.
| | - Anna Goussia
- Department of Pathology, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece.
| | | | - Mihalis I Panayiotidis
- Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne NE1 8ST, UK.
| | - Aglaia Pappa
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
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Fırat F, Özgül M, Türköz Uluer E, Inan S. Effects of caffeic acid phenethyl ester (CAPE) on angiogenesis, apoptosis and oxidatıve stress ın various cancer cell lines. Biotech Histochem 2019; 94:491-497. [PMID: 30991851 DOI: 10.1080/10520295.2019.1589574] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Cancer is a common cause of death worldwide. Approximately 80% of cancer patients use complementary or alternative medicines for treatment. Caffeic acid phenethyl ester (CAPE), the main active component of propolis, exhibits cytotoxic, antiproliferative and anti-cancer effects. Despite its anticancer effects CAPE exhibits no known harmful effects toward normal cells. We investigated the effects of CAPE on angiogenesis, apoptosis and oxidative stress using MDA MB-231, N2a and COLO 320 cell lines and CAPE treatments at 24 and 48 h. A two dimensional cell culture system was used and the findings were evaluated by an indirect immunohistochemical method and H-scores were calculated. CAPE was effective for all three cancer cell lines. After 24 and 48 h, we found a significant decrease in live cells and increased stress in the cells based on e-NOS and i-NOS levels.
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Affiliation(s)
- F Fırat
- Department of Histology-Embryology, Manisa Celal Bayar University , Uncubozkoy , Manisa , Turkey
| | - M Özgül
- Department of Histology-Embryology, Manisa Celal Bayar University , Uncubozkoy , Manisa , Turkey
| | - E Türköz Uluer
- Department of Histology-Embryology, Manisa Celal Bayar University , Uncubozkoy , Manisa , Turkey
| | - S Inan
- Department of Histology-Embryology, University of Economics , Izmir , Turkey
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36
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Gulzar M, Ali S, Khan FI, Khan P, Taneja P, Hassan MI. Binding mechanism of caffeic acid and simvastatin to the integrin linked kinase for therapeutic implications: a comparative docking and MD simulation studies. J Biomol Struct Dyn 2019; 37:4327-4337. [PMID: 30488773 DOI: 10.1080/07391102.2018.1546621] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Integrin linked kinase (ILK) is a Ser/Thr kinase, which regulates various integrin mediated signaling pathways, and is involved in cell adhesion, migration and differentiation. Alteration in the ILK is responsible for abnormal functioning of the cell system, which may lead to the cancer progression and metastasis. Caffeic acid (CA) and simvastatin are used as antioxidant and possess anticancer properties. Thus, inhibiting the kinase activity of ILK by CA and simvastatin may be implicated in the cancer therapy. In this study, we have performed molecular docking followed by 100 ns MD simulations to understand the interaction mechanism of ILK protein with the CA and simvastatin. Average potential energy was found to be highest in case of ILK-CA complex (-770,949 kJ/mol). Binding free energy was found to be higher in case of simvastatin than CA. Our results indicate that simvastatin binds more effectively to the active pocket of ILK. We further performed MTT assay to understand its anticancer potential. Simvastatin shows the IC50 values for HepG2 and MCF-7 as 19.18 ± 0.12 and 13.84 ± 0.22 µM, respectively. However, the IC50 value of CA on HepG2 and MCF-7 was reported as 175.50 ± 1.44 and 144.90 ± 1.53 µM, respectively. Our study provides a deeper insight into the binding mechanism of simvastatin and CA to ILK, which further opens a promising channel for their implications in cancer therapy.
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Affiliation(s)
- Mehak Gulzar
- Department of Biotechnology, Sharda University , Greater Noida , Uttar Pradesh, India
| | - Shahid Ali
- School of Food Science and Engineering, South China University of Technology , Guangzhou , People's Republic of China
| | - Faez Iqbal Khan
- Computational Mechanistic Chemistry and Drug Discovery, Rhodes University , Grahamstown , South Africa
| | - Parvez Khan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia , New Delhi , India
| | - Pankaj Taneja
- Department of Biotechnology, Sharda University , Greater Noida , Uttar Pradesh, India
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia , New Delhi , India
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37
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Amirova KM, Dimitrova P, Marchev AS, Aneva IY, Georgiev MI. Clinopodium vulgare L. (wild basil) extract and its active constituents modulate cyclooxygenase-2 expression in neutrophils. Food Chem Toxicol 2018; 124:1-9. [PMID: 30481570 DOI: 10.1016/j.fct.2018.11.054] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 11/21/2018] [Accepted: 11/24/2018] [Indexed: 12/26/2022]
Abstract
Clinopodium vulgare L. (wild basil) has a wide range of ethnopharmacological applications and accumulates a broad spectrum of phenolic compounds, recognized for their anti-inflammatory and anticancer properties. The triggered cyclooxygenase-2 (COX-2) expression is creating an immunosuppressive microenvironment in the inflamed tissue and considered to be the main cause of failure of even new anticancer-/immune-therapies. Nowadays, selective and novel plant-derived COX-2 inhibitors with safe profile are subject of profound research interest. This study aimed to analyze the metabolic profile of C. vulgare and search for phenolic molecules with potential biological properties. By application of 1H and 2D-NMR (Nuclear Magnetic Resonance) profiling, caffeic, chlorogenic acids and catechin were identified along with a bunch of primary and secondary metabolites. Further, the biological effect of C. vulgare extract (CVE) and its constituents on zymosan-induced COX-2 expression and apoptosis of murine neutrophils have been studied. The CVE, caffeic and chlorogenic acids inhibited zymosan-induced COX-2 expression in bone marrow neutrophils, in vitro and in vivo activated. The obtained data indicate that CVE may have a good potential to manipulate neutrophil functions, however, its action may depend on the cellular state, the inflammatory milieu and the relative content of caffeic and chlorogenic acid in the extract.
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Affiliation(s)
| | - Petya Dimitrova
- Department of Immunology, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 26 Georgi Bonchev Str., 1113, Sofia, Bulgaria
| | - Andrey S Marchev
- Center of Plant Systems Biology and Biotechnology, 4000, Plovdiv, Bulgaria; Group of Plant Cell Biotechnology and Metabolomics, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd., 4000, Plovdiv, Bulgaria
| | - Ina Y Aneva
- Institute of Biodiversity and Ecosystem Research, Bulgarian Academy of Sciences, 1113, Sofia, Bulgaria
| | - Milen I Georgiev
- Center of Plant Systems Biology and Biotechnology, 4000, Plovdiv, Bulgaria; Group of Plant Cell Biotechnology and Metabolomics, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd., 4000, Plovdiv, Bulgaria.
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Kabała-Dzik A, Rzepecka-Stojko A, Kubina R, Wojtyczka RD, Buszman E, Stojko J. Caffeic Acid Versus Caffeic Acid Phenethyl Ester in the Treatment of Breast Cancer MCF-7 Cells: Migration Rate Inhibition. Integr Cancer Ther 2018; 17:1247-1259. [PMID: 30246565 PMCID: PMC6247537 DOI: 10.1177/1534735418801521] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Epithelium mammary carcinoma is a cancer with a high death rate among women. One factor having a significant impact on metastasis is cell migration. The aim of this study was to compare migration rate inhibition of caffeic acid (CA) and its phenethyl ester (CAPE) on MCF-7 breast cancer cells. Microscopic evaluation was used to determine the morphology of carcinoma cells, before and after 24-hour treatment with CA and CAPE using a dose of 50 µM. The cytotoxic effect was measured by XTT-NR-SRB assay (tetrazolium hydroxide-neutral red-Sulforhodamine B) for 24-hour and 48-hour periods, using CA and CAPE, with doses of 50 and 100 µM. These doses were used to determine cell migration inhibition using a wound closure assay for 0-hour, 8-hour, 16-hour, and 24-hour periods. Both CA and CAPE treatments displayed cytotoxic activity in a dose- and time-dependent trend. CAPE displayed IC50 values more than twice as low as CA. IC50 values for the XTT assay were as follows: CA was 102.98 µM for 24 hours and 59.12 µM for 48 hours, while CAPE was 56.39 µM for 24 hours and 28.10 µM for 48 hours. For the NR assay: CA was 84.87 µM at 24 hours and 65.05 µM at 48 hours, while CAPE was 69.05 µM at 24 hours and 29.05 µM at 48 hours. For the SRB assay: At 24 hours, CA was 83.47 µM and 53.46 µM at 48 hours, while CAPE was 38.53 µM at 24 hours and 20.15 µM at 48 hours. Both polyphenols induced migration inhibition, resulting in practically halting the wound closure. CAPE produced better results than CA with the same doses and experiment times, though both CA and CAPE displayed cytotoxic activity against MCF-7 cells, as well as inhibited migration.
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Affiliation(s)
- Agata Kabała-Dzik
- 1 Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Poland
| | - Anna Rzepecka-Stojko
- 1 Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Poland
| | - Robert Kubina
- 1 Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Poland
| | - Robert Dariusz Wojtyczka
- 1 Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Poland
| | - Ewa Buszman
- 1 Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Poland
| | - Jerzy Stojko
- 1 Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Poland
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Ning W, Hu Z, Tang C, Yang L, Zhang S, Dong C, Huang J, Zhou HB. Novel Hybrid Conjugates with Dual Suppression of Estrogenic and Inflammatory Activities Display Significantly Improved Potency against Breast Cancer. J Med Chem 2018; 61:8155-8173. [PMID: 30053783 DOI: 10.1021/acs.jmedchem.8b00224] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
In this work, we developed a small library of novel OBHS-RES hybrid compounds with dual inhibition activities targeting both the estrogen receptor α (ERα) and NF-κB by incorporating resveratrol (RES), a known inhibitor of NF-κB, into a privileged indirect antagonism structural motif (OBHS, oxabicycloheptene sulfonate) of estrogen receptor (ER). The OBHS-RES conjugates could bind well to ER and showed remarkable ERα antagonistic activity, and they also exhibited excellent NO inhibition in macrophage RAW 264.7 cells. Compared with 4-hydroxytamoxifen, some of them showed better antiproliferative efficacy in MCF-7 cell lines with IC50 up to 3.7 μM. In vivo experiments in a MCF-7 breast cancer model in Balb/c nude mice indicated that compound 26a was more potent than tamoxifen. Exploration of the compliancy of the structure against ER specificity utilizing these types of isomeric three-dimensional ligands indicated that one enantiomer had much better biological activity than the other.
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Affiliation(s)
- Wentao Ning
- State Key Laboratory of Virology, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education , Wuhan University School of Pharmaceutical Sciences , Wuhan 430071 , China
| | - Zhiye Hu
- State Key Laboratory of Virology, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education , Wuhan University School of Pharmaceutical Sciences , Wuhan 430071 , China
| | - Chu Tang
- Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology , Xidian University , Xi'an 710126 , Shaanxi , China
| | - Lu Yang
- State Key Laboratory of Virology, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education , Wuhan University School of Pharmaceutical Sciences , Wuhan 430071 , China
| | - Silong Zhang
- State Key Laboratory of Virology, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education , Wuhan University School of Pharmaceutical Sciences , Wuhan 430071 , China
| | - Chune Dong
- State Key Laboratory of Virology, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education , Wuhan University School of Pharmaceutical Sciences , Wuhan 430071 , China
| | - Jian Huang
- College of Life Sciences , Wuhan University , Wuhan 430072 , China
| | - Hai-Bing Zhou
- State Key Laboratory of Virology, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education , Wuhan University School of Pharmaceutical Sciences , Wuhan 430071 , China
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40
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Gerogianni PS, Chatziathanasiadou MV, Diamantis DA, Tzakos AG, Galaris D. Lipophilic ester and amide derivatives of rosmarinic acid protect cells against H 2O 2-induced DNA damage and apoptosis: The potential role of intracellular accumulation and labile iron chelation. Redox Biol 2018; 15:548-556. [PMID: 29413966 PMCID: PMC5975196 DOI: 10.1016/j.redox.2018.01.014] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 01/24/2018] [Accepted: 01/31/2018] [Indexed: 12/31/2022] Open
Abstract
Phenolic acids represent abundant components contained in human diet. However, the negative charge in their carboxylic group limits their capacity to diffuse through biological membranes, thus hindering their access to cell interior. In order to promote the diffusion of rosmarinic acid through biological membranes, we synthesized several lipophilic ester- and amide-derivatives of this compound and evaluated their capacity to prevent H2O2-induced DNA damage and apoptosis in cultured human cells. Esterification of the carboxylic moiety with lipophilic groups strongly enhanced the capacity of rosmarinic acid to protect cells. On the other hand, the amide-derivatives were somewhat less effective but exerted less cytotoxicity at high concentrations. Cell uptake experiments, using ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS), illustrated different levels of intracellular accumulation among the ester- and amide-derivatives, with the first being more effectively accumulated, probably due to their extensive hydrolysis inside the cells. In conclusion, these results highlight the hitherto unrecognized fundamental importance of derivatization of diet-derived phenolic acids to unveil their biological potential.
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Affiliation(s)
- Paraskevi S Gerogianni
- Laboratory of Biological Chemistry, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece
| | - Maria V Chatziathanasiadou
- Laboratory of Organic Chemistry and Biochemistry, School of Natural Sciences, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece
| | - Dimitrios A Diamantis
- Laboratory of Organic Chemistry and Biochemistry, School of Natural Sciences, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece
| | - Andreas G Tzakos
- Laboratory of Organic Chemistry and Biochemistry, School of Natural Sciences, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece
| | - Dimitrios Galaris
- Laboratory of Biological Chemistry, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece.
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41
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Ushio A, Eto K. RBM3 expression is upregulated by NF‐κB p65 activity, protecting cells from apoptosis, during mild hypothermia. J Cell Biochem 2018; 119:5734-5749. [DOI: 10.1002/jcb.26757] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 01/25/2018] [Indexed: 01/19/2023]
Affiliation(s)
- Ayako Ushio
- Department of Biological SciencesGraduate School of Science and TechnologyKumamoto UniversityKumamotoJapan
| | - Ko Eto
- Department of Biological SciencesGraduate School of Science and TechnologyKumamoto UniversityKumamotoJapan
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42
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Propolis and Its Potential to Treat Gastrointestinal Disorders. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:2035820. [PMID: 29736177 PMCID: PMC5875067 DOI: 10.1155/2018/2035820] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 11/21/2017] [Indexed: 12/17/2022]
Abstract
There are a number of disorders that affect the gastrointestinal tract. Such disorders have become a global emerging disease with a high incidence and prevalence rates worldwide. Inflammatory and ulcerative processes of the stomach or intestines, such as gastritis, ulcers, colitis, and mucositis, afflict a significant proportion of people throughout the world. The role of herbal-derived medicines has been extensively explored in order to develop new effective and safe strategies to improve the available gastrointestinal therapies that are currently used in the clinical practice. Studies on the efficacy of propolis (a unique resinous aromatic substance produced by honeybees from different types of species of plants) are promising and propolis has been effective in the treatment of several pathological conditions. This review, therefore, summarizes and critiques the contents of some relevant published scientific papers (including those related to clinical trials) in order to demonstrate the therapeutic value of propolis and its active compounds in the treatment and prevention of gastrointestinal diseases.
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43
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Rajagopal C, Lankadasari MB, Aranjani JM, Harikumar KB. Targeting oncogenic transcription factors by polyphenols: A novel approach for cancer therapy. Pharmacol Res 2018; 130:273-291. [PMID: 29305909 DOI: 10.1016/j.phrs.2017.12.034] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 11/30/2017] [Accepted: 12/31/2017] [Indexed: 02/06/2023]
Abstract
Inflammation is one of the major causative factor of cancer and chronic inflammation is involved in all the major steps of cancer initiation, progression metastasis and drug resistance. The molecular mechanism of inflammation driven cancer is the complex interplay between oncogenic and tumor suppressive transcription factors which include FOXM1, NF-kB, STAT3, Wnt/β- Catenin, HIF-1α, NRF2, androgen and estrogen receptors. Several products derived from natural sources modulate the expression and activity of multiple transcription factors in various tumor models as evident from studies conducted in cell lines, pre-clinical models and clinical samples. Further combination of these natural products along with currently approved cancer therapies added an additional advantage and they considered as promising targets for prevention and treatment of inflammation and cancer. In this review we discuss the application of multi-targeting natural products by analyzing the literature and future directions for their plausible applications in drug discovery.
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Affiliation(s)
- Chitra Rajagopal
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India
| | - Manendra Babu Lankadasari
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India
| | - Jesil Mathew Aranjani
- Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - K B Harikumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India.
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44
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Liu X, Zhang X, Wang F, Liang X, Zeng Z, Zhao J, Zheng H, Jiang X, Zhang Y. Improvement in cerebral ischemia–reperfusion injury through the TLR4/NF-κB pathway after Kudiezi injection in rats. Life Sci 2017; 191:132-140. [DOI: 10.1016/j.lfs.2017.10.035] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Revised: 10/17/2017] [Accepted: 10/24/2017] [Indexed: 10/18/2022]
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45
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Yu HJ, Shin JA, Yang IH, Won DH, Ahn CH, Kwon HJ, Lee JS, Cho NP, Kim EC, Yoon HJ, Lee JI, Hong SD, Cho SD. Apoptosis induced by caffeic acid phenethyl ester in human oral cancer cell lines: Involvement of Puma and Bax activation. Arch Oral Biol 2017; 84:94-99. [DOI: 10.1016/j.archoralbio.2017.09.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 08/24/2017] [Accepted: 09/24/2017] [Indexed: 02/06/2023]
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46
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Yucel B, Sonmez M. Repression of oxidative phosphorylation sensitizes leukemia cell lines to cytarabine. Hematology 2017; 23:330-336. [DOI: 10.1080/10245332.2017.1402454] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Affiliation(s)
- Burcu Yucel
- Medical Faculty, Department of Medical Biology, Karadeniz Technical University, Trabzon, Turkey
| | - Mehmet Sonmez
- Medical Faculty, Department of Internal Medicine, Division of Hematology, Karadeniz Technical University, Trabzon, Turkey
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47
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Yang WZ, Zhou H, Yan Y. XIAP underlies apoptosis resistance of renal cell carcinoma cells. Mol Med Rep 2017; 17:125-130. [PMID: 29115633 PMCID: PMC5780075 DOI: 10.3892/mmr.2017.7925] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 09/06/2017] [Indexed: 01/28/2023] Open
Abstract
X-linked inhibitor of apoptosis (XIAP), a key member of the inhibitors of apoptosis protein family, can inhibit apoptosis by directly binding to the initiator caspase-9, −3 and −7, thereby promoting tumor cell survival during tumor progression. In the present study, XIAP basal expression levels were investigated and its contribution to the resistance to apoptosis was evaluated, in the RCC cell lines exposed to apoptosis-inducing drugs. This was investigated by histological methods and western blot analysis. Using RNA interference, elimination of XIAP in Caki-1 cells was also studied, and its contribution to the sensitivity to apoptosis induced through the intrinsic pathway was observed. Differences in XIAP expression were detected between ClearCa-2 and ClearCa-6 cell lines. ClearCa-6 cells with lower expression of XIAP were more sensitive to apoptosis-inducing drugs, compared with ClearCa-2 cells. However, the levels of XIAP expression in both cell lines were stable during apoptosis. Furthermore, a Caki-1 cell line with no XIAP expression was used, and was demonstrated to be more sensitive to the apoptosis induced by the mitochondrial pathway. These results suggested that downregulation of XIAP expression could enhance the sensitivity of RCC cells to apoptosis, and the basal expression of XIAP during apoptosis is stable. This may provide novel insight for targeted gene therapy against XIAP, in the clinic.
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Affiliation(s)
- Wen Zheng Yang
- Department of Anesthesiology, Beijing Shijitan Hospital, Beijing 100038, P.R. China
| | - Haijiang Zhou
- Department of Emergency Medicine, Beijing Chao‑Yang Hospital, Beijing 100038, P.R. China
| | - Yong Yan
- Department of Urology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, P.R. China
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Kabała-Dzik A, Rzepecka-Stojko A, Kubina R, Jastrzębska-Stojko Ż, Stojko R, Wojtyczka RD, Stojko J. Migration Rate Inhibition of Breast Cancer Cells Treated by Caffeic Acid and Caffeic Acid Phenethyl Ester: An In Vitro Comparison Study. Nutrients 2017; 9:nu9101144. [PMID: 29048370 PMCID: PMC5691760 DOI: 10.3390/nu9101144] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 10/03/2017] [Accepted: 10/03/2017] [Indexed: 12/20/2022] Open
Abstract
One of the deadliest cancers among women is a breast cancer. Research has shown that two natural substances occurring in propolis, caffeic acid (CA) and caffeic acid phenethyl ester (CAPE), have significant anticancer effects. The purpose of our in vitro study was to compare cytotoxic activity and migration rate inhibition using CA and CAPE (doses of 50 and 100 µm) against triple-negative, MDA-MB-231 breast adenocarcinoma line cells, drawn from Caucasian women. Viability was measured by XTT-NR-SRB assay (Tetrazolium hydroxide-Neutral Red-Sulforhodamine B) for 24 h and 48 h periods. Cell migration for wound healing assay was taken for 0 h, 8 h, 16 h, and 24 h periods. CAPE displayed more than two times higher cytotoxicity against MDA-MB-231 cells. IC50 values for the XTT assay were as follows: CA for 24 h and 48 h were 150.94 µM and 108.42 µM, respectively, while CAPE was 68.82 µM for 24 h and 55.79 µM for 48 h. For the NR assay: CA was 135.85 µM at 24 h and 103.23 µM at 48 h, while CAPE was 64.04 µM at 24 h and 53.25 µM at 48 h. For the SRB assay: CA at 24 h was 139.80 µM and at 48 h 103.98 µM, while CAPE was 66.86 µM at 24 h and 47.73 µM at 48 h. Both agents suspended the migration rate; however, CAPE displayed better activity. Notably, for the 100 µM CAPE dose, motility of the tested breast carcinoma cells was halted.
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Affiliation(s)
- Agata Kabała-Dzik
- Department of Pathology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Ostrogórska 30, 41-200 Sosnowiec, Poland.
| | - Anna Rzepecka-Stojko
- Department of Pharmaceutical Chemistry, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland.
| | - Robert Kubina
- Department of Pathology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Ostrogórska 30, 41-200 Sosnowiec, Poland.
| | - Żaneta Jastrzębska-Stojko
- Department of Anesthesiology and Intensive Care, Prof. K. Gibiński University Clinical Center, Medical University of Silesia in Katowice, Ceglana 35, 40-514 Katowice, Poland.
| | - Rafał Stojko
- Department of Women Health, School of Health Sciences, Medical University of Silesia in Katowice, Medyków 12, 40-752 Katowice, Poland.
| | - Robert Dariusz Wojtyczka
- Department and Institute of Microbiology and Virology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland.
| | - Jerzy Stojko
- Department of Toxicology and Bioanalysis, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland.
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Kabała-Dzik A, Rzepecka-Stojko A, Kubina R, Jastrzębska-Stojko Ż, Stojko R, Wojtyczka RD, Stojko J. Comparison of Two Components of Propolis: Caffeic Acid (CA) and Caffeic Acid Phenethyl Ester (CAPE) Induce Apoptosis and Cell Cycle Arrest of Breast Cancer Cells MDA-MB-231. Molecules 2017; 22:molecules22091554. [PMID: 28926932 PMCID: PMC6151426 DOI: 10.3390/molecules22091554] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 09/05/2017] [Accepted: 09/13/2017] [Indexed: 12/19/2022] Open
Abstract
Studies show that caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) are compounds with potent chemopreventive effects. Breast cancer is a common form of aggressive cancer among women worldwide. This study shows a comparison of CA and CAPE activity on triple-negative human caucasian breast adenocarcinoma line cells (MDA-MB-231). MDA-MB-231 cells were treated by CA and CAPE with doses of from 10 to 100 µM, for periods of 24 h and 48 h. Cytotoxicity MTT tests, apoptosis by Annexin V, and cell cycle with Dead Cell Assays were performed. Cytotoxic activity was greater for CAPE compared to CA (both incubation times, same dosage). IC50 values for CAPE were 27.84 µM (24 h) and 15.83 µM (48 h) and for CA > 10,000 µM (24 h) and > 1000 µM (48 h). Polyphenols induced apoptosis, while CAPE (dose dependently), induced a higher apoptotic effect. CAPE also induced cell cycle arrest in S phase (time and dose dependently), CA did it only for 50 and 100 µM. A dose dependent decline was seen for the G0/G1 phase (CAPE, 48 h), as well as elimination of phase G2/M by 100 µM of CAPE (only mild effect for CA). Comparing CA and CAPE activity on MDA-MB-231, CAPE clearly showed better activity for the same dosages and experiment times.
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Affiliation(s)
- Agata Kabała-Dzik
- Department of Pathology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Ostrogórska 30, Sosnowiec 41-200, Poland.
| | - Anna Rzepecka-Stojko
- Department of Pharmaceutical Chemistry, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, Sosnowiec 41-200, Poland.
| | - Robert Kubina
- Department of Pathology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Ostrogórska 30, Sosnowiec 41-200, Poland.
| | - Żaneta Jastrzębska-Stojko
- Department of Anesthesiology and Intensive Care, Prof. K. Gibiński University Clinical Center, Medical University of Silesia in Katowice, Ceglana 35, Katowice 40-514, Poland.
| | - Rafał Stojko
- Department of Women Health, School of Health Sciences, Medical University of Silesia in Katowice, Medyków 12, Katowice 40-752, Poland.
| | - Robert Dariusz Wojtyczka
- Department and Institute of Microbiology and Virology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, Sosnowiec 41-200, Poland.
| | - Jerzy Stojko
- Department of Toxicology and Bioanalysis, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, Sosnowiec 41-200, Poland.
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50
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El Menyiy N, Al Waili N, Bakour M, Al-Waili H, Lyoussi B. Protective Effect of Propolis in Proteinuria, Crystaluria, Nephrotoxicity and Hepatotoxicity Induced by Ethylene Glycol Ingestion. Arch Med Res 2017; 47:526-534. [PMID: 28262194 DOI: 10.1016/j.arcmed.2016.12.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 12/13/2016] [Indexed: 10/20/2022]
Abstract
BACKGROUND AND AIMS Propolis is a natural honeybee product with wide biological activities and potential therapeutic properties. The aim of the study is to evaluate the protective effect of propolis extract on nephrotoxicity and hepatotoxicity induced by ethylene glycol in rats. METHODS Five groups of rats were used. Group 1 received drinking water, group 2 received 0.75% ethylene-glycol in drinking water, group 3 received 0.75% ethylene-glycol in drinking water along with cystone 500 mg/kg/body weight (bw) daily, group 4 received 0.75% ethylene-glycol in drinking water along with propolis extract at a dose of 100 mg/kg/bw daily, and group 5 received 0.75% ethylene-glycol in drinking water along with propolis extract at a dose of 250 mg/kg/bw daily. The treatment continued for a total of 30 d. Urinalyses for pH, crystals, protein, creatinine, uric acid and electrolytes, and renal and liver function tests were performed. RESULTS Ethylene-glycol increased urinary pH, urinary volume, and urinary calcium, phosphorus, uric acid and protein excretion. It decreased creatinine clearance and magnesium and caused crystaluria. Treatment with propolis extract or cystone normalized the level of magnesium, creatinine, sodium, potassium and chloride. Propolis is more potent than cystone. Propolis extract alleviates urinary protein excretion and ameliorates the deterioration of liver and kidney function caused by ethylene glycol. CONCLUSIONS Propolis extract has a potential protective effect against ethylene glycol induced hepatotoxicity and nephrotoxicity and has a potential to treat and prevent urinary calculus, crystaluria and proteinuria.
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Affiliation(s)
- Nawal El Menyiy
- Laboratory Physiology-Pharmacology and Environmental Health, Faculty of Sciences DHM, University Sidi Mohamed Ben Abdallah, Fez, Morocco
| | - Noori Al Waili
- New York Medical Care for Nephrology, Richmond Hill, New York, USA.
| | - Meryem Bakour
- Laboratory Physiology-Pharmacology and Environmental Health, Faculty of Sciences DHM, University Sidi Mohamed Ben Abdallah, Fez, Morocco
| | - Hamza Al-Waili
- New York Medical Care for Nephrology, Richmond Hill, New York, USA
| | - Badiaa Lyoussi
- Laboratory Physiology-Pharmacology and Environmental Health, Faculty of Sciences DHM, University Sidi Mohamed Ben Abdallah, Fez, Morocco
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