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Shafi S, Khan MA, Ahmad J, Rabbani SA, Singh S, Najmi AK. Envisioning Glucose Transporters (GLUTs and SGLTs) as Novel Intervention against Cancer: Drug Discovery Perspective and Targeting Approach. Curr Drug Targets 2025; 26:109-131. [PMID: 39377414 DOI: 10.2174/0113894501335877240926101134] [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: 06/27/2024] [Revised: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 10/09/2024]
Abstract
Metabolic reprogramming and altered cellular energetics have been recently established as an important cancer hallmark. The modulation of glucose metabolism is one of the important characteristic features of metabolic reprogramming in cancer. It contributes to oncogenic progression by supporting the increased biosynthetic and bio-energetic demands of tumor cells. This oncogenic transformation consequently results in elevated expression of glucose transporters in these cells. Moreover, various cancers exhibit abnormal transporter expression patterns compared to normal tissues. Recent investigations have underlined the significance of glucose transporters in regulating cancer cell survival, proliferation, and metastasis. Abnormal regulation of these transporters, which exhibit varying affinities for hexoses, could enable cancer cells to efficiently manage their energy supply, offering a crucial edge for proliferation. Exploiting the upregulated expression of glucose transporters, GLUTs, and Sodium Linked Glucose Transporters (SGLTs), could serve as a novel therapeutic intervention for anti-cancer drug discovery as well as provide a unique targeting approach for drug delivery to specific tumor tissues. This review aims to discussthe previous and emerging research on the expression of various types of glucose transporters in tumor tissues, the role of glucose transport inhibitors as a cancer therapy intervention as well as emerging GLUT/SGLT-mediated drug delivery strategies that can be therapeutically employed to target various cancers.
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Affiliation(s)
- Sadat Shafi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Mohammad Ahmed Khan
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Javed Ahmad
- Department of Pharmaceutics, College of Pharmacy, Najran University, Kingdom of Saudi Arabia (KSA)
| | - Syed Arman Rabbani
- Department of Clinical Pharmacy and Pharmacology, Ras Al Khaimah College of Pharmacy, Ras Al Khaimah Medical and Health Science University, Ras Al Khaimah, United Arab Emirates
| | - Shailja Singh
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Abul Kalam Najmi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
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McLoone P, Oladejo TO, Kassym L, McDougall GJ. Honey Phytochemicals: Bioactive Agents With Therapeutic Potential for Dermatological Disorders. Phytother Res 2024; 38:5741-5764. [PMID: 39324175 DOI: 10.1002/ptr.8330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/27/2024]
Abstract
Honey has been reported to have a range of biological activities including antimicrobial, immunomodulatory, and wound healing effects. Indeed, medical-grade honey is currently used in hospitals for the clinical management of wound infections. Honey is also of scientific interest for its therapeutic effects on other dermatological disorders such as atopic dermatitis, rosacea, and skin cancer. Recent studies have uncovered that honey contains a range of phytochemicals including flavonoids, dicarboxylic acids, coumarins, and phenolic acids. In this review, PubMed was used to search the scientific literature on the biological properties of honey phytochemicals in relation to dermatological disorders and to evaluate their potential as bioactive agents, drugs, or cosmeceuticals for the treatment of skin disease. The review revealed that phytochemicals found in honey have antimicrobial, anti-inflammatory, antiaging, antioxidant, anticancer, depigmenting, photoprotective, wound healing, and skin barrier enhancing properties. Although further high-quality studies are required to establish clinical efficacy, these findings suggest that honey phytochemicals may have the potential to be used as bioactive agents for the management of a range of dermatological disorders including wounds, psoriasis, atopic dermatitis, vitiligo, rosacea, and skin cancer.
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Affiliation(s)
- Pauline McLoone
- School of Medicine, University of Kurdistan Hewlêr, Erbil, Iraq
- School of Molecular Biosciences, University of Glasgow, Glasgow, Scotland
| | - Toheeb Olalekan Oladejo
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Laura Kassym
- Department of General Medical Practice With a Course of Evidence-Based Medicine, NJSC, Astana Medical University, Astana, Kazakhstan
| | - Gordon J McDougall
- Plant Biochemistry and Food Quality Group, Environmental and Biochemical Sciences Department, The James Hutton Institute, Dundee, Scotland
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3
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Chlipała P, Tronina T, Dymarska M, Urbaniak M, Kozłowska E, Stępień Ł, Kostrzewa-Susłow E, Janeczko T. Multienzymatic biotransformation of flavokawain B by entomopathogenic filamentous fungi: structural modifications and pharmacological predictions. Microb Cell Fact 2024; 23:65. [PMID: 38402203 PMCID: PMC10893614 DOI: 10.1186/s12934-024-02338-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 02/16/2024] [Indexed: 02/26/2024] Open
Abstract
BACKGROUND Flavokawain B is one of the naturally occurring chalcones in the kava plant (Piper methysticum). It exhibits anticancer, anti-inflammatory and antimalarial properties. Due to its therapeutic potential, flavokawain B holds promise for the treatment of many diseases. However, due to its poor bioavailability and low aqueous solubility, its application remains limited. The attachment of a sugar unit impacts the stability and solubility of flavonoids and often determines their bioavailability and bioactivity. Biotransformation is an environmentally friendly way to improve the properties of compounds, for example, to increase their hydrophilicity and thus affect their bioavailability. Recent studies proved that entomopathogenic filamentous fungi from the genera Isaria and Beauveria can perform O-methylglycosylation of hydroxyflavonoids or O-demethylation and hydroxylation of selected chalcones and flavones. RESULTS In the present study, we examined the ability of entomopathogenic filamentous fungal strains of Beauveria bassiana, Beauveria caledonica, Isaria farinosa, Isaria fumosorosea, and Isaria tenuipes to transform flavokawain B into its glycosylated derivatives. The main process occurring during the reaction is O-demethylation and/or hydroxylation followed by 4-O-methylglycosylation. The substrate used was characterized by low susceptibility to transformations compared to our previously described transformations of flavones and chalcones in the cultures of the tested strains. However, in the culture of the B. bassiana KCh J1.5 and BBT, Metarhizium robertsii MU4, and I. tenuipes MU35, the expected methylglycosides were obtained with high yields. Cheminformatic analyses indicated altered physicochemical and pharmacokinetic properties in the derivatives compared to flavokawain B. Pharmacological predictions suggested potential anticarcinogenic activity, caspase 3 stimulation, and antileishmanial effects. CONCLUSIONS In summary, the study provided valuable insights into the enzymatic transformations of flavokawain B by entomopathogenic filamentous fungi, elucidating the structural modifications and predicting potential pharmacological activities of the obtained derivatives. The findings contribute to the understanding of the biocatalytic capabilities of these microbial cultures and the potential therapeutic applications of the modified flavokawain B derivatives.
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Affiliation(s)
- Paweł Chlipała
- Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Wrocław, Norwida 25, 50-375, Poland.
| | - Tomasz Tronina
- Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Wrocław, Norwida 25, 50-375, Poland
| | - Monika Dymarska
- Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Wrocław, Norwida 25, 50-375, Poland
| | - Monika Urbaniak
- Institute of Plant Genetics, Polish Academy of Sciences, Poznań, Strzeszyńska 34, 60-479, Poland
| | - Ewa Kozłowska
- Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Wrocław, Norwida 25, 50-375, Poland
| | - Łukasz Stępień
- Institute of Plant Genetics, Polish Academy of Sciences, Poznań, Strzeszyńska 34, 60-479, Poland
| | - Edyta Kostrzewa-Susłow
- Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Wrocław, Norwida 25, 50-375, Poland
| | - Tomasz Janeczko
- Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Wrocław, Norwida 25, 50-375, Poland.
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Zhang Z, Li X, Wang Y, Wei Y, Wei X. Involvement of inflammasomes in tumor microenvironment and tumor therapies. J Hematol Oncol 2023; 16:24. [PMID: 36932407 PMCID: PMC10022228 DOI: 10.1186/s13045-023-01407-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/08/2023] [Indexed: 03/19/2023] Open
Abstract
Inflammasomes are macromolecular platforms formed in response to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns, whose formation would cause maturation of interleukin-1 (IL-1) family members and gasdermin D (GSDMD), leading to IL-1 secretion and pyroptosis respectively. Several kinds of inflammasomes detecting different types of dangers have been found. The activation of inflammasomes is regulated at both transcription and posttranscription levels, which is crucial in protecting the host from infections and sterile insults. Present findings have illustrated that inflammasomes are involved in not only infection but also the pathology of tumors implying an important link between inflammation and tumor development. Generally, inflammasomes participate in tumorigenesis, cell death, metastasis, immune evasion, chemotherapy, target therapy, and radiotherapy. Inflammasome components are upregulated in some tumors, and inflammasomes can be activated in cancer cells and other stromal cells by DAMPs, chemotherapy agents, and radiation. In some cases, inflammasomes inhibit tumor progression by initiating GSDMD-mediated pyroptosis in cancer cells and stimulating IL-1 signal-mediated anti-tumor immunity. However, IL-1 signal recruits immunosuppressive cell subsets in other cases. We discuss the conflicting results and propose some possible explanations. Additionally, we also summarize interventions targeting inflammasome pathways in both preclinical and clinical stages. Interventions targeting inflammasomes are promising for immunotherapy and combination therapy.
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Affiliation(s)
- Ziqi Zhang
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Xue Li
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Yang Wang
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Yuquan Wei
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Xiawei Wei
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
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Tuli HS, Rath P, Chauhan A, Ramniwas S, Vashishth K, Varol M, Jaswal VS, Haque S, Sak K. Phloretin, as a Potent Anticancer Compound: From Chemistry to Cellular Interactions. Molecules 2022; 27:8819. [PMID: 36557950 PMCID: PMC9787340 DOI: 10.3390/molecules27248819] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 12/06/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Phloretin is a natural dihydrochalcone found in many fruits and vegetables, especially in apple tree leaves and the Manchurian apricots, exhibiting several therapeutic properties, such as antioxidant, antidiabetic, anti-inflammatory, and antitumor activities. In this review article, the diverse aspects of the anticancer potential of phloretin are addressed, presenting its antiproliferative, proapoptotic, antimetastatic, and antiangiogenic activities in many different preclinical cancer models. The fact that phloretin is a planar lipophilic polyphenol and, thus, a membrane-disrupting Pan-Assay Interference compound (PAIN) compromises the validity of the cell-based anticancer activities. Phloretin significantly reduces membrane dipole potential and, therefore, is expected to be able to activate a number of cellular signaling pathways in a non-specific way. In this way, the effects of this minor flavonoid on Bax and Bcl-2 proteins, caspases and MMPs, cytokines, and inflammatory enzymes are all analyzed in the current review. Moreover, besides the anticancer activities exerted by phloretin alone, its co-effects with conventional anticancer drugs are also under discussion. Therefore, this review presents a thorough overview of the preclinical anticancer potential of phloretin, allowing one to take the next steps in the development of novel drug candidates and move on to clinical trials.
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Affiliation(s)
- Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, India
| | - Prangya Rath
- Amity Institute of Environmental Sciences, Amity University, Noida 201303, India
| | - Abhishek Chauhan
- Amity Institute of Environmental Toxicology, Safety and Management, Amity University, Noida 201303, India
| | - Seema Ramniwas
- University Centre for Research & Development, University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali 140413, India
| | - Kanupriya Vashishth
- Advance Cardiac Centre Department of Cardiology, Post Graduate Institute of Medical Education and Research (PGIMER) Chandigarh, Chandigarh 160012, India
| | - Mehmet Varol
- Department of Molecular Biology and Genetics, Faculty of Science, Kotekli Campus, Mugla Sitki Kocman University, Mugla 48000, Turkey
| | - Vivek Sheel Jaswal
- Department of Chemistry and Chemical Science, School of Physical & Material Sciences, Central University of Himachal Pradesh, Dharamshala 176206, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan 45142, Saudi Arabia
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Potentiation of the Cytotoxic Activity of Nutraceutical Phloretin against Cervical Cancer by Formulation into Microemulsion. Pharm Chem J 2022. [DOI: 10.1007/s11094-022-02569-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Jayasankar V, Vrdoljak N, Roma A, Ahmed N, Tcheng M, Minden MD, Spagnuolo PA. Novel Mango Ginger Bioactive (2,4,6-Trihydroxy-3,5-diprenyldihydrochalcone) Inhibits Mitochondrial Metabolism in Combination with Avocatin B. ACS OMEGA 2022; 7:1682-1693. [PMID: 35071863 PMCID: PMC8771686 DOI: 10.1021/acsomega.1c04053] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 11/26/2021] [Indexed: 05/28/2023]
Abstract
Acute myeloid leukemia (AML) is an aggressive blood cancer with limited effective chemotherapy options and negative patient outcomes. Food-derived molecules such as avocatin B (Avo B), a fatty-acid oxidation (FAO) inhibitor, are promising novel therapeutics. The roots of the Curcuma amada plants have been historically used in traditional medicine, but isolated bioactive compounds have seldom been studied. Here, we report that 2,4,6-trihydroxy-3,5-diprenyldihydrochalcone (M1), a bioactive from C. Amada, possesses novel anticancer activity. This in vitro study investigated the antileukemia properties of M1 and its effects on mitochondrial metabolism. In combination with Avo B, M1 synergistically reduced AML cell line viability and patient-derived clonogenic growth with no effect on normal peripheral blood stem cells. Mechanistically, M1 alone inhibited mitochondria complex I, while the M1/Avo B combination inhibited FAO by 60%, a process essential to the synergy. These results identified a novel food-derived bioactive and its potential as a novel chemotherapeutic for AML.
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Affiliation(s)
- Varsha Jayasankar
- Department
of Food Science, University of Guelph, 50 Stone Rd., Guelph, Ontario N1G2W1, Canada
| | - Nikolina Vrdoljak
- Department
of Food Science, University of Guelph, 50 Stone Rd., Guelph, Ontario N1G2W1, Canada
| | - Alessia Roma
- Department
of Food Science, University of Guelph, 50 Stone Rd., Guelph, Ontario N1G2W1, Canada
| | - Nawaz Ahmed
- Department
of Food Science, University of Guelph, 50 Stone Rd., Guelph, Ontario N1G2W1, Canada
| | - Matthew Tcheng
- Department
of Food Science, University of Guelph, 50 Stone Rd., Guelph, Ontario N1G2W1, Canada
| | - Mark D. Minden
- University
Health Network, 610 University Avenue, Toronto, Ontario M5G 2C4, Canada
| | - Paul A. Spagnuolo
- Department
of Food Science, University of Guelph, 50 Stone Rd., Guelph, Ontario N1G2W1, Canada
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8
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Pliszka M, Szablewski L. Glucose Transporters as a Target for Anticancer Therapy. Cancers (Basel) 2021; 13:cancers13164184. [PMID: 34439338 PMCID: PMC8394807 DOI: 10.3390/cancers13164184] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/09/2021] [Accepted: 08/18/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary For mammalian cells, glucose is a major source of energy. In the presence of oxygen, a complete breakdown of glucose generates 36 molecules of ATP from one molecule of glucose. Hypoxia is a hallmark of cancer; therefore, cancer cells prefer the process of glycolysis, which generates only two molecules of ATP from one molecule of glucose, and cancer cells need more molecules of glucose in comparison with normal cells. Increased uptake of glucose by cancer cells is due to increased expression of glucose transporters. However, overexpression of glucose transporters, promoting the process of carcinogenesis, and increasing aggressiveness and invasiveness of tumors, may have also a beneficial effect. For example, upregulation of glucose transporters is used in diagnostic techniques such as FDG-PET. Therapeutic inhibition of glucose transporters may be a method of treatment of cancer patients. On the other hand, upregulation of glucose transporters, which are used in radioiodine therapy, can help patients with cancers. Abstract Tumor growth causes cancer cells to become hypoxic. A hypoxic condition is a hallmark of cancer. Metabolism of cancer cells differs from metabolism of normal cells. Cancer cells prefer the process of glycolysis as a source of ATP. Process of glycolysis generates only two molecules of ATP per one molecule of glucose, whereas the complete oxidative breakdown of one molecule of glucose yields 36 molecules of ATP. Therefore, cancer cells need more molecules of glucose in comparison with normal cells. Increased uptake of glucose by these cells is due to overexpression of glucose transporters, especially GLUT1 and GLUT3, that are hypoxia responsive, as well as other glucose transport proteins. Increased expression of these carrier proteins may be used in anticancer therapy. This phenomenon is used in diagnostic techniques such as FDG-PET. It is also suggested, and there are observations, that therapeutic inhibition of glucose transporters may be a method in treatment of cancer patients. On the other hand, there are described cases, in which upregulation of glucose transporters, as, for example, NIS, which is used in radioiodine therapy, can help patients with cancer. The aim of this review is the presentation of possibilities, and how glucose transporters can be used in anticancer therapy.
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Casarini TPA, Frank LA, Benin T, Onzi G, Pohlmann AR, Guterres SS. Innovative hydrogel containing polymeric nanocapsules loaded with phloretin: Enhanced skin penetration and adhesion. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 120:111681. [PMID: 33545843 DOI: 10.1016/j.msec.2020.111681] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/14/2020] [Accepted: 10/21/2020] [Indexed: 01/26/2023]
Abstract
Dermatological applications of phloretin are restricted by its poor aqueous solubility. Nanotechnology has been proposed as strategy to increase the apparent drug solubility in aqueous media. This study aimed to develop, characterize, and evaluate the antitumoral effects and safety of polymeric nanocapsules containing phloretin (NCPhl). Further, to incorporate NC-Phl in an innovative semi-solid formulation (HG-NCPhl) to evaluate its performance using porcine skin model. NC-Phl was prepared and the effects in MRC5, HACAT, and SK-mel28 cells were evaluated. Hydrogels were prepared with Lecigel ® and characterized for their nanotechnological properties, adhesion (in vitro washability), and penetration/permeation studies in porcine skin. NC-Phl had a cytotoxic effect against Sk-Mel-28 cells and the population doubling time was increased upon treatment with NC-Phl for longer culture periods; notably when cells were treated for 72 h and then followed for 7 days after the treatment was removed (p < 0.05). HG-NC-Phl was considered adhesive and had a higher capacity to penetrate all skin layers compared with HG-Phl (p < 0.05). The innovative hydrogel HGNC-Phl promoted a drug-reservoir in the stratum corneum and higher penetration of the flavonoid into the epidermis. Therefore, this approach can be considered as a platform to establish versatile dermatological solutions for both cosmeceutics and melanoma therapy.
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Affiliation(s)
- Talita Pizza Anunciato Casarini
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
| | - Luiza Abrahão Frank
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Tainara Benin
- Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Giovana Onzi
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Adriana Raffin Pohlmann
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Silvia Stanisçuaski Guterres
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
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Rachakhom W, Banjerdpongchai R. Effect of Calomelanone, a Dihydrochalcone Analogue, on Human Cancer Apoptosis/Regulated Cell Death in an In Vitro Model. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4926821. [PMID: 33415148 PMCID: PMC7769633 DOI: 10.1155/2020/4926821] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/24/2020] [Accepted: 12/07/2020] [Indexed: 12/18/2022]
Abstract
Calomelanone, 2',6'-dihydroxy-4,4'-dimethoxydihydrochalcone, possesses anticancer activities. This study was conducted to investigate the cytotoxic effect of calomelanone, a dihydrochalcone analogue, on human cancer cells and its associated mechanisms. The cytotoxic effect of calomelanone was measured by MTT assay. Annexin V-FITC/propidium iodide and DiOC6 staining that employed flow cytometry were used to determine the mode of cell death and reduction of mitochondrial transmembrane potential (MTP), respectively. Caspase activities were measured using specific substrates and colorimetric analysis. The expression levels of Bcl-2 family proteins were determined by immunoblotting. Reactive oxygen species were also measured using 2',7'-dihydrodichlorofluorescein diacetate and dihydroethidium (fluorescence dyes). Calomelanone was found to be toxic towards various human cancer cells, including acute promyelocytic HL-60 and monocytic leukemic U937 cells, in a dose-dependent manner at 24 h and human hepatocellular HepG2 cells at 48 h. However, the proliferation of HepG2 cells increased at 24 h. Calomelanone was found to induce apoptosis in HL-60 and U937 at 24 h and HepG2 apoptosis at 48 h via the intrinsic pathway by inducing MTP disruption. This compound also induced caspase-3, caspase-8, and caspase-9 activities. Calomelanone upregulated proapoptotic Bax and Bak and downregulated antiapoptotic Bcl-xL proteins in HepG2 cells. Moreover, signaling was also associated with oxidative stress in HepG2 cells. Calomelanone induced autophagy at 24 h of treatment, which was evidenced by staining with monodansylcadaverine (MDC) to represent autophagic flux. This was associated with a decrease of Akt (survival pathway) and an upregulation of Atg5 (the marker of autophagy). Thus, calomelanone induced apoptosis/regulated cell death in HL-60, U937, and HepG2 cells. However, it also induced autophagy in HepG2 depending on duration, dose, and type of cells. Thus, calomelanone could be used as a potential anticancer agent for cancer treatment. Nevertheless, acute and chronic toxicity should be further investigated in animals before conducting investigations in human patients.
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Affiliation(s)
- Wasitta Rachakhom
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Ratana Banjerdpongchai
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
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11
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Shang A, Liu HY, Luo M, Xia Y, Yang X, Li HY, Wu DT, Sun Q, Geng F, Li HB, Gan RY. Sweet tea (Lithocarpus polystachyus rehd.) as a new natural source of bioactive dihydrochalcones with multiple health benefits. Crit Rev Food Sci Nutr 2020; 62:917-934. [DOI: 10.1080/10408398.2020.1830363] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Ao Shang
- National Agricultural Science & Technology Center, Chengdu, China
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu, China
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Hong-Yan Liu
- National Agricultural Science & Technology Center, Chengdu, China
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu, China
| | - Min Luo
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Yu Xia
- National Agricultural Science & Technology Center, Chengdu, China
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu, China
| | - Xiao Yang
- National Agricultural Science & Technology Center, Chengdu, China
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu, China
| | - Hang-Yu Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Ding-Tao Wu
- Institute of Food Processing and Safety, College of Food Science, Sichuan Agricultural University, Ya’an, Sichuan, China
| | - Quancai Sun
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Fang Geng
- Key Laboratory of Coarse Cereal Processing (Ministry of Agriculture and Rural Affairs), School of Food and Biological Engineering, Chengdu University, Chengdu, China
| | - Hua-Bin Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Ren-You Gan
- National Agricultural Science & Technology Center, Chengdu, China
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu, China
- Key Laboratory of Coarse Cereal Processing (Ministry of Agriculture and Rural Affairs), School of Food and Biological Engineering, Chengdu University, Chengdu, China
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12
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Karabulut S, Toprak M. Biophysical study of phloretin with human serum albumin in liposomes using spectroscopic methods. EUROPEAN BIOPHYSICS JOURNAL: EBJ 2020; 49:463-472. [PMID: 32705322 DOI: 10.1007/s00249-020-01452-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 07/03/2020] [Accepted: 07/19/2020] [Indexed: 12/19/2022]
Abstract
The ability of drugs to diffuse through the lipid bilayer of cell membranes is important for their metabolism, distribution, and efficacy. In this study, the interaction between phloretin and human serum albumin (HSA) in an L-egg lecithin phosphatidylcholine (PC) liposome suspension was investigated by fluorescence and absorbance spectroscopy. The spectroscopic and fluorescence quenching experiments show that phloretin molecules penetrated into the lumen of the liposome. The partition coefficient of phloretin in the PC liposome suspensions was calculated from fluorescence quenching measurements. The results show that phloretin efficiently quenches the intrinsic fluorescence of HSA through a combination of dynamic and static quenching. The values of Gibbs free energy, and the enthalpy and entropic change in the binding process of phloretin with HSA in the PC liposome suspensions were negative, suggesting that the binding process of phloretin and HSA was spontaneous. Hydrogen bonding and van der Waals force interactions play an important role in the interaction between the two molecules. In addition, binding of phloretin to HSA in liposome suspensions was investigated by synchronous fluorescence spectroscopy.
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Affiliation(s)
- Seda Karabulut
- Department of Chemistry, Bingol University, 12000, Bingol, Turkey
| | - Mahmut Toprak
- Department of Chemistry, Bingol University, 12000, Bingol, Turkey.
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13
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Nakamura S, Kaneko K, Mitsui T, Ohtsubo K. Evaluation of the palatability and biofunctionality of brown rice germinated in red onion solution. Cereal Chem 2020. [DOI: 10.1002/cche.10305] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Sumiko Nakamura
- Faculty of Applied Life Sciences Niigata University of Pharmacy and Applied Life Sciences Niigata Japan
| | - Kentaro Kaneko
- Graduate School of Natural Sciences Niigata University Niigata Japan
| | - Toshiaki Mitsui
- Graduate School of Natural Sciences Niigata University Niigata Japan
| | - Ken'ichi Ohtsubo
- Faculty of Applied Life Sciences Niigata University of Pharmacy and Applied Life Sciences Niigata Japan
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14
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Alshangiti AM, Tuboly E, Hegarty SV, McCarthy CM, Sullivan AM, O'Keeffe GW. 4-Hydroxychalcone Induces Cell Death via Oxidative Stress in MYCN-Amplified Human Neuroblastoma Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:1670759. [PMID: 31885773 PMCID: PMC6915131 DOI: 10.1155/2019/1670759] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/21/2019] [Accepted: 11/20/2019] [Indexed: 12/26/2022]
Abstract
Neuroblastoma is an embryonal malignancy that arises from cells of sympathoadrenal lineage during the development of the nervous system. It is the most common pediatric extracranial solid tumor and is responsible for 15% of childhood deaths from cancer. Fifty percent of cases are diagnosed as high-risk metastatic disease with a low overall 5-year survival rate. More than half of patients experience disease recurrence that can be refractory to treatment. Amplification of the MYCN gene is an important prognostic indicator that is associated with rapid disease progression and a poor prognosis, highlighting the need for new therapeutic approaches. In recent years, there has been an increasing focus on identifying anticancer properties of naturally occurring chalcones, which are secondary metabolites with variable phenolic structures. Here, we report that 4-hydroxychalcone is a potent cytotoxin for MYCN-amplified IMR-32 and SK-N-BE (2) neuroblastoma cells, when compared to non-MYCN-amplified SH-SY5Y neuroblastoma cells and to the non-neuroblastoma human embryonic kidney cell line, HEK293t. Moreover, 4-hydroxychalcone treatment significantly decreased cellular levels of the antioxidant glutathione and increased cellular reactive oxygen species. In addition, 4-hydroxychalcone treatment led to impairments in mitochondrial respiratory function, compared to controls. In support of this, the cytotoxic effect of 4-hydroxychalcone was prevented by co-treatment with either the antioxidant N-acetyl-L-cysteine, a pharmacological inhibitor of oxidative stress-induced cell death (IM-54) or the mitochondrial reactive oxygen species scavenger, Mito-TEMPO. When combined with the anticancer drugs cisplatin or doxorubicin, 4-hydroxychalcone led to greater reductions in cell viability than was induced by either anti-cancer agent alone. In summary, this study identifies a cytotoxic effect of 4-hydroxychalcone in MYCN-amplified human neuroblastoma cells, which rationalizes its further study in the development of new therapies for pediatric neuroblastoma.
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Affiliation(s)
- Amnah M. Alshangiti
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
- Cork Neuroscience Centre, University College Cork, Cork, Ireland
| | - Eszter Tuboly
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
| | - Shane V. Hegarty
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
- Cork Neuroscience Centre, University College Cork, Cork, Ireland
| | - Cathal M. McCarthy
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
| | - Aideen M. Sullivan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
- Cork Neuroscience Centre, University College Cork, Cork, Ireland
| | - Gerard W. O'Keeffe
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
- Cork Neuroscience Centre, University College Cork, Cork, Ireland
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15
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Mariadoss AVA, Vinyagam R, Rajamanickam V, Sankaran V, Venkatesan S, David E. Pharmacological Aspects and Potential Use of Phloretin: A Systemic Review. Mini Rev Med Chem 2019; 19:1060-1067. [PMID: 30864525 DOI: 10.2174/1389557519666190311154425] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 07/18/2018] [Accepted: 08/08/2018] [Indexed: 12/27/2022]
Abstract
Over the past two decades, many researchers have concluded that a diet rich in polyphenolic compounds plays an important therapeutic role in reducing the risk of cancer, cardiovascular disease, inflammation, diabetes, and other degenerative diseases. Polyphenolic compounds have been reported to be involved in neutralization of reactive oxygen species and charged radicals, and have anticarcinogenic effects, hepatoprotective effects, low-glycaemic response, and other benefits. The benefits of fruits and vegetables may be partly attributable to polyphenolic compounds, which have antioxidant and free radical scavenging properties. Fruits such as apples contain a variety of phytochemicals, including (+)-catechin and (-)-epicatechin, phlorizin, phloretin quercetin, cyanidin-3-Ogalactoside, chlorogenic acid, and p-coumaric acid, all of which are strong antioxidants. Phloretin, a natural phenolic compound, is a dihydrochalcone, which is present in the apple. It exhibits a wide variety of activities such as antioxidative, anti-inflammatory, anti-microbial, anti-allergic, anticarcinogenic, anti-thrombotic, and hepatoprotective, besides being involved in the activation of apoptotic associated gene expression and signal transduction in molecular pathways. Despite a multitude of clinical studies, new efforts are needed in clinical research to determine the complete therapeutic potential of phloretin.
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Affiliation(s)
- Arokia V A Mariadoss
- Department of Biotechnology, Thiruvalluvar University, Serkadu, Vellore- 632115 Tamil Nadu, India
| | - Ramachandran Vinyagam
- Department of Biotechnology, Thiruvalluvar University, Serkadu, Vellore- 632115 Tamil Nadu, India
| | - Vinothkumar Rajamanickam
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Vijayalakshmi Sankaran
- Department of Biotechnology, Thiruvalluvar University, Serkadu, Vellore- 632115 Tamil Nadu, India
| | - Sathish Venkatesan
- Department of Biotechnology, Thiruvalluvar University, Serkadu, Vellore- 632115 Tamil Nadu, India
| | - Ernest David
- Department of Biotechnology, Thiruvalluvar University, Serkadu, Vellore- 632115 Tamil Nadu, India
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16
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Choi BY. Biochemical Basis of Anti-Cancer-Effects of Phloretin-A Natural Dihydrochalcone. Molecules 2019; 24:molecules24020278. [PMID: 30642127 PMCID: PMC6359539 DOI: 10.3390/molecules24020278] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 01/08/2019] [Accepted: 01/10/2019] [Indexed: 12/26/2022] Open
Abstract
Apple is a rich source of bioactive phytochemicals that help improve health by preventing and/or curing many disease processes, including cancer. One of the apple polyphenols is phloretin [2′,4′,6′-Trihydroxy-3-(4-hydroxyphenyl)-propiophenone], which has been widely investigated for its antioxidant, anti-inflammatory and anti-cancer activities in a wide array of preclinical studies. The efficacy of phloretin in suppressing xenograft tumor growth in athymic nude mice implanted with a variety of human cancer cells, and the ability of the compound to interfere with cancer cells signaling, have made it a promising candidate for anti-cancer drug development. Mechanistically, phloretin has been reported to arrest the growth of tumor cells by blocking cyclins and cyclin-dependent kinases and induce apoptosis by activating mitochondria-mediated cell death. The blockade of the glycolytic pathway via downregulation of GLUT2 mRNA and proteins, and the inhibition of tumor cells migration, also corroborates the anti-cancer effects of phloretin. This review sheds light on the molecular targets of phloretin as a potential anti-cancer and anti-inflammatory natural agent.
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Affiliation(s)
- Bu Young Choi
- Department of Pharmaceutical Science & Engineering, Seowon University, Cheongju, Chungbuk 361-742, Korea.
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17
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Saraei R, Marofi F, Naimi A, Talebi M, Ghaebi M, Javan N, Salimi O, Hassanzadeh A. Leukemia therapy by flavonoids: Future and involved mechanisms. J Cell Physiol 2018; 234:8203-8220. [PMID: 30500074 DOI: 10.1002/jcp.27628] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 09/25/2018] [Indexed: 12/11/2022]
Abstract
Flavonoids are a varied family of phytonutrients (plant chemicals) usually are detected in fruits and vegetables. In this big family, there exist more than 10,000 members that is separated into six chief subtypes: isoflavonols, flavonoenes, flavones, flavonols, anthocyanins, and chalcones. The natural compounds, such as fruits, have visible positive effects in regulating of survival involved signaling pathways that performance as the regulator of cell survival, growth, and proliferation. Researchers have established that commonly consumption up flavonoids decreases incidence and development risk of certain cancers, especially leukemia. Flavonoids have been able to induce apoptosis and stimulate cell cycle arrest in cancer cells via different pathways. Similarly, they have antiangiogenesis and antimetastasis capability, which were shown in wide ranges of cancer cells, particularly, leukemia. It seems that flavonoid because of their widespread approval, evident safety and low rate of side effects, have hopeful anticarcinogenic potential for leukemia therapy. Based on the last decade reports, the most important acting mechanisms of these natural compounds in leukemia cells are stimulating of apoptosis pathways by upregulation of caspase 3, 8, 9 and poly ADP-ribose polymerase (PARP) and proapoptotic proteins, particularly Bax activation. As well, they can induce cell cycle arrest in target cells not only via increasing of activated levels of p21 and p53 but also by inhibition of cyclins and cyclin-dependent kinases. Furthermore, attenuation of neclear factor-κB and signal transducer and activator of transcription 3 activation, suppression of signaling pathway and downregulation of intracellular antiapoptotic proteins are other significant antileukemic function mechanism of flavonoids. Overall, it appears that flavonoids are promising and effective compounds in the field of leukemia therapy. In this review, we tried to accumulate and revise most promising flavonoids and finally declared their major working mechanisms in leukemia cells.
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Affiliation(s)
- Raedeh Saraei
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Division of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faroogh Marofi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Division of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Adel Naimi
- Department of Immunology, Division of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Talebi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahnaz Ghaebi
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Naser Javan
- Department of Clinical Biochemistry and Laboratories Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Omid Salimi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Hassanzadeh
- Department of Immunology, Division of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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18
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p53 and glucose metabolism: an orchestra to be directed in cancer therapy. Pharmacol Res 2018; 131:75-86. [DOI: 10.1016/j.phrs.2018.03.015] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 02/23/2018] [Accepted: 03/20/2018] [Indexed: 12/14/2022]
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19
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Zhou M, Zheng J, Bi J, Wu X, Lyu J, Gao K. Synergistic inhibition of colon cancer cell growth by a combination of atorvastatin and phloretin. Oncol Lett 2018; 15:1985-1992. [PMID: 29399200 DOI: 10.3892/ol.2017.7480] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Accepted: 11/20/2017] [Indexed: 01/14/2023] Open
Abstract
Atorvastatin (ATST), a drug commonly used to reduce the levels of cholesterol and low-density lipoproteins, is a prospective agent for the prevention of colorectal cancer in patients with hyperlipidemia. ATST in combination with functional components is a promising strategy for cancer chemoprevention. In the present study, the growth inhibitory effect of ATST combined with phloretin (PT) on SW620 and HCT116 colon cancer cells was investigated. The results of MTT assays indicated that the combination of PT and ATST markedly reduced cell survival in both cell lines compared with PT or ATST treatment administered individually. The interaction indexes between PT and ATST, which were used to analyze their interaction pattern, were computed by the median-effect equation. The interaction indexes of each PT and ATST concentration pair were <1.0, which indicated a strong synergistic effect between the two compounds. The data obtained by flow cytometry and western blot analysis of cleaved-poly (ADP-ribose) polymerase indicated a synergistic effect resulted in apoptosis and cell cycle arrest at the G2/M checkpoint. Furthermore, combined treatment with PT and ATST markedly downregulated the expression of cyclin B and upregulated the expression of phospho-cdc2 and Myt1, which suggested that the activation of cdc2 was downregulated. This combined treatment strategy enhanced the anti-cancer activity of ATST at a relatively low dosage and suggested a possible method of preventing colorectal cancer in patients with hyperlipidemia.
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Affiliation(s)
- Mo Zhou
- Institute of Food Science and Technology, CAAS, Key Laboratory of Agro-Products Processing, Ministry of Agriculture, Beijing 100193, P.R. China
| | - Jinkai Zheng
- Institute of Food Science and Technology, CAAS, Key Laboratory of Agro-Products Processing, Ministry of Agriculture, Beijing 100193, P.R. China
| | - Jinfeng Bi
- Institute of Food Science and Technology, CAAS, Key Laboratory of Agro-Products Processing, Ministry of Agriculture, Beijing 100193, P.R. China
| | - Xinye Wu
- Institute of Food Science and Technology, CAAS, Key Laboratory of Agro-Products Processing, Ministry of Agriculture, Beijing 100193, P.R. China
| | - Jian Lyu
- Institute of Food Science and Technology, CAAS, Key Laboratory of Agro-Products Processing, Ministry of Agriculture, Beijing 100193, P.R. China
| | - Kun Gao
- Institute of Food Science and Technology, CAAS, Key Laboratory of Agro-Products Processing, Ministry of Agriculture, Beijing 100193, P.R. China
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20
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Wu KH, Ho CT, Chen ZF, Chen LC, Whang-Peng J, Lin TN, Ho YS. The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter. J Food Drug Anal 2018. [DOI: 10.1016/j.jfda.2017.03.009 pmid: 29389559] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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21
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Zhang MG, Lee JY, Gallo RA, Tao W, Tse D, Doddapaneni R, Pelaez D. Therapeutic targeting of oncogenic transcription factors by natural products in eye cancer. Pharmacol Res 2017; 129:365-374. [PMID: 29203441 DOI: 10.1016/j.phrs.2017.11.033] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 11/15/2017] [Accepted: 11/30/2017] [Indexed: 02/08/2023]
Abstract
Carcinogenesis has a multifactorial etiology, and the underlying molecular pathogenesis is still not entirely understood, especially for eye cancers. Primary malignant intraocular neoplasms are relatively rare, but delayed detection and inappropriate management contribute to poor outcomes. Conventional treatment, such as orbital exenteration, chemotherapy, or radiotherapy, alone results in high mortality for many of these malignancies. Recent sequential multimodal therapy with a combination of high-dose chemotherapy, followed by appropriate surgery, radiotherapy, and additional adjuvant chemotherapy has helped dramatically improve management. Transcription factors are proteins that regulate gene expression by modulating the synthesis of mRNA. Since transcription is a dominant control point in the production of many proteins, transcription factors represent key regulators for numerous cellular functions, including proliferation, differentiation, and apoptosis, making them compelling targets for drug development. Natural compounds have been studied for their potential to be potent yet safe chemotherapeutic drugs. Since the ancient times, plant-derived bioactive molecules have been used to treat dreadful diseases like cancer, and several refined pharmaceutics have been developed from these compounds. Understanding targeting mechanisms of oncogenic transcription factors by natural products can add to our oncologic management toolbox. This review summarizes the current findings of natural products in targeting specific oncogenic transcription factors in various types of eye cancer.
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Affiliation(s)
- Michelle G Zhang
- Dr Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - John Y Lee
- Dr Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Ryan A Gallo
- Dr Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Wensi Tao
- Dr Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - David Tse
- Dr Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Ravi Doddapaneni
- Dr Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
| | - Daniel Pelaez
- Dr Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Biomedical Engineering, University of Miami College of Engineering, Coral Gables, FL, 33146, USA.
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22
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Starkova J, Hermanova I, Hlozkova K, Hararova A, Trka J. Altered Metabolism of Leukemic Cells: New Therapeutic Opportunity. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2017; 336:93-147. [PMID: 29413894 DOI: 10.1016/bs.ircmb.2017.07.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The cancer metabolic program alters bioenergetic processes to meet the higher demands of tumor cells for biomass production, nucleotide synthesis, and NADPH-balancing redox homeostasis. It is widely accepted that cancer cells mostly utilize glycolysis, as opposed to normal cells, in which oxidative phosphorylation is the most employed bioenergetic process. Still, studies examining cancer metabolism had been overlooked for many decades, and it was only recently discovered that metabolic alterations affect both the oncogenic potential and therapeutic response. Since most of the published works concern solid tumors, in this comprehensive review, we aim to summarize knowledge about the metabolism of leukemia cells. Leukemia is a malignant disease that ranks first and fifth in cancer-related deaths in children and adults, respectively. Current treatment has reached its limits due to toxicity, and there has been a need for new therapeutic approaches. One of the possible scenarios is improved use of established drugs and another is to introduce new druggable targets. Herein, we aim to describe the complexity of leukemia metabolism and highlight cellular processes that could be targeted therapeutically and enhance the effectiveness of current treatments.
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Affiliation(s)
- Julia Starkova
- CLIP-Childhood Leukaemia Investigation Prague, Charles University, Prague, Czech Republic; Second Faculty of Medicine, Charles University, Prague, Czech Republic.
| | - Ivana Hermanova
- CLIP-Childhood Leukaemia Investigation Prague, Charles University, Prague, Czech Republic; Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Katerina Hlozkova
- CLIP-Childhood Leukaemia Investigation Prague, Charles University, Prague, Czech Republic; Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Alzbeta Hararova
- Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jan Trka
- CLIP-Childhood Leukaemia Investigation Prague, Charles University, Prague, Czech Republic; Second Faculty of Medicine, Charles University, Prague, Czech Republic; University Hospital Motol, Prague, Czech Republic
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Wu KH, Ho CT, Chen ZF, Chen LC, Whang-Peng J, Lin TN, Ho YS. The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter. J Food Drug Anal 2017; 26:221-231. [PMID: 29389559 PMCID: PMC9332637 DOI: 10.1016/j.jfda.2017.03.009] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 03/23/2017] [Accepted: 03/29/2017] [Indexed: 01/09/2023] Open
Abstract
Human triple-negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer. Glucose transporters (GLUTs) are required for glucose uptake in malignant cancer cells and are ideal targets for cancer therapy. To determine whether the inhibition of GLUTs could be used in TNBC cell therapy, the apple polyphenol phloretin (Ph) was used as a specific antagonist of GLUT2 protein function in human TNBC cells. Interestingly, we found that Ph (10–150 μM, for 24 h) inhibited cell growth and arrested the cell cycle in MDA-MB-231 cells in a p53 mutant-dependent manner, which was confirmed by pre-treatment of the cells with a p53-specific dominant-negative expression vector. We also found that Ph treatment (10–150 μM, for 24 h) significantly decreased the migratory activity of the MDA-MB-231 cells through the inhibition of paxillin/FAK, Src, and alpha smooth muscle actin (α-sMA) and through the activation of E-cadherin. Furthermore, the anti-tumorigenic effect of Ph (10, 50 mg/kg or DMSO twice a week for six weeks) was demonstrated in vivo using BALB/c nude mice bearing MDA-MB-231 tumor xenografts. A decrease in N-cadherin, vimentin and an increase in p53, p21 and E-cadherin were detected in the tumor tissues. In conclusion, inhibition of GLUT2 by the apple polyphenol Ph could potentially suppress TNBC tumor cell growth and metastasis.
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Affiliation(s)
- Kuan-Hsun Wu
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan; Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Chi-Tang Ho
- Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA
| | - Zhao-Feng Chen
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Li-Ching Chen
- Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan; Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
| | - Jacqueline Whang-Peng
- Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
| | - Teng-Nan Lin
- Institute of Biomedical Sciences, Academia Sinica, Taiwan.
| | - Yuan-Soon Ho
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan; School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
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24
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Lin ST, Tu SH, Yang PS, Hsu SP, Lee WH, Ho CT, Wu CH, Lai YH, Chen MY, Chen LC. Apple Polyphenol Phloretin Inhibits Colorectal Cancer Cell Growth via Inhibition of the Type 2 Glucose Transporter and Activation of p53-Mediated Signaling. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2016; 64:6826-6837. [PMID: 27538679 DOI: 10.1021/acs.jafc.6b02861] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Glucose transporters (GLUTs) are required for glucose uptake in malignant cells, and they can be used as molecular targets for cancer therapy. An RT-PCR analysis was performed to investigate the mRNA levels of 14 subtypes of GLUTs in human colorectal cancer (COLO 205 and HT-29) and normal (FHC) cells. RT-PCR (n = 27) was used to assess the differences in paired tissue samples (tumor vs normal) isolated from colorectal cancer patients. GLUT2 was detected in all tested cells. The average GLUT2 mRNA level in 12 of 27 (44.4%) cases was 2.4-fold higher in tumor compared to normal tissues (*, p = 0.027). Higher GLUT2 mRNA expression was preferentially detected in advanced-stage tumors (stage 0 vs 3 = 16.38-fold, 95% CI = 9.22-26.54-fold; *, p = 0.029). The apple polyphenol phloretin (Ph) and siRNA methods were used to inhibit GLUT2 protein expression. Ph (0-100 μM, for 24 h) induced COLO 205 cell growth cycle arrest in a p53-dependent manner, which was confirmed by pretreatment of the cells with a p53-specific dominant negative expression vector. Hepatocyte nuclear factor 6 (HNF6), which was previously reported to be a transcription factor that activates GLUT2 and p53, was also induced by Ph (0-100 μM, for 24 h). The antitumor effect of Ph (25 mg/kg or DMSO twice a week for 6 weeks) was demonstrated in vivo using BALB/c nude mice bearing COLO 205 tumor xenografts. In conclusion, targeting GLUT2 could potentially suppress colorectal tumor cell invasiveness.
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Affiliation(s)
- Sheng-Tsai Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital , New Taipei City, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan
| | - Shih-Hsin Tu
- TMU Taipei Cancer Center, Taipei Medical University , Taipei, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan
- Breast Medical Center, Taipei Medical University Hospital , Taipei, Taiwan
| | - Po-Sheng Yang
- Department of Surgery, Mackay Memorial Hospital , Taipei, Taiwan
- Department of Medicine, Mackay Medical College , New Taipei City, Taiwan
- Nursing and Management, Mackay Junior College of Medicine , Taipei, Taiwan
| | - Sung-Po Hsu
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan
- Graduate Institue of Medical Sciences, College of Medicine, Taipei Medical University , Taipei, Taiwan
| | - Wei-Hwa Lee
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan
- Department of Pathology, Taipei Medical University-Shuang Ho Hospital , Jhonghe City, Taiwan
| | - Chi-Tang Ho
- Department of Food Science, Rutgers University , New Brunswick, New Jersey 08901, United States
| | - Chih-Hsiung Wu
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan
- Department of Surgery, En Chu Kong Hospital , New Taipei City 237, Taiwan
| | - Yu-Hsin Lai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital , New Taipei City, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan
| | - Ming-Yao Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital , New Taipei City, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan
| | - Li-Ching Chen
- TMU Taipei Cancer Center, Taipei Medical University , Taipei, Taiwan
- Breast Medical Center, Taipei Medical University Hospital , Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan
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Pawłowska-Góral K, Kimsa-Dudek M, Synowiec-Wojtarowicz A, Orchel J, Glinka M, Gawron S. Effect of static magnetic fields and phloretin on antioxidant defense system of human fibroblasts. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2016; 23:14989-14996. [PMID: 27080405 PMCID: PMC4956710 DOI: 10.1007/s11356-016-6653-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 04/05/2016] [Indexed: 06/05/2023]
Abstract
The available evidence from in vitro and in vivo studies is deemed not sufficient to draw conclusions about the potential health effects of static magnetic field (SMF) exposure. Therefore, the aim of the present study was to determine the influence of static magnetic fields and phloretin on the redox homeostasis of human dermal fibroblasts. Control fibroblasts and fibroblasts treated with phloretin were subjected to the influence of static magnetic fields. Three chambers with static magnetic fields of different intensities (0.4, 0.55, and 0.7 T) were used in the study. Quantification of superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), glutathione peroxidase 1 (GPX1), microsomal glutathione S-transferase 1 (MGST1), glutathione reductase (GSR), and catalase (CAT) messenger RNAs (mRNAs) was performed by means of real-time reverse transcription PCR (QRT-PCR) technique. Superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activities were measured using a commercially available kit. No significant differences were found in SOD1, SOD2, GPX1, MGST1, GSR, and CAT mRNA levels among the studied groups in comparison to the control culture without phloretin and without the magnet. There were also no changes in SOD, GPx, and CAT activities. In conclusion, our study indicated that static magnetic fields generated by permanent magnets do not exert a negative influence on the oxidative status of human dermal fibroblasts. Based on these studies, it may also be concluded that phloretin does not increase its antioxidant properties under the influence of static magnetic fields. However, SMF-induced modifications at the cellular and molecular level require further clarification.
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Affiliation(s)
- Katarzyna Pawłowska-Góral
- Department of Food and Nutrition, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Jednosci 8, 41-200, Sosnowiec, Poland
| | - Magdalena Kimsa-Dudek
- Department of Food and Nutrition, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Jednosci 8, 41-200, Sosnowiec, Poland.
| | - Agnieszka Synowiec-Wojtarowicz
- Department of Food and Nutrition, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Jednosci 8, 41-200, Sosnowiec, Poland
| | - Joanna Orchel
- Department of Molecular Biology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Jednosci 8, 41-200, Sosnowiec, Poland
| | - Marek Glinka
- Institute of Electrical Drives and Machines KOMEL, 188 Rozdzienskiego Street, 40-203, Katowice, Poland
| | - Stanisław Gawron
- Institute of Electrical Drives and Machines KOMEL, 188 Rozdzienskiego Street, 40-203, Katowice, Poland
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Inhibition of Ovalitenin A on Proliferation of HeLa Cells via Apoptosis, G2/M Cell Cycle Arrest, and Down-regulation of COX-2. CHINESE HERBAL MEDICINES 2016. [DOI: 10.1016/s1674-6384(16)60048-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Chen P, Bai P, Luo G, Su H, Shen R, Liu Z, Zhang N, Fang L, Liu C. Role of Anti-apoptotic Activity of Antioxidants in Conferring Protection Against Prostate Cancer. INT J PHARMACOL 2016. [DOI: 10.3923/ijp.2016.304.316] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Rana S, Bhushan S. Apple phenolics as nutraceuticals: assessment, analysis and application. JOURNAL OF FOOD SCIENCE AND TECHNOLOGY 2016; 53:1727-38. [PMID: 27413201 PMCID: PMC4926896 DOI: 10.1007/s13197-015-2093-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Revised: 09/20/2015] [Accepted: 11/03/2015] [Indexed: 01/08/2023]
Abstract
Humankind is presently engulfed by convenience quench, modern life style and urbanized diet system leading to progression in array of health disorders. The past decade confronted cardiometabolic disorder (21.8 %), lower respiratory and chronic obstructive lung disease (12.5 %) as the major causes of death world over. In anticipation, scientific communities' have demonstrated the role of healthy diets, especially those rich in fruits and vegetables, for management of such health related issues. These horticultural crops are considered as a good source of polyphenols such as dihydrochalcones, flavanols, flavonols, anthocyanins and phenolic acids. The present article reviews the efforts made to assess the potential of apple phenolic compounds present in fresh fruits, leaves, bark and pomace as dietary polyphenols. Considering the positive impact of such phytochemicals on human health, various nutraceuticals, dietary supplements and phenolic-rich food products are presently available on market shelves. On analytical front, improved instrumentation based on liquid chromatography (HPLC, UPLC, LC/MS/MS) have made the assessment of phenolics more rapid and reliable. Thus, owing to the emergent interest in natural compounds, it is pertinent to discuss the latest significant research findings on therapeutic aspects along with probable metabolic mechanisms of dietary polyphenols found in apples and their implications on human health.
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Affiliation(s)
- Shalika Rana
- />Academy of Scientific and Innovative Research, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176061 India
- />Division of Biotechnology, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176061 India
| | - Shashi Bhushan
- />Academy of Scientific and Innovative Research, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176061 India
- />Division of Biotechnology, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176061 India
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de Oliveira MR. Phloretin-induced cytoprotective effects on mammalian cells: A mechanistic view and future directions. Biofactors 2016; 42:13-40. [PMID: 26826024 DOI: 10.1002/biof.1256] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 11/19/2015] [Indexed: 11/11/2022]
Abstract
Phloretin (C15 H14 O5 ), a dihydrochalcone flavonoid, is mainly found in fruit, leaves, and roots of apple tree. Phloretin exerts antioxidant, anti-inflammatory, and anti-tumor activities in mammalian cells through mechanisms that have been partially elucidated throughout the years. Phloretin bioavailability is well known in humans, but still remains to be better studied in experimental animals, such as mouse and rat. The focus of the present review is to gather information regarding the mechanisms involved in the phloretin-elicited effects in different in vitro and in vivo experimental models. Several manuscripts were analyzed and data raised by authors were described and discussed here in a mechanistic manner. Comparisons between the effects elicited by phloretin and phloridzin were made whenever possible, as well as with other polyphenols, clarifying questions about the use of phloretin as a potential therapeutic agent. Toxicological aspects associated to phloretin exposure were also discussed here. Furthermore, a special section containing future directions was created as a suggestive guide towards the elucidation of phloretin-related actions in mammalian cells and tissues.
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Affiliation(s)
- Marcos Roberto de Oliveira
- Department of Chemistry/ICET, Postgraduate Program in Chemistry (PPGQ), Federal University of Mato Grosso (UFMT), CEP, Cuiaba, MT, Brazil
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Ye CL, Lai YF. 2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone, from buds of Cleistocalyx operculatus, induces apoptosis in human hepatoma SMMC-7721 cells through a reactive oxygen species-dependent mechanism. Cytotechnology 2014; 68:331-41. [PMID: 25260543 DOI: 10.1007/s10616-014-9786-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Accepted: 09/13/2014] [Indexed: 12/31/2022] Open
Abstract
Nowadays, much effort is being devoted to detect new substances that not only significantly induce the death of tumor cells, but also have little side effect on normal cells. Our previous study showed that 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) exhibited significant cytotoxic potential with an IC50 value of 32.3 ± 1.13 μM against SMMC-7721 cells and could induce SMMC-7721 cells apoptosis. In the present study, we found that DMC was almost nontoxic to human normal liver L-02 and human normal fetal lung fibroblast HFL-1 cells as their IC50 values (111.0 ± 4.57 and 152.0 ± 4.83 µM for L-02 and HFL-1 cells, respectively) were much higher. To further explore the apoptotic mechanism of DMC, we investigated the role of the reactive oxygen species (ROS) in the apoptosis induced by DMC in SMMC-7721 cells. Our results suggested that the cytotoxicity and the generation of intracellular ROS were inhibited by N-acetylcysteine (NAC). Reversal of apoptosis in NAC pretreated cells indicated the involvement of ROS in DMC-induced apoptosis. The loss of mitochondrial membrane potential (ΔΨm) induced by DMC was significantly blocked by NAC. NAC also prevented the decrease of Caspase-3 and -9 activities, the increase of Bcl-2 protein expression and the decrease of p53 and PUMA protein expressions. Together, these results indicated that ROS played a key role in the apoptosis induced by DMC in human hepatoma SMMC-7721 cells.
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Affiliation(s)
- Chun-Lin Ye
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, 310023, People's Republic of China.
| | - Yi-Feng Lai
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, 310023, People's Republic of China
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Qian Y, Wang X, Chen X. Inhibitors of glucose transport and glycolysis as novel anticancer therapeutics. World J Transl Med 2014; 3:37-57. [DOI: 10.5528/wjtm.v3.i2.37] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 03/25/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Metabolic reprogramming and altered energetics have become an emerging hallmark of cancer and an active area of basic, translational, and clinical cancer research in the recent decade. Development of effective anticancer therapeutics may depend on improved understanding of the altered cancer metabolism compared to that of normal cells. Changes in glucose transport and glycolysis, which are drastically upregulated in most cancers and termed the Warburg effect, are one of major focuses of this new research area. By taking advantage of the new knowledge and understanding of cancer’s mechanisms, numerous therapeutic agents have been developed to target proteins and enzymes involved in glucose transport and metabolism, with promising results in cancer cells, animal tumor models and even clinical trials. It has also been hypothesized that targeting a pathway or a process, such as glucose transport or glucose metabolism, rather than a specific protein or enzyme in a signaling pathway may be more effective. This is based on the observation that cancer somehow can always bypass the inhibition of a target drug by switching to a redundant or compensatory pathway. In addition, cancer cells have higher dependence on glucose. This review will provide background information on glucose transport and metabolism in cancer, and summarize new therapeutic developments in basic and translational research in these areas, with a focus on glucose transporter inhibitors and glycolysis inhibitors. The daunting challenges facing both basic and clinical researchers of the field are also presented and discussed.
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Anand MAV, Suresh K. Biochemical profiling and chemopreventive activity of phloretin on 7,12-Dimethylbenz (a) anthracene induced oral carcinogenesis in male golden Syrian hamsters. Toxicol Int 2014; 21:179-85. [PMID: 25253928 PMCID: PMC4170560 DOI: 10.4103/0971-6580.139805] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES The present study was designed to examine the chemopreventive effects of phloretin against 7, 12-dimethylbenz (a) anthracene (DMBA) induced buccal pouch carcinogenesis in male golden Syrian hamsters in order to discover resources to improve the traditional medicine. MATERIALS AND METHODS Hamsters were divided into four groups of 10 animals each. Group I was served as an untreated control. Group II hamsters were painted with 0.5% DMBA in liquid paraffin on the left buccal pouches three times a week for 14 weeks. Group III hamsters were orally administrated with phloretin at a dose of 40 mg/kg body Weight (b.wt) on days alternate to DMBA application. Group IV hamsters were orally administrated with phloretin alone and served as the drug control. The experiment was terminated at the end of fourteenth week. The experimental animal's tumors were subjected into morphological examination and subsequently screened the pathological changes and estimate the activities of bi-products of lipid peroxidation, antioxidants enzymes and phase I and II detoxification enzyme status. RESULTS In DMBA alone treated hamster showed increased levels of lipid peroxidation by products, leads to decreased levels of enzymatic and non-enzymatic antioxidants status, activities of phase I and II detoxification enzyme status were altered. Normalized the neoplastic changes, decreased the levels of lipid by products, retain the antioxidants and restored the phase I and II enzymes were observed in phloretin administrated animals during DMBA induced oral carcinogenesis. CONCLUSION Phloretin has possible chemopreventive role in which modulating the antioxidant and detoxification enzyme status, thereby retarding DMBA induced buccal pouch carcinogenesis.
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Affiliation(s)
- M. Arokia Vijaya Anand
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Tamil Nadu, India
| | - K. Suresh
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Tamil Nadu, India
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Talekar M, Boreddy SR, Singh A, Amiji M. Tumor aerobic glycolysis: new insights into therapeutic strategies with targeted delivery. Expert Opin Biol Ther 2014; 14:1145-59. [PMID: 24762115 DOI: 10.1517/14712598.2014.912270] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Cancer cells acclimatize to the harsh tumor microenvironment by altering cellular metabolism in favor of aerobic glycolysis. This process provides a source of energy and also generates essential components for macromolecular biosynthesis, which enables cellular survival. As the dependence of cancer cells on glycolysis affects tumorigenesis, it has become an attractive target for therapeutic intervention. Several preclinical studies have shown the effectiveness of using biological targets from the glycolytic pathway for anticancer therapy. AREAS COVERED This review provides an insight into the glycolytic pathway, highlighting potential targets for glycolytic inhibition. We then discuss recent advancement in delivery strategies that have the potential to circumvent some of the problems posed by current glycolytic inhibitors, enabling resurrection of abandoned therapeutic agents. EXPERT OPINION Targeting the glycolysis pathway is a tactical approach for cancer therapy. However, the current nonspecific therapeutic strategies have several drawbacks such as poor bioavailability, unfavorable pharmacokinetic profile and associated nonspecific toxicity, thereby limiting preclinical investigation. In recent years, nanoparticle systems have received recognition for the delivery of therapeutic agents directly to the tumor tissue. Thus, it is envisaged that this strategy can be expanded for the delivery of current glycolytic inhibitors specifically to tumor tissues providing improved anticancer activity.
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Affiliation(s)
- Meghna Talekar
- Northeastern University, Pharmaceutical Sciences , 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115 , USA
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34
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Lin C, Wang L, Wang H, Fang S, Zhang Q, Yang L, Guo H, Lin P, Zhang J, Wang X. Lithocarpus Polystachyus Rehd Leaf Aqueous Extract Inhibits Human Breast Cancer Growth In Vitro and In Vivo. Nutr Cancer 2014; 66:613-24. [DOI: 10.1080/01635581.2014.894094] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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35
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Bindu PJ, Mahadevan KM, Naik TRR, Harish BG. Synthesis, DNA binding, docking and photocleavage studies of quinolinyl chalcones. MEDCHEMCOMM 2014. [DOI: 10.1039/c4md00185k] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
A series of simple quinoline–chalcone conjugates have been synthesized and evaluated for their nucleolytic activity. The compounds 3c and 3d exhibited promising DNA binding and DNA photocleavage studies.
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Affiliation(s)
- P. J. Bindu
- Department of Studies and Research in Chemistry
- Kuvempu University
- , India
| | - K. M. Mahadevan
- Department of Studies and Research in Chemistry
- Kuvempu University
- , India
| | - T. R. Ravikumar Naik
- Department of Center of Nano Science and Engineering
- Indian Institute of Science
- Bangalore 560 012, India
| | - B. G. Harish
- Department of Biotechnology
- M.S. Ramaiah Institute of Technology
- Bengaluru, India
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36
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Lin CC, Chu CL, Ng CS, Lin CY, Chen DY, Pan IH, Huang KJ. Immunomodulation of phloretin by impairing dendritic cell activation and function. Food Funct 2014; 5:997-1006. [DOI: 10.1039/c3fo60548e] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Stompor M, Potaniec B, Szumny A, Zieliński P, Żołnierczyk AK, Anioł M. Microbial synthesis of dihydrochalcones using Rhodococcus and Gordonia species. ACTA ACUST UNITED AC 2013. [DOI: 10.1016/j.molcatb.2013.09.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Huang AC, Wilde A, Ebmeyer J, Skouroumounis GK, Taylor DK. Examination of the phenolic profile and antioxidant activity of the leaves of the Australian native plant Smilax glyciphylla. JOURNAL OF NATURAL PRODUCTS 2013; 76:1930-1936. [PMID: 24050300 DOI: 10.1021/np4005163] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Together with the sweet principle component glycyphyllin A (3), seven phenolic compounds including two new dihydrochalcone rhamnopyranosides, glycyphyllin B (1) and glycyphyllin C (2), and five known flavonoids, catechin (4), kaempferol-3-O-β-D-glucopyranoside (5), quercetin-3-O-β-D-glucopyranoside (6), kaempferol-3-O-β-neohesperidoside (7), and 2R,3R-dihydrokaempferol-3-O-β-D-glucopyranoside (8), have been isolated from the ethanolic extract of the leaves of Smilax glyciphylla for the first time. The structures of these compounds were characterized by spectroscopic methods including UV, MS, and 1D and 2D NMR. In vitro antioxidant capacity tests employing FRAP and DPPH assays indicated that 1, 4, and 6 exhibited potent antioxidant activity and are the key phenolics responsible for the antioxidant activity of the leaf extract of S. glyciphylla.
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Affiliation(s)
- An-Cheng Huang
- School of Agriculture, Food and Wine, The University of Adelaide , Waite Campus, Urrbrae 5064, Adelaide, South Australia, Australia
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Induction of apoptosis in human hepatoma SMMC-7721 cells using 2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone, a chalcone from buds of Cleistocalyx operculatus. Food Sci Biotechnol 2013. [DOI: 10.1007/s10068-013-0232-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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40
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Regioselective monobromination of (E)-1-(2′-hydroxy-4′,6′-dimethoxyphenyl)-3-aryl-2-propen-1-ones using bromodimethylsulfonium bromide and synthesis of 8-bromoflavones and 7-bromoaurones. Tetrahedron Lett 2012. [DOI: 10.1016/j.tetlet.2012.06.122] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Shin JW, Kundu JK, Surh YJ. Phloretin inhibits phorbol ester-induced tumor promotion and expression of cyclooxygenase-2 in mouse skin: extracellular signal-regulated kinase and nuclear factor-κB as potential targets. J Med Food 2011; 15:253-7. [PMID: 22181070 DOI: 10.1089/jmf.2011.1851] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The present study investigated the effect of phloretin [2',4',6'-trihydroxy-3-(4-hydroxyphenyl)-propiophenone] on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and explored the underlying molecular mechanisms. Topical application of phloretin significantly inhibited 7,12-dimethylbenz[a]anthracene-initiated and TPA-promoted mouse skin carcinogenesis. Pretreatment with phloretin on the dorsal skin of mice inhibited TPA-induced COX-2 expression in a dose-dependent manner. To elucidate the molecular mechanism underlying COX-2 inhibition by phloretin, we examined its effect on TPA-induced activation of nuclear factor-κB (NF-κB), a ubiquitous transcription factor responsible for TPA-induced COX-2 expression in mouse skin. Topically applied phloretin decreased the TPA-induced DNA binding of NF-κB. In addition, phloretin inhibited the phosphorylation as well as the catalytic activity of extracellular signal-regulated kinase (ERK), which was previously found to activate NF-κB and induce COX-2 expression in TPA-treated mouse skin. Taken together, the inhibitory effects of phloretin on TPA-induced NF-κB activation and COX-2 expression through the modulation of ERK signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis.
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Affiliation(s)
- Jun-Wan Shin
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
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Tada KI, Kawahara KI, Matsushita S, Hashiguchi T, Maruyama I, Kanekura T. MK615, a Prunus mume Steb. Et Zucc ('Ume') extract, attenuates the growth of A375 melanoma cells by inhibiting the ERK1/2-Id-1 pathway. Phytother Res 2011; 26:833-8. [PMID: 22076920 DOI: 10.1002/ptr.3645] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Revised: 07/14/2011] [Accepted: 07/14/2011] [Indexed: 01/13/2023]
Abstract
The Japanese apricot, a commonly consumed food called 'Ume' in Japan, has been used for a traditional Japanese medicine for centuries. MK615, an extract of compounds from 'Ume', has strong antitumorigenic and antiinflammatory effects including the induction of apoptosis and autophagy, and inhibition of cytokine production mediated via the inhibition of MAPKs signaling including ERK-1/2, JNK and p38MAPK. The inhibitor of DNA binding 1 (Id-1), a basic helix-loop-helix (bHLH) transcription factor family, is essential for DNA binding and the transcriptional regulation of various proteins that play important roles in the development, progression and invasion of tumors. In melanoma, Id-1 is constitutively expressed in the late and early stages, suggesting it as a therapeutic target in patients with melanoma. This study reports that MK615 profoundly reduced both the mRNA- and protein expression levels of Id-1 and inhibited cell growth in A375 melanoma cells. MK615 markedly inhibited the phosphorylation of ERK1/2, which is associated with Id-1 protein expression in A375 cells. Id-1-specific RNAi induced the death of A375 cells. Moreover, the expression of Bcl-2 was decreased by both MK615 and Id-1-specific RNAi in A375 cells. The results suggest that MK615 is a potential therapeutic agent for treating malignant melanoma.
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Affiliation(s)
- Ko-ichi Tada
- Department of Dermatology, Cardiovascular and Respiratory Disorders Advanced Therapeutics, Kagoshima University, Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
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Acceleration of germination of super-hard rice cultivar EM10 by soaking with red onion. Biosci Biotechnol Biochem 2011; 75:572-4. [PMID: 21389608 DOI: 10.1271/bbb.100621] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Red onion accelerated the germination of rice seeds and inhibited microbial infestation during germination. After germination with red onion for 16 h at 35 °C, super-hard rice EM10 showed a higher germination ratio (2.3 times), and it contained more GABA (2.3 times) and glucose (2.9 times) than that soaked without onion. Due to soaking with red onion, germinated EM10 was fortified with quercetin (18 mg/100 g).
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Pedrini FS, Chiaradia LD, Licínio MA, de Moraes ACR, Curta JC, Costa A, Mascarello A, Creczinsky-Pasa TB, Nunes RJ, Yunes RA, Santos-Silva MC. Induction of apoptosis and cell cycle arrest in L-1210 murine lymphoblastic leukaemia cells by (2E)-3-(2-naphthyl)-1-(3'-methoxy-4'-hydroxy-phenyl)-2-propen-1-one. J Pharm Pharmacol 2011; 62:1128-36. [PMID: 20796191 DOI: 10.1111/j.2042-7158.2010.01141.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVES New compounds with biological targets and less cytotoxicity to normal cells are necessary for cancer therapy. In this work ten synthetic chalcones derived from 2-naphtaldehyde were evaluated for their cytotoxic effect in murine acute lymphoblastic leukemia cells L-1210. METHODS A series of ten chalcones derived from 2-naphtaldehyde and corresponding acetophenones were prepared by aldolic condensation, using methanol as solvent under basic conditions, at room temperature for 24 h. The cell viability was determined by MTT colorimeter method. The cell cycle phase analysis was carried out by flow cytometry after propidium iodide staining. The apoptosis induction was assessed by exposure to phosphatidylserine (ANNEXIN V-FITC). Cytometric analysis was performed to evaluate the expression of p53, Bcl-2 and Bax protein. The caspase-3 expression was studied by immunoblotting analysis. KEY FINDINGS A preliminary screening of a series of ten chalcones derived from 2-naphtaldehyde showed that chalcone 8, (2E)-3-(2-naphtyl)-1-(3'-methoxy-4'-hydroxy-phenyl)-2-propen-1-one, had the highest cytotoxic effect (IC50 of 54 microM), but not in normal human lymphocytes. To better understand the cytotoxic mechanism of chalcone 8, its effect on cell cycle and apoptosis was assessed. Our results showed that chalcone 8 caused cell cycle arrest in the G2/M phase and a significant increase in the proportion of cells in the subG0/G1 phase. Our results also demonstrated that chalcone 8 promoted a modification in Bax:Bcl-2 ratio and increased p53 expression and caspase-3 activation. CONCLUSIONS The studied chalcone 8 has cytotoxic effect against L-1210 lymphoblastic leukaemic cells, and this effect is associated with increase of p-53 and Bax expression.
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Affiliation(s)
- Fernanda Spezia Pedrini
- Departamento de Análises Clínicas, Universidade Federal de Santa Catarina, Campus Trindade, Florianópolis, Brasil
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Garg NK, Mangal S, Sahu T, Mehta A, Vyas SP, Tyagi RK. Evaluation of anti-apoptotic activity of different dietary antioxidants in renal cell carcinoma against hydrogen peroxide. Asian Pac J Trop Biomed 2011; 1:57-63. [PMID: 23569726 PMCID: PMC3609144 DOI: 10.1016/s2221-1691(11)60069-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2010] [Revised: 09/27/2010] [Accepted: 10/15/2010] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE To evaluate the anti-apoptotic and radical scavenging activities of dietary phenolics, namely ascorbic acid,α-tocopherol acetate, citric acid, salicylic acid, and estimate H2O2-induced apoptosis in renal cell carcinoma cells. METHODS The intracellular antioxidant potency of antioxidants was investigated. H2O2-induced apoptosis in RCC-26 was assayed with the following parameters: cell viability (% apoptosis), nucleosomal damage and DNA fragmentation, bcl-2 levels and flow cytometery analysis (ROS production evaluation). RESULTS The anticancer properties of antioxidants such as ascorbic acid, α-tocopherol acetate, citric acid, salicylic acid with perdurable responses were investigated. It was observed that these antioxidants had protective effect (anti-apoptotic activity) against hydrogen peroxide (H2O2) in renal cell carcinoma (RCC-26) cell line. CONCLUSIONS This study reveals and proves the anticancer properties. However, in cancer cell lines anti-apoptotic activity can indirectly reflect the cancer promoter activity through radicals scavenging, and significantly protect nucleus and bcl-2.
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Affiliation(s)
- Neeraj K Garg
- Department of Pharmaceutical Sciences, Dr. H. S. Gour University, Sagar, (M.P.), India
| | - Sharad Mangal
- Department of Pharmaceutical Sciences, Dr. H. S. Gour University, Sagar, (M.P.), India
| | - Tejram Sahu
- Biologie et génétiqjue du paludisme, Institut Pasteur, 28 Rue Du Docteur Roux, 75724 Paris Cedex 15, France
| | - Abhinav Mehta
- Department of Pharmaceutical Sciences, Dr. H. S. Gour University, Sagar, (M.P.), India
| | - Suresh P Vyas
- Department of Pharmaceutical Sciences, Dr. H. S. Gour University, Sagar, (M.P.), India
| | - Rajeev K Tyagi
- Biomedical Parasitology Unit, Pasteur Institute, 25-28 Rue Du Dr Roux, 75724 Paris Cedex 15, France
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Kim MS, Kwon JY, Kang NJ, Lee KW, Lee HJ. Phloretin Induces Apoptosis in H-Ras MCF10A Human Breast Tumor Cells through the Activation of p53 via JNK and p38 Mitogen-Activated Protein Kinase Signaling. Ann N Y Acad Sci 2009; 1171:479-83. [DOI: 10.1111/j.1749-6632.2009.04692.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Controlling transgene expression in subcutaneous implants using a skin lotion containing the apple metabolite phloretin. Proc Natl Acad Sci U S A 2009; 106:10638-43. [PMID: 19549857 DOI: 10.1073/pnas.0901501106] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Adjustable control of therapeutic transgenes in engineered cell implants after transdermal and topical delivery of nontoxic trigger molecules would increase convenience, patient compliance, and elimination of hepatic first-pass effect in future therapies. Pseudomonas putida DOT-T1E has evolved the flavonoid-triggered TtgR operon, which controls expression of a multisubstrate-specific efflux pump (TtgABC) to resist plant-derived defense metabolites in its rhizosphere habitat. Taking advantage of the TtgR operon, we have engineered a hybrid P. putida-mammalian genetic unit responsive to phloretin. This flavonoid is contained in apples, and, as such, or as dietary supplement, regularly consumed by humans. The engineered mammalian phloretin-adjustable control element (PEACE) enabled adjustable and reversible transgene expression in different mammalian cell lines and primary cells. Due to the short half-life of phloretin in culture, PEACE could also be used to program expression of difficult-to-produce protein therapeutics during standard bioreactor operation. When formulated in skin lotions and applied to the skin of mice harboring transgenic cell implants, phloretin was able to fine-tune target genes and adjust heterologous protein levels in the bloodstream of treated mice. PEACE-controlled target gene expression could foster advances in biopharmaceutical manufacturing as well as gene- and cell-based therapies.
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Yang KC, Tsai CY, Wang YJ, Wei PL, Lee CH, Chen JH, Wu CH, Ho YS. Apple polyphenol phloretin potentiates the anticancer actions of paclitaxel through induction of apoptosis in human hep G2 cells. Mol Carcinog 2009; 48:420-31. [PMID: 18767070 DOI: 10.1002/mc.20480] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Phloretin (Ph), which can be obtained from apples, apple juice, and cider, is a known inhibitor of the type II glucose transporter (GLUT2). In this study, real-time PCR analysis of laser-capture microdissected (LCM) human hepatoma cells showed elevated expression (>5-fold) of GLUT2 mRNA in comparison with nonmalignant hepatocytes. In vitro and in vivo studies were performed to assess Ph antitumor activity when combined with paclitaxel (PTX) for treatment of human liver cancer cells. Inhibition of GLUT2 by Ph potentiated the anticancer effects of PTX, resensitizing human liver cancer cells to drugs. These results demonstrate that 50-150 microM Ph significantly potentiates DNA laddering induced in Hep G2 cells by 10 nM PTX. Activity assays showed that caspases 3, 8, and 9 are involved in this apoptosis. The antitumor therapeutic efficacy of Ph (10 mg/kg body weight) was determined in cells of the SCID mouse model that were treated in parallel with PTX (1 mg/kg body weight). The Hep G2-xenografted tumor volume was reduced more than fivefold in the Ph + PTX-treated mice compared to the PTX-treated group. These results suggest that Ph may be useful for cancer chemotherapy and chemoprevention.
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Affiliation(s)
- Kuo-Ching Yang
- Division of Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, School of Medicine, Taipei Medical University, Taipei, Taiwan
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Structural antitumoral activity relationships of synthetic chalcones. Int J Mol Sci 2009; 10:221-231. [PMID: 19333443 PMCID: PMC2662465 DOI: 10.3390/ijms10010221] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2008] [Revised: 12/31/2008] [Accepted: 01/04/2009] [Indexed: 11/17/2022] Open
Abstract
Relationships between the structural characteristic of synthetic chalcones and their antitumoral activity were studied. Treatment of HepG2 cells for 24 h with synthetic 2’-hydroxychalcones resulted in apoptosis induction and dose-dependent inhibition of cell proliferation. The calculated reactivity indexes and the adiabatic electron affinities using the DFT method including solvent effects, suggest a structure-activity relationship between the Chalcones structure and the apoptosis in HepG2 cells. The absence of methoxy substituents in the B ring of synthetic 2’-hydroxychalcones, showed the mayor structure-activity pattern along the series.
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