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1
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Estrogenic flavonoids and their molecular mechanisms of action. J Nutr Biochem 2023; 114:109250. [PMID: 36509337 DOI: 10.1016/j.jnutbio.2022.109250] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/02/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022]
Abstract
Flavonoids are a major group of phytoestrogens associated with physiological effects, and ecological and social impacts. Although the estrogenic activity of flavonoids was reported by researchers in the fields of medical, environmental and food studies, their molecular mechanisms of action have not been comprehensively reviewed. The estrogenic activity of the respective classes of flavonoids, anthocyanidins/anthocyanins, 2-arylbenzofurans/3-arylcoumarins/α-methyldeoxybenzoins, aurones/chalcones/dihydrochalcones, coumaronochromones, coumestans, flavans/flavan-3-ols/flavan-4-ols, flavanones/dihydroflavonols, flavones/flavonols, homoisoflavonoids, isoflavans, isoflavanones, isoflavenes, isoflavones, neoflavonoids, oligoflavonoids, pterocarpans/pterocarpenes, and rotenone/rotenoids, was summarized through a comprehensive literature search, and their structure-activity relationship, biological activities, signaling pathways, and applications were discussed. Although the respective classes of flavonoids contained at least one chemical mimicking estrogen, the mechanisms varied, such as those with estrogenic, anti-estrogenic, non-estrogenic, and biphasic activities, and additional activities through crosstalk/bypassing, which exert biological activities through cell signaling pathways. Such mechanistic variations of estrogen action are not limited to flavonoids and are observed among other broad categories of chemicals, thus this group of chemicals can be termed as the "estrogenome". This review article focuses on the connection of estrogen action mainly between the outer and the inner environments, which represent variations of chemicals and biological activities/signaling pathways, respectively, and form the basis to understand their applications. The applications of chemicals will markedly progress due to emerging technologies, such as artificial intelligence for precision medicine, which is also true of the study of the estrogenome including estrogenic flavonoids.
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2
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Mitra S, Dash R, Sohel M, Chowdhury A, Munni YA, Ali C, Hannan MA, Islam T, Moon IS. Targeting Estrogen Signaling in the Radiation-induced Neurodegeneration: A Possible Role of Phytoestrogens. Curr Neuropharmacol 2023; 21:353-379. [PMID: 35272592 PMCID: PMC10190149 DOI: 10.2174/1570159x20666220310115004] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/01/2022] [Accepted: 03/06/2022] [Indexed: 11/22/2022] Open
Abstract
Radiation for medical use is a well-established therapeutic method with an excellent prognosis rate for various cancer treatments. Unfortunately, a high dose of radiation therapy comes with its own share of side effects, causing radiation-induced non-specific cellular toxicity; consequently, a large percentage of treated patients suffer from chronic effects during the treatment and even after the post-treatment. Accumulating data evidenced that radiation exposure to the brain can alter the diverse cognitive-related signaling and cause progressive neurodegeneration in patients because of elevated oxidative stress, neuroinflammation, and loss of neurogenesis. Epidemiological studies suggested the beneficial effect of hormonal therapy using estrogen in slowing down the progression of various neuropathologies. Despite its primary function as a sex hormone, estrogen is also renowned for its neuroprotective activity and could manage radiation-induced side effects as it regulates many hallmarks of neurodegenerations. Thus, treatment with estrogen and estrogen-like molecules or modulators, including phytoestrogens, might be a potential approach capable of neuroprotection in radiation-induced brain degeneration. This review summarized the molecular mechanisms of radiation effects and estrogen signaling in the manifestation of neurodegeneration and highlighted the current evidence on the phytoestrogen mediated protective effect against radiationinduced brain injury. This existing knowledge points towards a new area to expand to identify the possible alternative therapy that can be taken with radiation therapy as adjuvants to improve patients' quality of life with compromised cognitive function.
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Affiliation(s)
- Sarmistha Mitra
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju38066, Republic of Korea
| | - Raju Dash
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju38066, Republic of Korea
| | - Md. Sohel
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail-1902, Bangladesh
| | - Apusi Chowdhury
- Department of Pharmaceutical Science, North-South University, Dhaka-12 29, Bangladesh
| | - Yeasmin Akter Munni
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju38066, Republic of Korea
| | - Chayan Ali
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala SE-751 08, Sweden
| | - Md. Abdul Hannan
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh-2202, Bangladesh
| | - Tofazzal Islam
- Institute of Biotechnology and Genetic Engineering (IBGE), Bangabandhu Sheikh Mujibur Rahman Agricultural University (BSMRAU), Gazipur, Bangladesh
| | - Il Soo Moon
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju38066, Republic of Korea
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3
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Farabegoli F, Granja A, Magalhães J, Purgato S, Voltattorni M, Pinheiro M. Epigallocatechin-3-gallate Delivered in Nanoparticles Increases Cytotoxicity in Three Breast Carcinoma Cell Lines. ACS OMEGA 2022; 7:41872-41881. [PMID: 36440117 PMCID: PMC9685782 DOI: 10.1021/acsomega.2c01829] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 07/15/2022] [Indexed: 06/16/2023]
Abstract
The anticancer activity of epigallocatechin-3-gallate (EGCG), orally administrated, is limited by poor bioavailability, absorption, and unpredictable distribution in human tissues. EGCG charged nanoparticles may represent an opportunity to overcome these limitations. We assayed two different kinds of lipid nanoparticles (LNPs and LNPs functionalized with folic acid) charged with EGCG on three breast carcinoma cell lines (MCF-7, MDA-MB-231, and MCF-7TAM) and the human normal MCF10A mammary epithelial cells. Both LNPs loaded with EGCG, at low concentrations, induced a significant cytotoxicity in the three breast carcinoma cells but not in MCF10A cells. In view of a future application, both LNPs and LNPs-FA were found to be very suitable for in vitro studies and useful to improve EGCG administration in vivo. Since they are produced by inexpensive procedures using bioavailable, biocompatible, and biodegradable molecules, they represent an applicable tool for a more rationale use of EGCG as an anti-cancer agent.
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Affiliation(s)
- Fulvia Farabegoli
- FaBiT,
Department of Pharmacy and Biotechnology, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy
| | - Andreia Granja
- LAQV,
REQUIMTE, Departamento de Ciências Químicas, Faculdade
de Farmácia, Universidade do Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Joana Magalhães
- LAQV,
REQUIMTE, Departamento de Ciências Químicas, Faculdade
de Farmácia, Universidade do Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Stefania Purgato
- FaBiT,
Department of Pharmacy and Biotechnology, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy
| | - Manuela Voltattorni
- FaBiT,
Department of Pharmacy and Biotechnology, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy
| | - Marina Pinheiro
- LAQV,
REQUIMTE, Departamento de Ciências Químicas, Faculdade
de Farmácia, Universidade do Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal
- Life
and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4704-553 Braga, Portugal
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4
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Rossi V, Govoni M, Farabegoli F, Di Stefano G. Lactate is a potential promoter of tamoxifen resistance in MCF7 cells. Biochim Biophys Acta Gen Subj 2022; 1866:130185. [PMID: 35661802 DOI: 10.1016/j.bbagen.2022.130185] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 05/05/2022] [Accepted: 05/31/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Tamoxifen is a widely used estrogen receptor inhibitor, whose clinical success is limited by the development of acquired resistance. This compound was also found to inhibit mitochondrial function, causing increased glycolysis and lactate production. Lactate has been widely recognized as a signaling molecule, showing the potential of modifying gene expression. These metabolic effects of tamoxifen can by hypothesized to contribute in driving drug resistance. METHODS To test this hypothesis, we used MCF7 cells together with a tamoxifen resistant cell line (MCF7-TAM). Experiments were aimed at verifying whether enhanced lactate exposure can affect the phenotype of MCF7 cells, conferring them features mirroring those observed in the tamoxifen resistant culture. RESULTS The obtained results suggested that enhanced lactate in MCF7 cells medium can increase the expression of tafazzin (TAZ) and telomerase complex (TERC, TERT) genes, reducing the cells' attitude to undergo senescence. In long term lactate-exposed cells, signs of EGFR activation, a pathway related to acquired tamoxifen resistance, was also observed. CONCLUSIONS The obtained results suggested lactate as a potential promoter of tamoxifen resistance. The off-target effects of this compound could play a role in hindering its therapeutic efficacy. GENERAL SIGNIFICANCE The features of acquired tamoxifen resistance have been widely characterized at the molecular level; in spite of their heterogeneity, poorly responsive cells were often found to display upregulated glycolysis. Our results suggest that this metabolic asset is not simply a result of neoplastic progression, but can play an active part in driving this process.
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Affiliation(s)
- Valentina Rossi
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy
| | - Marzia Govoni
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy
| | - Fulvia Farabegoli
- Department of Pharmacy and Biotechnology, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy
| | - Giuseppina Di Stefano
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy.
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Núñez-Iglesias MJ, Novio S, García C, Pérez-Muñuzuri ME, Martínez MC, Santiago JL, Boso S, Gago P, Freire-Garabal M. Co-Adjuvant Therapy Efficacy of Catechin and Procyanidin B2 with Docetaxel on Hormone-Related Cancers In Vitro. Int J Mol Sci 2021; 22:7178. [PMID: 34281228 PMCID: PMC8268784 DOI: 10.3390/ijms22137178] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 01/16/2023] Open
Abstract
Prostate (PC) and breast cancer (BC) are heterogeneous hormonal cancers. Treatment resistance and adverse effects are the main limitations of conventional chemotherapy treatment. The use of sensitizing agents could improve the effectiveness of chemotherapeutic drugs as well as obviate these limitations. This study analyzes the effect of single catechin (CAT), procyanidin B2 (ProB2) treatment as well as the co-adjuvant treatment of each of these compounds with docetaxel (DOCE). We used PC- and BC-derived cell lines (PC3, DU-145, T47D, MCF-7 and MDA-MB-231). The short and long-term pro-apoptotic, anti-proliferative and anti-migratory effects were analyzed. RT-qPCR was used to discover molecular bases of the therapeutic efficacy of these compounds. ProB2 treatment induced a two- to five-fold increase in anti-proliferative and pro-apoptotic effects compared to single DOCE treatment, and also had a more sensitizing effect than DOCE on DU145 cells. Regarding BC cells, ProB2- and CAT-mediated sensitization to DOCE anti-proliferative and pro-apoptotic effects was cell-independent and cell-dependent, respectively. Combined treatment led to high-efficacy effects on MCF-7 cells, which were associated to the up-regulation of CDKN1A, BAX, caspase 9 and E-cadherin mRNA under combined treatment compared to single DOCE treatment. CAT and ProB2 can enhance the efficacy of DOCE therapy on PC and BC cells by the sensitizing mechanism.
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Affiliation(s)
- Mª Jesús Núñez-Iglesias
- SNL Laboratory, School of Medicine and Dentistry, University of Santiago de Compostela, c/San Francisco, s/n, Santiago de Compostela, 15782 A Coruña, Spain; (M.J.N.-I.); (C.G.); (M.E.P.-M.); (M.F.-G.)
| | - Silvia Novio
- SNL Laboratory, School of Medicine and Dentistry, University of Santiago de Compostela, c/San Francisco, s/n, Santiago de Compostela, 15782 A Coruña, Spain; (M.J.N.-I.); (C.G.); (M.E.P.-M.); (M.F.-G.)
| | - Carlota García
- SNL Laboratory, School of Medicine and Dentistry, University of Santiago de Compostela, c/San Francisco, s/n, Santiago de Compostela, 15782 A Coruña, Spain; (M.J.N.-I.); (C.G.); (M.E.P.-M.); (M.F.-G.)
| | - Mª Elena Pérez-Muñuzuri
- SNL Laboratory, School of Medicine and Dentistry, University of Santiago de Compostela, c/San Francisco, s/n, Santiago de Compostela, 15782 A Coruña, Spain; (M.J.N.-I.); (C.G.); (M.E.P.-M.); (M.F.-G.)
| | - María-Carmen Martínez
- Group of Viticulture, Olive and Rose (VIOR), Misión Biológica de Galicia, Consejo Superior de Investigaciones Científicas (CSIC), Carballeira 8, 36143 Salcedo, Spain; (M.-C.M.); (J.-L.S.); (S.B.); (P.G.)
| | - José-Luis Santiago
- Group of Viticulture, Olive and Rose (VIOR), Misión Biológica de Galicia, Consejo Superior de Investigaciones Científicas (CSIC), Carballeira 8, 36143 Salcedo, Spain; (M.-C.M.); (J.-L.S.); (S.B.); (P.G.)
| | - Susana Boso
- Group of Viticulture, Olive and Rose (VIOR), Misión Biológica de Galicia, Consejo Superior de Investigaciones Científicas (CSIC), Carballeira 8, 36143 Salcedo, Spain; (M.-C.M.); (J.-L.S.); (S.B.); (P.G.)
| | - Pilar Gago
- Group of Viticulture, Olive and Rose (VIOR), Misión Biológica de Galicia, Consejo Superior de Investigaciones Científicas (CSIC), Carballeira 8, 36143 Salcedo, Spain; (M.-C.M.); (J.-L.S.); (S.B.); (P.G.)
| | - Manuel Freire-Garabal
- SNL Laboratory, School of Medicine and Dentistry, University of Santiago de Compostela, c/San Francisco, s/n, Santiago de Compostela, 15782 A Coruña, Spain; (M.J.N.-I.); (C.G.); (M.E.P.-M.); (M.F.-G.)
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Ling YTQ, Heng YX, Chan HH, Yap YJ, Lee SY, Koh RY, Liew YK, Manaf SNQ, Ang DTC, Mok KL. Evaluation of biocompatible palm-based polymeric surfactants for potential natural rubber latex stabilisation applications. J RUBBER RES 2021. [DOI: 10.1007/s42464-021-00104-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Paternal Inheritance of Bisphenol A Cardiotoxic Effects: The Implications of Sperm Epigenome. Int J Mol Sci 2021; 22:ijms22042125. [PMID: 33672782 PMCID: PMC7924642 DOI: 10.3390/ijms22042125] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/10/2021] [Accepted: 02/18/2021] [Indexed: 12/13/2022] Open
Abstract
Parental exposure to bisphenol A (BPA) has been linked to a greater incidence of congenital diseases. We have demonstrated that BPA induces in zebrafish males an increase in the acetylation of sperm histones that is transmitted to the blastomeres of the unexposed progeny. This work is aimed to determine whether histone hyperacetylation promoted by paternal exposure to BPA is the molecular mechanism underlying the cardiogenesis impairment in the descendants. Zebrafish males were exposed to 100 and 2000 µg/L BPA during early spermatogenesis and mated with non-exposed females. We analyzed in the progeny the expression of genes involved in cardiogenesis and the epigenetic profile. Once the histone hyperacetylation was confirmed, treatment with epigallocatechin gallate (EGCG), an inhibitor of histone acetyltransferases, was assayed on F1 embryos. Embryos from males exposed to 2000 µg/L BPA overexpressed the transcription factor hand2 and the receptor esr2b, showing their own promoters—as well as that of kat6a—an enrichment in H3K9ac. In embryos treated with EGCG, both gene expression and histone acetylation (global and specific) returned to basal levels, and the phenotype was recovered. As shown by the results, the histone hyperacetylated landscape promoted by BPA in the sperm alters the chromatin structure of the progeny, leading to the overexpression of the histone acetyltransferase and genes involved in cardiogenesis.
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8
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Selvaraj J, John JBA, Joghee NM, Antony J, Wadhwani A, Natarajan J. Coumarin-Fatty Acid Conjugates as Potential ERα/AKT-1 Antagonists for ER Positive Breast Cancer. Anticancer Agents Med Chem 2021; 20:437-449. [PMID: 31746305 DOI: 10.2174/1871520619666191028104339] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 08/04/2019] [Accepted: 08/07/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND Current drugs used for the treatment of hormone-dependent breast cancer function as anti-estrogens in the breast, in addition to Estrogen Receptor (ER) agonists in the uterus, thus elevate a woman's risk of developing uterine cancer. This is due to the lack of selective binding and partial agonistic effect of these drugs towards estrogen receptors. In recent years, therefore, researchers have turned their attention towards antiestrogens devoid of these agonist properties and thus have a mechanism of action different from the existing drugs. OBJECTIVE In this context, we report here the design, development and in vitro evaluation of some novel pharmacophores containing coumarin and fatty acid scaffolds for their anti-breast cancer activity. METHODS A library of coumarin-fatty acid conjugates was designed using structure-based drug design approach. The conjugates which have shown good in silico results were then synthesized, characterized and evaluated for their anti-breast cancer activity by MTT assay, Apoptotic assay, Cell proliferation assay, Estrogen binding assay and Gene expression study. RESULTS Out of the fifteen compounds screened, two compounds, SAC-2 and LNAC-2, showed good activity with IC50 values 22µg/ml, 25μg/ml, respectively. These compounds suppressed the proliferation of ER overexpressed MCF-7 cells, increased ERα degradation and hence inactivate the ERα pathway. ER binding assay and gene expression RT-PCR study reveal that SAC-2 downregulated the expression of ERα receptor and AKT-1 gene. CONCLUSION Compound SAC-2 is a good antagonist to ER and hence has a potential for treating breast cancer and other cancers where AKT plays an important role.
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Affiliation(s)
- Jubie Selvaraj
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, India
| | - Jameera B A John
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, India
| | - Nanjan M Joghee
- Director, Research (Retd), JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, India
| | - Justin Antony
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, India
| | - Ashish Wadhwani
- Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, India
| | - Jawahar Natarajan
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, India
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Bonmati-Carrion MA, Tomas-Loba A. Melatonin and Cancer: A Polyhedral Network Where the Source Matters. Antioxidants (Basel) 2021; 10:antiox10020210. [PMID: 33535472 PMCID: PMC7912767 DOI: 10.3390/antiox10020210] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/24/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Melatonin is one of the most phylogenetically conserved signals in biology. Although its original function was probably related to its antioxidant capacity, this indoleamine has been “adopted” by multicellular organisms as the “darkness signal” when secreted in a circadian manner and is acutely suppressed by light at night by the pineal gland. However, melatonin is also produced by other tissues, which constitute its extrapineal sources. Apart from its undisputed chronobiotic function, melatonin exerts antioxidant, immunomodulatory, pro-apoptotic, antiproliferative, and anti-angiogenic effects, with all these properties making it a powerful antitumor agent. Indeed, this activity has been demonstrated to be mediated by interfering with various cancer hallmarks, and different epidemiological studies have also linked light at night (melatonin suppression) with a higher incidence of different types of cancer. In 2007, the World Health Organization classified night shift work as a probable carcinogen due to circadian disruption, where melatonin plays a central role. Our aim is to review, from a global perspective, the role of melatonin both from pineal and extrapineal origin, as well as their possible interplay, as an intrinsic factor in the incidence, development, and progression of cancer. Particular emphasis will be placed not only on those mechanisms related to melatonin’s antioxidant nature but also on the recently described novel roles of melatonin in microbiota and epigenetic regulation.
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Affiliation(s)
- Maria-Angeles Bonmati-Carrion
- Chronobiology Laboratory, Department of Physiology, IMIB-Arrixaca, University of Murcia, 30100 Murcia, Spain
- Ciber Fragilidad y Envejecimiento Saludable, 28090 Madrid, Spain
- Correspondence: (M.-A.B.-C.); (A.T.-L.)
| | - Antonia Tomas-Loba
- Circadian Rhythm and Cancer Laboratory, Department of Physiology, IMIB-Arrixaca, University of Murcia, 30120 Murcia, Spain
- Correspondence: (M.-A.B.-C.); (A.T.-L.)
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Zhang D, Nichols HB, Troester M, Cai J, Bensen JT, Sandler DP. Tea consumption and breast cancer risk in a cohort of women with family history of breast cancer. Int J Cancer 2020; 147:876-886. [PMID: 31837003 DOI: 10.1002/ijc.32824] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 11/30/2019] [Accepted: 12/04/2019] [Indexed: 02/06/2023]
Abstract
Laboratory studies have observed chemopreventive effects of black and green tea on breast cancer development, but few epidemiologic studies have identified such effects. We investigated the association between tea consumption and breast cancer risk using data from 45,744 U.S. and Puerto Rican women participating in the Sister Study. Frequency and serving size of black and green tea consumption were measured at cohort enrollment. Breast cancer diagnoses were reported during follow-up and confirmed by medical record review. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). We further investigated potential variation according to estrogen receptor (ER) status, menopausal status and body mass index (BMI). Overall, 81.6 and 56.0% of women drank black or green tea, respectively. A total of 2,809 breast cancer cases were identified in the cohort. The multivariable model suggested an inverse association between black (≥5 vs. 0 cups/week: HR = 0.88, 95% CI 0.78, 1.00, p-trend = 0.08) and green tea (≥5 vs. 0 cups/week: HR = 0.82, 95% CI 0.70, 0.95, p-trend < 0.01) consumption and breast cancer risk. We did not observe differences by ER characteristics, menopausal status or BMI. In conclusion, our study suggests drinking at least five cups of green or black tea per week may be associated with decreased breast cancer risk.
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Affiliation(s)
- Dongyu Zhang
- Department of Oncology, Georgetown University School of Medicine, Washington, DC.,Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC
| | - Hazel B Nichols
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC
| | - Melissa Troester
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC
| | - Jianwen Cai
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC
| | - Jeannette T Bensen
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC
| | - Dale P Sandler
- Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC
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11
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Estrogenic biological activity and underlying molecular mechanisms of green tea constituents. Trends Food Sci Technol 2020. [DOI: 10.1016/j.tifs.2019.11.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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12
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Li Y, Zhang T, Liu Q, He J. PEG-Derivatized Dual-Functional Nanomicelles for Improved Cancer Therapy. Front Pharmacol 2019; 10:808. [PMID: 31379579 PMCID: PMC6659352 DOI: 10.3389/fphar.2019.00808] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 06/24/2019] [Indexed: 02/05/2023] Open
Abstract
Polymeric micelles have attracted considerable attention for effective delivery of poorly water-soluble cancer drugs. Polyethylene glycol (PEG), which has been approved for human use by the US Food and Drug Administration, is the most commonly used hydrophilic component of polymeric micelles because it is biocompatible and biodegradable. One disadvantage of traditional polymeric micelles is that they include a large amount of inert carrier materials, which do not contribute to therapeutic activity but increase cost and toxicity risk. A better alternative may be "dual-functional" micellar carriers, in which the hydrophobic carrier material (conjugated to PEG) has intrinsic therapeutic activity that complements, or even synergizes with, the antitumor activity of the drug cargo. This review summarizes recent progress in the development of PEG-derivatized dual-functional nanomicelles and surveys the evidence of their feasibility and promise for cancer therapy.
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Affiliation(s)
- Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
| | - Ting Zhang
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
| | - Jinhan He
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China.,Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
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13
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Samavat H, Wu AH, Ursin G, Torkelson CJ, Wang R, Yu MC, Yee D, Kurzer MS, Yuan JM. Green Tea Catechin Extract Supplementation Does Not Influence Circulating Sex Hormones and Insulin-Like Growth Factor Axis Proteins in a Randomized Controlled Trial of Postmenopausal Women at High Risk of Breast Cancer. J Nutr 2019; 149:619-627. [PMID: 30926986 PMCID: PMC6461722 DOI: 10.1093/jn/nxy316] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/15/2018] [Accepted: 12/14/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Consumption of green tea has been associated with reduced risk of breast cancer. Hormonal modulation has been suggested as one of the potential underlying mechanisms; however, it has yet to be fully elucidated in large, long-term human clinical trials. OBJECTIVE We investigated the effects of decaffeinated green tea extract (GTE) on circulating sex hormones and insulin-like growth factor (IGF) proteins. METHODS We conducted a placebo-controlled double-blind randomized clinical trial recruiting from 8 clinical centers in Minnesota. Participants were 538 healthy postmenopausal women randomly assigned to the GTE group (463 completed the study; mean age = 60.0 y) and 537 to the placebo group (474 completed; mean age = 59.7 y). Women in the GTE group orally took 4 decaffeinated capsules containing 1315 mg total catechins including 843 mg epigallocatechin-3-gallate daily for 1 y, whereas women in the placebo group took similar capsules containing no tea catechins. Blood sex hormones (estrone, estradiol, androstenedione, testosterone, and sex hormone-binding globulin) and IGF proteins (IGF-1 and IGF binding protein-3) were quantified at baseline and months 6 (for IGF proteins only) and 12, and were assessed as secondary outcomes of the study using a mixed-effect repeated-measures ANOVA model. RESULTS Women in the GTE group had significantly higher blood total estradiol (16%; P = 0.02) and bioavailable estradiol (21%; P = 0.03) than in the placebo group at month 12. There was a statistically significant interaction between GTE supplementation and duration of treatment on estradiol and bioavailable estradiol (both Ps for interaction = 0.001). The catechol-O-methyltransferase genotype did not influence blood sex hormones before or after GTE supplementation. The circulating concentrations of IGF proteins were comparable between GTE and placebo groups at all 3 time points. CONCLUSION These results suggest that a 12-mo GTE supplementation significantly increases circulating estradiol concentrations in healthy postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00917735.
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Affiliation(s)
- Hamed Samavat
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
| | - Anna H Wu
- Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA
| | - Giske Ursin
- Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA
- Cancer Registry of Norway, Oslo, Norway
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Carolyn J Torkelson
- Department of Family Medicine and Community Health, University of Minnesota Medical School, Minneapolis, MN
| | - Renwei Wang
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - Mimi C Yu
- Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA (retired)
| | - Douglas Yee
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN
- Department of Medicine, University of Minnesota, Minneapolis, MN
- Department of Pharmacology, University of Minnesota, Minneapolis, MN
| | - Mindy S Kurzer
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
| | - Jian-Min Yuan
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
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Lombó M, González-Rojo S, Fernández-Díez C, Herráez MP. Cardiogenesis impairment promoted by bisphenol A exposure is successfully counteracted by epigallocatechin gallate. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2019; 246:1008-1019. [PMID: 31126002 DOI: 10.1016/j.envpol.2019.01.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 12/11/2018] [Accepted: 01/02/2019] [Indexed: 05/18/2023]
Abstract
Exposure to the emerging contaminant bisphenol A (BPA) is ubiquitous and associated with cardiovascular disorders. BPA effect as endocrine disruptor is widely known but other mechanisms underlying heart disease, such as epigenetic modifications, remain still unclear. A compound of green tea, epigallocatechin gallate (EGCG), may act both as anti-estrogen and as inhibitor of some epigenetic enzymes. The aims of this study were to analyze the molecular processes related to BPA impairment of heart development and to prove the potential ability of EGCG to neutralize the toxic effects caused by BPA on cardiac health. Zebrafish embryos were exposed to 2000 and 4000 μg/L BPA and treated with 50 and 100 μM EGCG. Heart malformations were assessed at histological level and by confocal imaging. Expression of genes involved in cardiac development, estrogen receptors and epigenetic enzymes was analyzed by qPCR whereas epigenetic modifications were evaluated by whole mount immunostaining. BPA embryonic exposure led to changes in cardiac phenotype, induced an overexpression of hand2, a crucial factor for cardiomyocyte differentiation, increased the expression of estrogen receptor (esr2b), promoted an overexpression of a histone acetyltransferase (kat6a) and also caused an increase in histone acetylation, both mechanisms being able to act in sinergy. EGCG treatment neutralized all the molecular alterations caused by BPA, allowing the embryos to go on with a proper heart development. Both molecular mechanisms of BPA action (estrogenic and epigenetic) likely lying behind cardiogenesis impairment were successfully counteracted by EGCG treatment.
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Affiliation(s)
- Marta Lombó
- Department of Molecular Biology, Faculty of Biology and Environmental Sciences, Universidad de León, Campus de Vegazana, León, 24071, Spain
| | - Silvia González-Rojo
- Department of Molecular Biology, Faculty of Biology and Environmental Sciences, Universidad de León, Campus de Vegazana, León, 24071, Spain
| | - Cristina Fernández-Díez
- Department of Molecular Biology, Faculty of Biology and Environmental Sciences, Universidad de León, Campus de Vegazana, León, 24071, Spain
| | - María Paz Herráez
- Department of Molecular Biology, Faculty of Biology and Environmental Sciences, Universidad de León, Campus de Vegazana, León, 24071, Spain.
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15
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Sugiyama I, Kaihatsu K, Soma Y, Kato N, Sadzuka Y. Dual-effect liposomes with increased antitumor effects against 67-kDa laminin receptor-overexpressing tumor cells. Int J Pharm 2018; 541:206-213. [DOI: 10.1016/j.ijpharm.2018.02.041] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 02/13/2018] [Accepted: 02/23/2018] [Indexed: 12/01/2022]
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16
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Mitochondrial biogenesis and metabolic hyperactivation limits the application of MTT assay in the estimation of radiation induced growth inhibition. Sci Rep 2018; 8:1531. [PMID: 29367754 PMCID: PMC5784148 DOI: 10.1038/s41598-018-19930-w] [Citation(s) in RCA: 207] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 01/05/2018] [Indexed: 01/19/2023] Open
Abstract
Metabolic viability based high throughput assays like MTT and MTS are widely used in assessing the cell viability. However, alteration in both mitochondrial content and metabolism can influence the metabolic viability of cells and radiation is a potential mitochondrial biogenesis inducer. Therefore, we tested if MTT assay is a true measure of radiation induced cell death in widely used cell lines. Radiation induced cellular growth inhibition was performed by enumerating cell numbers and metabolic viability using MTT assay at 24 and 48 hours (hrs) after exposure. The extent of radiation induced reduction in cell number was found to be larger than the decrease in MTT reduction in all the cell lines tested. We demonstrated that radiation induces PGC-1α and TFAM to stimulate mitochondrial biogenesis leading to increased levels of SDH-A and enhanced metabolic viability. Radiation induced disturbance in calcium (Ca2+) homeostasis also plays a crucial role by making the mitochondria hyperactive. These findings suggest that radiation induces mitochondrial biogenesis and hyperactivation leading to increased metabolic viability and MTT reduction. Therefore, conclusions drawn on radiation induced growth inhibition based on metabolic viability assays are likely to be erroneous as it may not correlate with growth inhibition and/or loss of clonogenic survival.
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17
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Hallman K, Aleck K, Quigley M, Dwyer B, Lloyd V, Szmyd M, Dinda S. The regulation of steroid receptors by epigallocatechin-3-gallate in breast cancer cells. BREAST CANCER-TARGETS AND THERAPY 2017; 9:365-373. [PMID: 28579831 PMCID: PMC5447698 DOI: 10.2147/bctt.s131334] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
It has been reported that phytoestrogen epigallocatechin gallate (EGCG) suppresses cancer cell proliferation and may have antitumor properties. In this study, we analyzed the effects of EGCG on estrogen receptor α (ERα) and progesterone receptor in hormone-dependent T-47D breast cancer cells. Western blot analysis revealed EGCG induced a concentration-dependent decrease in ERα protein levels, with a 56% reduction occurring with 60 µM EGCG when compared to controls. Downregulation of ERα protein levels was observed after 24-hour co-treatment of T-47D cells with 60 µM EGCG and 10 nM 17β-estradiol (E2). The proliferative effect of E2 on cell viability was reversed when treated in combination with EGCG. In contrast, the combination of EGCG with the pure ER antagonist, ICI 182, 780, showed no further reduction in cell number as only 5% of the cells were viable after 6 days of treatment. These studies may provide further understanding of the interactions among flavonoids and steroid receptors in breast cancer cells.
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Affiliation(s)
- Kelly Hallman
- Biomedical Diagnostic and Therapeutic Sciences, School of Health Sciences, Center for Biomedical Research, Oakland University, Rochester, MI, USA
| | - Katie Aleck
- Biomedical Diagnostic and Therapeutic Sciences, School of Health Sciences, Center for Biomedical Research, Oakland University, Rochester, MI, USA
| | - Meghan Quigley
- Biomedical Diagnostic and Therapeutic Sciences, School of Health Sciences, Center for Biomedical Research, Oakland University, Rochester, MI, USA
| | - Brigitte Dwyer
- Biomedical Diagnostic and Therapeutic Sciences, School of Health Sciences, Center for Biomedical Research, Oakland University, Rochester, MI, USA
| | - Victoria Lloyd
- Biomedical Diagnostic and Therapeutic Sciences, School of Health Sciences, Center for Biomedical Research, Oakland University, Rochester, MI, USA
| | - Monica Szmyd
- Biomedical Diagnostic and Therapeutic Sciences, School of Health Sciences, Center for Biomedical Research, Oakland University, Rochester, MI, USA
| | - Sumi Dinda
- Biomedical Diagnostic and Therapeutic Sciences, School of Health Sciences, Center for Biomedical Research, Oakland University, Rochester, MI, USA
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18
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Preparation and characterization of (-)-Epigallocatechin-3-gallate (EGCG)-loaded nanoparticles and their inhibitory effects on Human breast cancer MCF-7 cells. Sci Rep 2017; 7:45521. [PMID: 28349962 PMCID: PMC5368574 DOI: 10.1038/srep45521] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 02/27/2017] [Indexed: 12/31/2022] Open
Abstract
We were employing nanotechnology to improve the targeting ability of (−)-Epigallocatechin-3-gallate (EGCG) towards MCF-7 cells, and two kinds of EGCG nanoparticles (FA-NPS-PEG and FA-PEG-NPS) were obtained, besides, their characteristics and effects on MCF-7 cells were studied. The results indicated that (i) both FA-NPS-PEG and FA-PEG-NPS have high stabilities; (ii) their particles sizes were 185.0 ± 13.5 nm and 142.7 ± 7.2 nm, respectively; (iii) their encapsulation efficiencies of EGCG were 90.36 ± 2.20% and 39.79 ± 7.54%, respectively. (iv) there was no cytotoxicity observed in EGCG, FA-NPS-PEG and FA-PEG-NPS toward MCF-7 cells over all concentrations (0~400 μg/mL) tested; (v) EGCG, FA-NPS-PEG and FA-PEG-NPS inhibited MCF-7 cells proliferation in dose-dependent manners, with the average IC50 of 470.5 ± 33.0, 65.9 ± 0.4 and 66.6 ± 0.6 μg/mL; (vi) EGCG, FA-NPS-PEG and FA-PEG-NPS could modulated the expressions of several key regulatory proteins in PI3K-Akt pathway such as up-regulation of PTEN, p21 and Bax, and down-regulation of p-PDK1, p-AKT, CyclinD1 and Bcl-2, which gave an illustration about the mechanism by which EGCG nanoparticles inhibited MCF-7 cells proliferation. In this study, EGCG nanoparticles can significantly enhance the targeting ability and efficacy of EGCG, which is considered to an experimental foundation for further research on its activity, targeting ability and metabolism in vivo.
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Chowdhury A, Sarkar J, Chakraborti T, Pramanik PK, Chakraborti S. Protective role of epigallocatechin-3-gallate in health and disease: A perspective. Biomed Pharmacother 2016; 78:50-59. [DOI: 10.1016/j.biopha.2015.12.013] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Revised: 12/03/2015] [Accepted: 12/15/2015] [Indexed: 12/28/2022] Open
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Krisnamurti DGB, Louisa M, Anggraeni E, Wanandi SI. Drug Efflux Transporters Are Overexpressed in Short-Term Tamoxifen-Induced MCF7 Breast Cancer Cells. Adv Pharmacol Sci 2016; 2016:6702424. [PMID: 26981116 PMCID: PMC4769734 DOI: 10.1155/2016/6702424] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 01/11/2016] [Accepted: 01/13/2016] [Indexed: 11/17/2022] Open
Abstract
Tamoxifen is the first line drug used in the treatment of estrogen receptor-positive (ER+) breast cancer. The development of multidrug resistance (MDR) to tamoxifen remains a major challenge in the treatment of cancer. One of the mechanisms related to MDR is decrease of drug influx via overexpression of drug efflux transporters such as P-glycoprotein (P-gp/MDR1), multidrug resistance associated protein (MRP), or BCRP (breast cancer resistance protein). We aimed to investigate whether the sensitivity of tamoxifen to the cells is maintained through the short period and whether the expressions of several drug efflux transporters have been upregulated. We exposed MCF7 breast cancer cells with tamoxifen 1 μM for 10 passages (MCF7 (T)). The result showed that MCF7 began to lose their sensitivity to tamoxifen from the second passage. MCF7 (T) also showed a significant increase in all transporters examined compared with MCF7 parent cells. The result also showed a significant increase of CC50 in MCF7 (T) compared to that in MCF7 (97.54 μM and 3.04 μM, resp.). In conclusion, we suggest that the expression of several drug efflux transporters such as P-glycoprotein, MRP2, and BCRP might be used and further studied as a marker in the development of tamoxifen resistance.
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Affiliation(s)
| | - Melva Louisa
- Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Indonesia, Jakarta 10430, Indonesia
| | - Erlia Anggraeni
- Master Program in Biomedicine, Faculty of Medicine, University of Indonesia, Jakarta 10430, Indonesia
| | - Septelia Inawati Wanandi
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Indonesia, Jakarta 10430, Indonesia
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21
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Green Tea Catechin, EGCG, Suppresses PCB 102-Induced Proliferation in Estrogen-Sensitive Breast Cancer Cells. Int J Breast Cancer 2015; 2015:163591. [PMID: 26783468 PMCID: PMC4691479 DOI: 10.1155/2015/163591] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 11/19/2015] [Accepted: 11/23/2015] [Indexed: 02/08/2023] Open
Abstract
The persistence of polychlorinated biphenyls (PCBs) in the environment is of considerable concern since they accumulate in human breast tissue and may stimulate the growth of estrogen-sensitive tumors. Studies have shown that EGCG from green tea can modify estrogenic activity and thus may act as a cancer chemopreventive agent. In the present study, we evaluated the individual and combined effects of PCB 102 and EGCG on cell proliferation using an estrogen-sensitive breast cancer cell line MCF-7/BOS. PCB 102 (1-10 μM) increased cell proliferation in a dose-dependent manner. Furthermore, the proliferative effects of PCB 102 were mediated by ERα and could be abrogated by the selective ERα antagonist MPP. EGCG (10-50 μM) caused a dose-dependent inhibition of PCB 102-induced cell proliferation, with nearly complete inhibition at 25 μM EGCG. The antiproliferative action of EGCG was mediated by ERβ and could be blocked by the ERβ-specific inhibitor PHTPP. In conclusion, EGCG suppressed the proliferation-stimulating activity of the environmental estrogen PCB 102 which may be helpful in the chemoprevention of breast cancer.
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22
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Kiyama R, Wada-Kiyama Y. Estrogenic endocrine disruptors: Molecular mechanisms of action. ENVIRONMENT INTERNATIONAL 2015; 83:11-40. [PMID: 26073844 DOI: 10.1016/j.envint.2015.05.012] [Citation(s) in RCA: 192] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 05/26/2015] [Accepted: 05/27/2015] [Indexed: 05/20/2023]
Abstract
A comprehensive summary of more than 450 estrogenic chemicals including estrogenic endocrine disruptors is provided here to understand the complex and profound impact of estrogen action. First, estrogenic chemicals are categorized by structure as well as their applications, usage and effects. Second, estrogenic signaling is examined by the molecular mechanism based on the receptors, signaling pathways, crosstalk/bypassing and autocrine/paracrine/homeostatic networks involved in the signaling. Third, evaluation of estrogen action is discussed by focusing on the technologies and protocols of the assays for assessing estrogenicity. Understanding the molecular mechanisms of estrogen action is important to assess the action of endocrine disruptors and will be used for risk management based on pathway-based toxicity testing.
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Affiliation(s)
- Ryoiti Kiyama
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
| | - Yuko Wada-Kiyama
- Department of Physiology, Nippon Medical School, Bunkyo-ku, Tokyo 113-8602, Japan
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23
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Singh P, Bast F. Screening of multi-targeted natural compounds for receptor tyrosine kinases inhibitors and biological evaluation on cancer cell lines, in silico and in vitro. Med Oncol 2015; 32:233. [PMID: 26298529 DOI: 10.1007/s12032-015-0678-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 08/08/2015] [Indexed: 12/27/2022]
Abstract
Receptors for growth factors encompass within the superfamily of receptor tyrosine kinases and are known to regulate numerous biological processes including cellular growth, proliferation, metabolism, survival, cell differentiation and apoptosis. These receptors have recently caught the attention of the researchers as an attractive target to combat cancer owing to the evidence suggesting their over-expression in cancer cells. Therefore, we studied receptor-based molecular docking of IR (PDB; 3ETA), IGF1R (PDB; 1K3A), EGFR (PDB; 1M17), VEGFIR (PDB; 3HNG), and VEGFIIR (PDB; 2OH4) against natural compounds. Further, in vitro investigation of the biological effect of lead molecules in an array of cancer cell lines was done. All selected natural compounds were docked with the X-ray crystal structure of selected protein by employing GLIDE (Grid-based Ligand Docking with Energetics) Maestro 9.6. InterBioScreen natural compounds docked with each selected protein molecules by using GLIDE high throughput virtual screening. On the basis of Gscore, we select 20 compounds along with 68 anticancer compounds for GLIDE extra precision molecular docking. It was discovered in this study that compound epigallocatechin gallate (EGCG) yielded magnificent Gscore with IGF1R (PDB; 1K3A) and VEGFIIR (PDB; 2OH4), and protein-ligand interactions are chart out. Effect of EGCG on biological activity such as mRNA expression of selected protein, cell proliferation, oxidative stress, and cell migration was reported after the 48 h treatments in cancer cell lines. The RT-PCR densitometric bands analysis showed that compound EGCG reduced the mRNA expression of IGF1R, VEGFIIR, and mTOR at 80 μM concentration. Moreover, EGCG significantly reduced cell proliferation and ROS generation after 48 h treatments. Our result also indicated a reduction in the potential for cell migration that might show in vivo anti-metastasis activity of EGCG.
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Affiliation(s)
- Pushpendra Singh
- Centre for Biosciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, 151001, Punjab, India
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Esmaeili MA. Combination of siRNA-directed gene silencing with epigallocatechin-3-gallate (EGCG) reverses drug resistance in human breast cancer cells. J Chem Biol 2015; 9:41-52. [PMID: 26855680 DOI: 10.1007/s12154-015-0144-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Accepted: 07/14/2015] [Indexed: 11/30/2022] Open
Abstract
Elevated expression of NF-E2-related factor 2 (Nrf2), a nuclear transcription factor, is a frequent genetic abnormality seen in this malignancy and is an important contributor to chemoresistance in cancer therapy. In the present study, we investigated if Nrf2 was associated with drug resistance in tamoxifen-resistant MCF-7 (MCF-7/TAM) cells, and whether EGCG, major flavonoid isolated from green tea, could reverse drug resistance in MCF-7/TAM cells. Our results showed that the endogenous expression of Nrf2 as well as its target proteins heme oxygenase-1, NADP (H):quinone oxidoreductase in MCF-7/TAM cells was higher than that in MCF-7 cells. Epicatechin gallate (EGCG) significantly sensitizes MCF-7/TAM cells to tamoxifen and dramatically reduced Nrf2 expression at both the messenger RNA and protein, leading to a reduction of Nrf2-downstream genes. In addition, using siRNA technique, we found that the intracellular Nrf2 protein level was significantly decreased in MCF-7/TAM cells and tamoxifen resistance was partially reversed by Nrf2 siRNA. Combination of siRNA-directed gene silencing with EGCG downregulated the Nrf2-dependent response and partly reversed tamoxifen resistance in MCF-7/TAM cells in a synergic manner. These results suggested that combining the chemotherapeutic effect of EGCG with siRNA-mediated Nrf2 knock-down results in the feasibility of using Nrf2 inhibitors to increase efficacy of chemotherapeutic drugs.
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Affiliation(s)
- Mohammad Ali Esmaeili
- Department of Biology, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G.C., Tehran, Iran
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Expression profiling of genes modulated by estrogen, EGCG or both in MCF-7 breast cancer cells. GENOMICS DATA 2015; 5:210-2. [PMID: 26484257 PMCID: PMC4583662 DOI: 10.1016/j.gdata.2015.05.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 05/24/2015] [Indexed: 01/20/2023]
Abstract
(−)-Epigallocatechin-3-gallate (EGCG) is one of the most potent and the most studied green tea catechin. Reports on mechanisms of EGCG action and its cellular targets are plenty. Compelling evidences in the literature in favor of ER being one of its targets suggest that EGCG may have a significant impact on estrogen regulated gene expression. Despite the possible implications on breast cancer chemoprevention or therapy, this aspect of EGCG action has not been adequately investigated. In order to address this issue, we have obtained gene expression profiles of MCF-7 breast cancer cells treated with ethanol (vehicle control) and those treated with estrogen, EGCG or both, using microarrays. Here, we have presented in detail the design and execution of the microarray experiment, quality control checks and analysis of microarray data. The utility and importance of the data generated in this work have been discussed in the context of the background literature. Our data is available in the Gene Expression Omnibus (GEO) database with the identifier GSE56245.
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Epigallocatechin-3-gallate enhances the therapeutic effects of leptomycin B on human lung cancer a549 cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:217304. [PMID: 25922640 PMCID: PMC4397486 DOI: 10.1155/2015/217304] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 03/16/2015] [Accepted: 03/17/2015] [Indexed: 12/20/2022]
Abstract
Our previous studies have shown Leptomycin B (LMB) is a promising antilung cancer drug. Epigallocatechin-3-gallate (EGCG) has antitumor properties but a debatable clinical application. The objective of this study is to evaluate the combination therapeutic effect of LMB and EGCG and its molecular mechanisms in human lung cancer A549 cells. Increased cytotoxicity was observed in LMB+EGCG-treated cells compared to LMB-treated cells. Elevated ROS was maximized 2 h after treatment, and LMB+EGCG-treated cells had higher ROS levels compared to LMB. N-Acetyl-L-cysteine (NAC) studies confirmed the oxidative role of LMB and/or EGCG treatment. In comparison to the control, CYP3A4, SOD, GPX1, and p21 mRNA expression levels were increased 7.1-, 2.0-, 4.6-, and 13.1-fold in LMB-treated cells, respectively, while survivin was decreased 42.6-fold. Additionally, these increases of CYP3A4, SOD, and GPX1 were significantly reduced, while p21 was significantly increased in LMB+EGCG-treated cells compared to LMB-treated cells. The qRT-PCR results for p21 and survivin were further confirmed by Western blot. Our study first shows that LMB produces ROS and is possibly metabolized by CYP3A4, GPX1, and SOD in A549 cells, and combination treatment of LMB and EGCG augments LMB-induced cytotoxicity through enhanced ROS production and the modulation of drug metabolism and p21/survivin pathways.
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27
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Comparative studies on the antioxidant capacities and catechin profiles of conventional and organic green tea. ACTA ACUST UNITED AC 2015. [DOI: 10.1007/s13765-015-0045-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Caffeine and Caffeic Acid Inhibit Growth and Modify Estrogen Receptor and Insulin-like Growth Factor I Receptor Levels in Human Breast Cancer. Clin Cancer Res 2015; 21:1877-87. [DOI: 10.1158/1078-0432.ccr-14-1748] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 02/02/2015] [Indexed: 11/16/2022]
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Yiannakopoulou EC. Interaction of green tea catechins with breast cancer endocrine treatment: a systematic review. Pharmacology 2014; 94:245-8. [PMID: 25471334 DOI: 10.1159/000369170] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 10/16/2014] [Indexed: 11/19/2022]
Abstract
Recent data have shown strong chemopreventive and possibly cancer chemotherapeutic effects of green tea polyphenols and EGCG against breast cancer. This systematic review aims to synthesize data on the possible interaction of green tea catechins with breast cancer endocrine treatment. Electronic databases were searched with the appropriate search terms. Experimental trials suggest a synergistic interaction of green tea catechins with tamoxifen or raloxifene in the treatment of estrogen receptor-positive and estrogen receptor-negative breast cancer through estrogen receptor-dependent and -independent mechanisms. No evidence of an interaction of green tea catechins with aromatase inhibitors or fulvestrant has been reported. As green tea catechins are natural compounds with a rather favorable safety profile, the strategy of co-administrating green tea catechins with tamoxifen seems to be a rational approach in chemoprevention, adjuvant and metastatic breast cancer treatment that needs further investigation.
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Affiliation(s)
- Eugenia C Yiannakopoulou
- Department of Medical Laboratories, Faculty of Health and Caring Professions, Technological Educational Institute of Athens, Athens, Greece
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Li MJ, Yin YC, Wang J, Jiang YF. Green tea compounds in breast cancer prevention and treatment. World J Clin Oncol 2014; 5:520-528. [PMID: 25114865 PMCID: PMC4127621 DOI: 10.5306/wjco.v5.i3.520] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Revised: 02/12/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is the most common cancer among women. In recent years, many in vitro and in vivo studies indicate that green tea possesses anti-cancer effects. The epidemiological studies, however, have produced inconclusive results in humans. Likewise, results from animal models about the preventive or therapeutic effects of green tea components are inconclusive. The mechanisms by which green tea intake may influence the risk of breast cancer in humans remain elusive mechanisms by which green tea intake may influence. Here, we review recent studies of green tea polyphenols and their applications in the prevention and treatment of breast cancer. Furthermore, we discuss the effect of green tea components on breast cancer by reviewing epidemiological studies, animal model studies and clinical trials. At last, we discuss the mechanisms by which green tea components suppress the development and recurrence of breast cancer. A better understanding of the mechanisms will improve the utilization of green tea in breast cancer prevention and therapy and pave the way to novel prevention and treatment strategies for breast cancer.
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A RXR ligand 6-OH-11-O-hydroxyphenanthrene with antitumour properties enhances (-)-epigallocatechin-3-gallate activity in three human breast carcinoma cell lines. BIOMED RESEARCH INTERNATIONAL 2014; 2014:853086. [PMID: 25013807 PMCID: PMC4072039 DOI: 10.1155/2014/853086] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 05/05/2014] [Indexed: 12/18/2022]
Abstract
(−)-Epigallocatechin-3-gallate (EGCG) and chemotherapeutic agents cotreatment can improve cytotoxicity against cancer cells. We showed that EGCG and the rexinoid 6-OH-11-O-hydroxyphenanthrene (IIF), given together, were cytotoxic toward MCF-7, MCF-7TAM, and MDA-MB-231, three breast carcinoma cell lines showing different molecular characteristics. Cell growth arrest and apoptosis were greater after EGCG and IIF cotreatment than after individual administration. Cytotoxicity was related to upregulation of 67-kDa laminin receptor (LR67), one of the principal molecular targets of EGCG, and activation of the nuclear retinoic X receptors (RXRs) pathway. Furthermore, the transcription factor Forkhead box O3 (Foxo3a), a protein able to trigger apoptosis through upregulation of genes necessary for cell death, was activated. EGCG and IIF cotreatment produced a significant nuclear import of Foxo3a from the cytoplasm in MCF-7, MCF-7TAM, and MDA-MB-231 cells. In MCF-7TAM cells only, Foxo3a nuclear localization was associated with p473AKT downregulation. For the first time we showed that when EGCG and IIF, two harmless molecules, were given together, they might increase cytotoxicity in three breast carcinoma cell lines, two of them being representative of poorly responsive breast carcinoma types.
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Zhou DH, Wang X, Feng Q. EGCG enhances the efficacy of cisplatin by downregulating hsa-miR-98-5p in NSCLC A549 cells. Nutr Cancer 2014; 66:636-44. [PMID: 24712372 DOI: 10.1080/01635581.2014.894101] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
In the current study, the enhanced efficacy of cisplatin caused by (-)-epigallocatechin-3-gallate (EGCG) in nonsmall cell lung cancer (NSCLC) A549 cells was observed. The tumor size was significantly smaller in vivo in the combination of cisplatin and EGCG group, as compared with cisplatin-only group. However, in NCI-H460 cells, another kind of NSCLC cells, the efficacy of cisplatin was antagonized by EGCG. MiRNA microarray showed that hsa-miR-98-5p and hsa-miR-125a-3p were differentially expressed after EGCG treatment in these 2 cell lines. After transfection of hsa-miR-98-5p inhibitor, the survival fraction of both A549 and NCI-H460 cells was decreased upon cisplatin treatment. Meanwhile, as a critical regulator in the cisplatin-induced apoptosis, p53 was elevated by silencing of hsa-miR-98-5p. These results suggested that EGCG inhibited the expression of hsa-miR-98-5p, followed by an increase of p53, thus the efficacy of cisplatin was enhanced. Bioinformatics analysis showed that hsa-miR-125a-3p might have a strong connection with classical MAPK pathway. Taken together, these findings indicate that hsa-miR-98-5p could be a potential target in clinical cisplatin treatment of NSCLC. The combination of EGCG and cisplatin might be an effective therapeutic strategy in treating some type of NSCLC, although the possibility of antagonistic interactions must also be taken into account.
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Affiliation(s)
- Dong-Hu Zhou
- a Department of Nutrition and Food Safety, Key Laboratory of Toxicology, School of Public Health , Nanjing Medical University , Nanjing , Jiangsu , China
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Won YS, Lee JH, Kwon SJ, Kim JY, Park KH, Lee MK, Seo KI. α-Mangostin-induced apoptosis is mediated by estrogen receptor α in human breast cancer cells. Food Chem Toxicol 2014; 66:158-165. [PMID: 24480042 DOI: 10.1016/j.fct.2014.01.040] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 01/20/2014] [Accepted: 01/22/2014] [Indexed: 12/13/2022]
Abstract
In this study, we evaluated the effects of α-mangostin on cell growth inhibition and induction of apoptosis in MCF-7 ERα-positive human breast cancer cells. Our results showed that α-mangostin inhibited MCF-7 cell proliferation whereas ERα-negative MDA-MB-231 cells were less sensitive to the agent. Additionally, α-mangostin effectively induced apoptosis as evidenced by the appearance of apoptotic nuclei observed with Hoechst 33258 staining and evaluation of sub-G1 DNA contents by flow cytometry. α-Mangostin also activated caspases-8, -9, and -7; increased the protein levels of Bax, p53, and cytosolic cytochrome c; and induced PARP cleavage while reducing Bid and Bcl-2 protein expression. In addition, apoptosis-inducing factor (AIF) was transported from mitochondria to the cytosol after α-mangostin treatment. α-mangostin also induced apoptosis in 17-β-estradiol (E2)-stimulated MCF-7 cells in parallel with the non-stimulated cells. Moreover, treatment with 10μM α-mangostin for 48h specifically decreased the expression of ERα and pS2, an estrogen-responsive gene, in MCF-7 cells. Furthermore, knockdown of ERα expression in MCF-7 cells with siRNA attenuated α-mangostin-induced cell growth inhibition and caspase-7 activation. These results suggest that ERα is required for α-mangostin-induced growth inhibition and apoptosis in human breast cancer cells. Therefore, α-mangostin may be used to prevent and treat of ER-positive breast cancer.
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Affiliation(s)
- Yeong-Seon Won
- Department of Food and Nutrition, Sunchon National University, Suncheon 540-950, Republic of Korea; Department of Bioscience and Biotechnology, Kyushu University, Fukuoka 812-8581, Japan
| | - Ju-Hye Lee
- Department of Food and Nutrition, Sunchon National University, Suncheon 540-950, Republic of Korea
| | - Soon-Jae Kwon
- School of Food Science and Biotechnology, Kyungpook National University, Daegu 702-701, Republic of Korea
| | - Jae-Yong Kim
- Jeonnam Institute of National Resources Research, Jangheung 529-851, Republic of Korea
| | - Ki-Hun Park
- Division of Applied Life Science, IALS, Graduate School of Gyeongsang National University, Jinju 660-701, Republic of Korea
| | - Mi-Kyung Lee
- Department of Food and Nutrition, Sunchon National University, Suncheon 540-950, Republic of Korea
| | - Kwon-Il Seo
- Department of Food and Nutrition, Sunchon National University, Suncheon 540-950, Republic of Korea.
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Kim KC, Lee C. Reversal of Cisplatin resistance by epigallocatechin gallate is mediated by downregulation of axl and tyro 3 expression in human lung cancer cells. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2014; 18:61-6. [PMID: 24634598 PMCID: PMC3951825 DOI: 10.4196/kjpp.2014.18.1.61] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 12/08/2013] [Accepted: 12/27/2013] [Indexed: 01/23/2023]
Abstract
Lung cancer is still the number one cause of death from cancer worldwide. The clinical effect of platinum-based chemotherapy for non-small cell lung cancer is constrained by the resistance to drug. To overcome chemo-resistance, various modified treatment including combination therapy has been used, but overall survival has not been improved yet. In this study, chemo-resistant lung cancer cells, A549/Cis and H460/Cis, were developed by long-term exposure of cells to cisplatin and the proliferative capability of these resistant cells was verified to be reduced. We found cytotoxic effect of epigallocatechin gallate (EGCG), a major catechin derived from green tea, on both the parental lung cancer cells, A549 and H460, and their cisplatin resistant cells, A549/Cis and H460/Cis. ELISA and Western blot analysis revealed that EGCG was able to increase interlukine-6 (IL-6) production per cell, whereas its downstream effector Signal transducers and activators of transcription 3 (STAT3) phosphorylation was not changed by EGCG, indicating that IL-6/STAT3 axis is not the critical signaling to be inhibited by EGCG. We next found that EGCG suppresses the expression of both Axl and Tyro 3 receptor tyrosine kinases at mRNA and protein level, explaining the cytotoxic effect of EGCG on lung cancer cells, especially, regardless of cisplatin resistance. Taken together, these data suggest that EGCG impedes proliferation of lung cancer cells including their chemo-resistant variants through downregulation of Axl and Tyro 3 expression.
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Affiliation(s)
- Kyung-Chan Kim
- Department of Internal Medicine, College of Medicine, Catholic University of Daegu, Daegu 705-718, Korea
| | - Chuhee Lee
- Department of Biochemistry and Molecular Biology, School of Medicine, Yeungnam University, Daegu 705-717, Korea
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Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism. Exp Cell Res 2013; 319:1784-1795. [DOI: 10.1016/j.yexcr.2013.05.001] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 04/02/2013] [Accepted: 05/02/2013] [Indexed: 12/16/2022]
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Lecumberri E, Dupertuis YM, Miralbell R, Pichard C. Green tea polyphenol epigallocatechin-3-gallate (EGCG) as adjuvant in cancer therapy. Clin Nutr 2013; 32:894-903. [PMID: 23582951 DOI: 10.1016/j.clnu.2013.03.008] [Citation(s) in RCA: 171] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 02/26/2013] [Accepted: 03/09/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Green tea catechins, especially epigallocatechin-3-gallate (EGCG), have been associated with cancer prevention and treatment. This has resulted in an increased number of studies evaluating the effects derived from the use of this compound in combination with chemo/radiotherapy. This review aims at compiling latest literature on this subject. METHODS Keywords including EGCG, cancer, chemotherapy, radiotherapy and side effects, were searched using PubMed and ScienceDirect databases to identify, analyze, and summarize the research literature on this topic. Most of the studies on this subject up to date are preclinical. Relevance of the findings, impact factor, and date of publication were critical parameters for the studies to be included in the review. RESULTS Additive and synergistic effects of EGCG when combined with conventional cancer therapies have been proposed, and its anti-inflammatory and antioxidant activities have been related to amelioration of cancer therapy side effects. However, antagonistic interactions with certain anticancer drugs might limit its clinical use. CONCLUSIONS The use of EGCG could enhance the effect of conventional cancer therapies through additive or synergistic effects as well as through amelioration of deleterious side effects. Further research, especially at the clinical level, is needed to ascertain the potential role of EGCG as adjuvant in cancer therapy.
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Affiliation(s)
- Elena Lecumberri
- Clinical Nutrition, Geneva University Hospital, 1211 Geneva, Switzerland
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De Amicis F, Russo A, Avena P, Santoro M, Vivacqua A, Bonofiglio D, Mauro L, Aquila S, Tramontano D, Fuqua SAW, Andò S. In vitro mechanism for downregulation of ER-α expression by epigallocatechin gallate in ER+/PR+ human breast cancer cells. Mol Nutr Food Res 2013; 57:840-53. [PMID: 23322423 DOI: 10.1002/mnfr.201200560] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Revised: 10/24/2012] [Accepted: 12/05/2012] [Indexed: 12/15/2022]
Abstract
SCOPE Exposure of the breast to estrogens and other sex hormones is an important cancer risk factor and estrogen receptor downregulators are attracting significant clinical interest. Epigallocatechin gallate (EGCG), a polyphenolic compound found in green tea, has gained considerable attention for its antitumor properties. Here we aimed to investigate the molecular mechanisms through which EGCG regulates ER-α expression in ER+ PR+ breast cancer cells. MATERIAL AND METHODS Western blotting analysis, real-time PCR, and transient transfections of deletion fragments of the ER-α gene promoter show that EGCG downregulates ER-α protein, mRNA, and gene promoter activity with a concomitant reduction of ER-α genomic and nongenomic signal. These events occur through p38(MAPK) /CK2 activation, causing the release from Hsp90 of progesterone receptor B (PR-B) and its consequent nuclear translocation as evidenced by immunofluorescence studies. EMSA, and ChIP assay reveal that, upon EGCG treatment, PR-B is recruited at the half-PRE site on ER-α promoter. This is concomitant with the formation of a corepressor complex containing NCoR and HDAC1 while RNA polymerase II is displaced. The events are crucially mediated by PR-B isoform, since they are abrogated with PR-B siRNA. CONCLUSION Our data provide evidence for a mechanism by which EGCG downregulates ER-α and explains the inhibitory action of EGCG on the proliferation of ER+ PR+ cancer cells tested. We suggest that the EGCG/PR-B signaling should be further exploited for clinical approach.
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De Amicis F, Santoro M, Guido C, Russo A, Aquila S. Epigallocatechin gallate affects survival and metabolism of human sperm. Mol Nutr Food Res 2012; 56:1655-64. [DOI: 10.1002/mnfr.201200190] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 08/01/2012] [Accepted: 08/13/2012] [Indexed: 11/11/2022]
Affiliation(s)
- Francesca De Amicis
- Centro Sanitario; University of Calabria, Arcavacata di Rende (CS); Italy
- Department of Pharmaco-Biology; University of Calabria; Arcavacata di Rende (CS); Italy
| | - Marta Santoro
- Centro Sanitario; University of Calabria, Arcavacata di Rende (CS); Italy
- Post-graduate School in Clinical Pathology; University of Calabria, Arcavacata di Rende (CS); Italy
| | - Carmela Guido
- Centro Sanitario; University of Calabria, Arcavacata di Rende (CS); Italy
| | - Alessandra Russo
- Centro Sanitario; University of Calabria, Arcavacata di Rende (CS); Italy
| | - Saveria Aquila
- Centro Sanitario; University of Calabria, Arcavacata di Rende (CS); Italy
- Department of Pharmaco-Biology; University of Calabria; Arcavacata di Rende (CS); Italy
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Farabegoli F, Vettraino M, Manerba M, Fiume L, Roberti M, Di Stefano G. Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways. Eur J Pharm Sci 2012; 47:729-38. [PMID: 22954722 DOI: 10.1016/j.ejps.2012.08.012] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2012] [Revised: 07/31/2012] [Accepted: 08/16/2012] [Indexed: 12/13/2022]
Abstract
Galloflavin (GF), a recently identified lactate dehydrogenase inhibitor, hinders the proliferation of cancer cells by blocking glycolysis and ATP production. The aim of the present experiments was to study the effect of this compound on breast cancer cell lines reproducing different pathological subtypes of this tumor: MCF-7 (the well differentiated form), MDA-MB-231 (the aggressive triple negative tumor) and MCF-Tam (a sub-line of MCF-7 with acquired tamoxifen resistance). We observed marked differences in the energetic metabolism of these cell lines. Compared to MCF-7 cells, both MDA-MB-231 and MCF-Tam cells exhibited higher LDH levels and glucose uptake and showed lower capacity of oxygen consumption. In spite of these differences, GF exerted similar growth inhibitory effects. This result was explained by the finding of a constitutively activated stress response in MDA-MB-231 and MCF-Tam cells, which reproduce the poor prognosis tumor forms. As a further proof, different signaling pathways were found to be involved in the antiproliferative action of GF. In MCF-7 cells we observed a down regulation of the ERα-mediated signaling needed for cell survival. On the contrary, in MCF-Tam and MDA-MB-231 cells growth inhibition appeared to be contributed by an oxidative stress condition. The prevalent mechanism of cell death was found to be apoptosis induction. Because of the clinical relevance of breast cancer forms having the triple negative and/or chemoresistant phenotype, our results showing comparable effects of GF even on aggressively growing cells encourage further studies to verify the potential of this compound in improving the chemotherapy of breast cancer.
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Affiliation(s)
- F Farabegoli
- Department of Experimental Pathology, University of Bologna, via San Giacomo 14, 40126 Bologna, Italy
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Crew KD, Brown P, Greenlee H, Bevers TB, Arun B, Hudis C, McArthur HL, Chang J, Rimawi M, Vornik L, Cornelison TL, Wang A, Hibshoosh H, Ahmed A, Terry MB, Santella RM, Lippman SM, Hershman DL. Phase IB randomized, double-blinded, placebo-controlled, dose escalation study of polyphenon E in women with hormone receptor-negative breast cancer. Cancer Prev Res (Phila) 2012; 5:1144-54. [PMID: 22827973 DOI: 10.1158/1940-6207.capr-12-0117] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor-negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade ≥II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400 mg (grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals.
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Affiliation(s)
- Katherine D Crew
- Herbert Irving Comprehensive Cancer Center, Columbia University, 161 Fort Washington Ave, 10-1072, New York, NY 10032, USA.
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Lenz B, Müller CP, Stoessel C, Sperling W, Biermann T, Hillemacher T, Bleich S, Kornhuber J. Sex hormone activity in alcohol addiction: integrating organizational and activational effects. Prog Neurobiol 2011; 96:136-63. [PMID: 22115850 DOI: 10.1016/j.pneurobio.2011.11.001] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2011] [Revised: 11/03/2011] [Accepted: 11/08/2011] [Indexed: 01/06/2023]
Abstract
There are well-known sex differences in the epidemiology and etiopathology of alcohol dependence. Male gender is a crucial risk factor for the onset of alcohol addiction. A directly modifying role of testosterone in alcohol addiction-related behavior is well established. Sex hormones exert both permanent (organizational) and transient (activational) effects on the human brain. The sensitive period for these effects lasts throughout life. In this article, we present a novel early sex hormone activity model of alcohol addiction. We propose that early exposure to sex hormones triggers structural (organizational) neuroadaptations. These neuroadaptations affect cellular and behavioral responses to adult sex hormones, sensitize the brain's reward system to the reinforcing properties of alcohol and modulate alcohol addictive behavior later in life. This review outlines clinical findings related to the early sex hormone activity model of alcohol addiction (handedness, the second-to-fourth-finger length ratio, and the androgen receptor and aromatase) and includes clinical and preclinical literature regarding the activational effects of sex hormones in alcohol drinking behavior. Furthermore, we discuss the role of the hypothalamic-pituitary-adrenal and -gonadal axes and the opioid system in mediating the relationship between sex hormone activity and alcohol dependence. We conclude that a combination of exposure to sex hormones in utero and during early development contributes to the risk of alcohol addiction later in life. The early sex hormone activity model of alcohol addiction may prove to be a valuable tool in the development of preventive and therapeutic strategies.
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Affiliation(s)
- Bernd Lenz
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Germany.
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42
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Wu AH, Butler LM. Green tea and breast cancer. Mol Nutr Food Res 2011; 55:921-30. [PMID: 21538855 DOI: 10.1002/mnfr.201100006] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Revised: 02/16/2011] [Accepted: 03/01/2011] [Indexed: 01/22/2023]
Abstract
The identification of modifiable lifestyle factors that could reduce the risk of breast cancer is a research priority. Despite the enormous chemopreventive potential of green tea and compelling evidence from animal studies, its role in breast cancer development in humans is still unclear. Part of the uncertainty is related to the relatively small number of epidemiological studies on green tea and breast cancer and that the overall results from case-control studies and prospective cohort studies are discordant. In addition, the mechanisms by which green tea intake may influence risk of breast cancer in humans remain not well studied. We review the human studies that have evaluated the relationship between green tea intake and four biomarkers (sex steroid hormones, mammographic density, insulin-like growth factor, adiponectin) that are believed to be important in breast cancer development. Results from these biomarker studies are also inconclusive. Limitations of observational studies and areas of further investigations are discussed.
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Affiliation(s)
- Anna H Wu
- Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
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(-)-Epigallocatechin-3-gallate down-regulates EGFR, MMP-2, MMP-9 and EMMPRIN and inhibits the invasion of MCF-7 tamoxifen-resistant cells. Biosci Rep 2011; 31:99-108. [PMID: 20446926 DOI: 10.1042/bsr20090143] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The activation of the EGFR (epidermal growth factor receptor) signalling pathway is one of the key mechanisms underlying the development of resistance to tamoxifen in breast cancer patients. As EGCG [(-)-epigallocatechin-3-gallate], the most active catechin present in green tea, has been shown to down-regulate EGFR, we studied the effects of 10-100 μg/ml EGCG treatment on growth and invasion in a breast carcinoma cell line resistant to tamoxifen [MCF-7Tam (MCF-7 breast carcinoma cell line resistant to tamoxifen) cells] and parental MCF-7. A dose-dependent down-regulation of EGFR mRNA expression and protein level occurred after 50 μg/ml EGCG treatment of MCF-7Tam cells. EGFR molecules on the plasma membrane surface of MCF-7Tam cells significantly decreased. EGFR phosphorylation (Tyr-992, Tyr-1045 and Tyr-1068) was higher in MCF-7Tam than in MCF-7 and it was reduced by EGCG treatment. ERK (extracellular regulated kinase) and phospho-ERK p42/44 were also down-regulated by EGCG treatment and in vitro cell growth and invasion decreased. MMP-2 (matrix metalloproteinase-2) and MMP-9, which are implicated in cell invasion and metastasis, and EMMPRIN (extracellular matrix metalloproteinase inducer), a glycoprotein able to activate MMPs, were significantly reduced after 50 μg/ml EGCG treatment. In keeping with this, TIMP-1 (tissue inhibitor of metalloproteinases-1) and TIMP-2, which down-regulate MMPs, increased after EGCG treatment. Altogether, the present data demonstrated that EGCG could attenuate the tamoxifen-resistant phenotype of MCF-7Tam cells. EGCG could stop MCF-7Tam cell growth and in vitro invasion through down-regulation of EGFR and other molecules implicated in aggressive biological behaviour. The present data support the hypothesis that EGCG is an interesting molecule to be investigated in tamoxifen-resistant breast carcinoma.
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Kim JH, Pan JH, Heo W, Lee H, Kwon EG, Lee HG, Shin DH, Liu RH, Kim YJ. Effects of cellulase from Aspergillus niger and solvent pretreatments on the extractability of organic green tea waste. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2010; 58:10747-10751. [PMID: 20843026 DOI: 10.1021/jf102346p] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
As green tea is being consumed in larger amounts, more green tea waste is being produced. Following extraction, several bioactive compounds may exist in the waste including polyphenols and amino acids. It was found that an Aspergillus niger cellulase treatment of green tea waste increased the extractability of various nutritional and functional components after pretreatments with various extraction solvents such as cold water (CW), hot water (HW), sulfuric acid (SA), hydrochloric acid (HA), and methanol (Me). After the residue was treated with cellulase from Aspergillus niger, the amounts of polyphenols, total catechins, and reducing sugars in the HW extract were increased by 64.6, 941.2, and 350.9%, respectively. In particular, levels of epigallocatechin, epicatechin, and gallic acid were significantly enhanced compared to those in the nontreated control. However, protein extraction was not significantly affected, and cellulase treatment was not more efficient for caffeine extraction compared to phenolic extraction. Among the four extraction solvents, HW and SA showed relatively higher extractabilities as compared to the other groups (CW, HA, and Me). These results indicate that cellulase from A. niger can increase the extractability of green tea waste when combined with certain solvent pretreatments. Consequently, the residual functional compounds and essential nutrients from cellulase-treated green tea waste have the potential to be applied in the production of new functional foods.
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Affiliation(s)
- Jae Hun Kim
- Department of Food and Biotechnology, Korea University, Chunggnam 339-700, Korea
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45
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Fernandez JW, Rezai-Zadeh K, Obregon D, Tan J. EGCG functions through estrogen receptor-mediated activation of ADAM10 in the promotion of non-amyloidogenic processing of APP. FEBS Lett 2010; 584:4259-67. [PMID: 20849853 DOI: 10.1016/j.febslet.2010.09.022] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Revised: 08/29/2010] [Accepted: 09/10/2010] [Indexed: 01/21/2023]
Abstract
Estrogen depletion following menopause has been correlated with an increased risk of developing Alzheimer's disease (AD). We previously explored the beneficial effect of (-)-epigallocatechin-3-gallate (EGCG) on AD mice and found increased non-amyloidogenic processing of amyloid precursor protein (APP) through the α-secretase a disintegrin and metallopeptidase domain 10 (ADAM10). Our results in this study suggest that EGCG-mediated enhancement of non-amyloidogenic processing of APP is mediated by the maturation of ADAM10 via an estrogen receptor-α (ERα)/phosphoinositide 3-kinase/Ak-transforming dependent mechanism, independent of furin-mediated ADAM10 activation. These data support prior assertions that central selective ER modulation could be a therapeutic target for AD and support the use of EGCG as a well-tolerated alternative to estrogen therapy in the prophylaxis and treatment of this disease.
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Affiliation(s)
- Jamie Winderbaum Fernandez
- Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Tampa, FL 33613, USA.
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Tran PLCHB, Kim SA, Choi HS, Yoon JH, Ahn SG. Epigallocatechin-3-gallate suppresses the expression of HSP70 and HSP90 and exhibits anti-tumor activity in vitro and in vivo. BMC Cancer 2010; 10:276. [PMID: 20537126 PMCID: PMC2927993 DOI: 10.1186/1471-2407-10-276] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2009] [Accepted: 06/10/2010] [Indexed: 11/13/2022] Open
Abstract
Background Epigallocatechin-3-gallate (EGCG), one of the major catechins in green tea, is a potential chemopreventive agent for various cancers. The aim of this study was to examine the effect of EGCG on the expression of heat shock proteins (HSPs) and tumor suppression. Methods Cell colony formation was evaluated by a soft agar assay. Transcriptional activity of HSP70 and HSP90 was determined by luciferase reporter assay. An EGCG-HSPs complex was prepared using EGCG attached to the cyanogen bromide (CNBr)-activated Sepharose 4B. In vivo effect of EGCG on tumor growth was examined in a xenograft model. Results Treatment with EGCG decreased cell proliferation and colony formation of MCF-7 human breast cancer cells. EGCG specifically inhibited the expression of HSP70 and HSP90 by inhibiting the promoter activity of HSP70 and HSP90. Pretreatment with EGCG increased the stress sensitivity of MCF-7 cells upon heat shock (44°C for 1 h) or oxidative stress (H2O2, 500 μM for 24 h). Moreover, treatment with EGCG (10 mg/kg) in a xenograft model resulted in delayed tumor incidence and reduced tumor size, as well as the inhibition of HSP70 and HSP90 expression. Conclusions Overall, these findings demonstrate that HSP70 and HSP90 are potent molecular targets of EGCG and suggest EGCG as a drug candidate for the treatment of human cancer.
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Affiliation(s)
- Phan L C H B Tran
- Department of Pathology, Chosun University, College of Dentistry, Gwangju 501-759, Republic of Korea
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Wang P, Henning SM, Heber D. Limitations of MTT and MTS-based assays for measurement of antiproliferative activity of green tea polyphenols. PLoS One 2010; 5:e10202. [PMID: 20419137 PMCID: PMC2855713 DOI: 10.1371/journal.pone.0010202] [Citation(s) in RCA: 266] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Accepted: 03/25/2010] [Indexed: 01/19/2023] Open
Abstract
Background The chemopreventive effect of green tea polyphenols, such as (-)-epigallocatechin-3-gallate (EGCG), has been well demonstrated in cell culture studies. However, a wide range of IC50 concentrations has been observed in published studies of the anti-proliferative activity of EGCG from different laboratories. Although the susceptibility to EGCG treatment is largely dependent on cancer cell type, the particular cell viability and proliferation assays utilized may significantly influence quantitative results reported in the literature. Methodology/Principal Findings We compared five widely used methods to measure cell proliferation and viability after EGCG treatment using LNCaP prostate cancer cells and MCF-7 breast cancer cells. Both methods using dyes to quantify adenosine triphosphate (ATP) and deoxynucleic acid (DNA) showed accuracy in the measurement of viable cells when compared to trypan blue assay and results showed good linear correlation (r = 0.95). However, the use of MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) as indicators of metabolically active mitochondria overestimated the number of viable cells by comparison with the ATP, DNA, or trypan blue determinations. As a result, the observed IC50 concentration of EGCG was 2-fold higher using MTT and MTS compared to dyes quantifying ATP and DNA. In contrast, when cells were treated with apigenin MTT and MTS assays showed consistent results with ATP, DNA, or trypan blue assays. Conclusions/Significance These results demonstrate that MTT and MTS -based assays will provide an underestimation of the anti-proliferative effect of EGCG, and suggest the importance of careful evaluation of the method for in vitro assessment of cell viability and proliferation depending on the chemical nature of botanical supplements.
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Affiliation(s)
- Piwen Wang
- Center for Human Nutrition, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Susanne M. Henning
- Center for Human Nutrition, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
- * E-mail:
| | - David Heber
- Center for Human Nutrition, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
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Farabegoli F, Papi A, Bartolini G, Ostan R, Orlandi M. (-)-Epigallocatechin-3-gallate downregulates Pg-P and BCRP in a tamoxifen resistant MCF-7 cell line. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2010; 17:356-362. [PMID: 20149610 DOI: 10.1016/j.phymed.2010.01.001] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2009] [Revised: 10/28/2009] [Accepted: 01/14/2010] [Indexed: 05/28/2023]
Abstract
We investigated the anticancer effect of EGCG treatment on a breast carcinoma cell line resistant to tamoxifen (MCF-7Tam cells). As there are no reports about the molecular mechanisms implicated in EGCG treatment of tamoxifen resistant breast carcinoma cells, we studied the effects of EGCG treatment on three plasma membrane proteins that are involved in the mechanism of drug-resistance: Multidrug Resistance Protein (MRP1), P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). EGCG treatment (10-100 microg/ml for 24-72 hours) caused cell growth inhibition and dose-dependent apoptosis: after 100 microg/ml EGCG treatment for 24 hours, Bax expression increased and Bcl2 expression decreased (p<0.05). Coherently, Annexin V-FITC apoptosis assay detected a significant increase in labelled cells (p<0.05). EGCG did not affect MRP1: in contrast, 100 microg/ml EGCG administration caused P-gp decrease to 53% of control cells (p<0.001) and this effect was not due to downregulation of P-gp gene expression. EGCG induced P-gp decrease even when MG132, a strong proteasome inhibitor, was given together with EGCG to MCF-7Tam cells. EGCG treatment also inhibited BCRP activity: mRNA transcription and protein level did not change after treatment, but mitoxantrone test demonstrated a strong inhibition of BCRP activity (p<0.001). In conclusion, the present results showed that EGCG could down-regulate the activity of two molecules that play a key role in drug metabolism and transport and that are highly expressed in tamoxifen resistant breast carcinoma cells. The interaction of EGCG and drugs used in the therapy of estrogen sensitive breast carcinoma ought to be subject of studies and the potential use of EGCG in drug-resistant diseases ought to be better considered.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters/genetics
- ATP-Binding Cassette Transporters/metabolism
- Antineoplastic Agents, Phytogenic/pharmacology
- Antineoplastic Agents, Phytogenic/therapeutic use
- Apoptosis/drug effects
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Camellia sinensis/chemistry
- Catechin/analogs & derivatives
- Catechin/pharmacology
- Catechin/therapeutic use
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Dose-Response Relationship, Drug
- Down-Regulation
- Drug Resistance, Neoplasm/drug effects
- Gene Expression
- Humans
- Leupeptins/pharmacology
- Mitoxantrone/pharmacology
- Multidrug Resistance-Associated Proteins/genetics
- Multidrug Resistance-Associated Proteins/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Plant Extracts/pharmacology
- Plant Extracts/therapeutic use
- Protease Inhibitors/pharmacology
- Protease Inhibitors/therapeutic use
- Proto-Oncogene Proteins c-bcl-2/metabolism
- RNA, Messenger/metabolism
- Tamoxifen
- bcl-2-Associated X Protein/metabolism
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Affiliation(s)
- F Farabegoli
- Department of Experimental Pathology, Via San Giacomo, 14, University of Bologna, 40126 Bologna, Italy.
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Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells. Cell Mol Immunol 2010; 7:123-32. [PMID: 20140007 DOI: 10.1038/cmi.2010.1] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Epigallocatechin-3-gallate (EGCG), a bioactive component of green tea, has been reported to exert anti-inflammatory effects on immune cells. EGCG is also shown to activate the metabolic regulator, adenosine 5'-monophosphate-activated protein kinase (AMPK). Reports have also indicated that EGCG inhibits the immune-stimulated phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. The PI3K/Akt/mTOR pathway has been implicated in mesangial cell activation in lupus. Mesangial cells from MRL/lpr lupus-like mice are hyper-responsive to immune stimulation and overproduce nitric oxide (NO) and other inflammatory mediators when stimulated. In our current studies, we sought to determine the mechanism by which EGCG attenuates immune-induced expression of pro-inflammatory mediators. Cultured mesangial cells from MRL/lpr mice were pre-treated with various concentrations of EGCG and stimulated with lipopolysaccharide (LPS)/interferon (IFN)-gamma. EGCG activated AMPK and blocked LPS/IFN-gamma-induced inflammatory mediator production (iNOS expression, supernatant NO and interleukin-6). Interestingly, EGCG attenuated inflammation during AMPK inhibition indicating that the anti-inflammatory effect of EGCG may be partially independent of AMPK activation. Furthermore, we found that EGCG effectively inhibited the immune-stimulated PI3K/Akt/mTOR pathway independently of AMPK, by decreasing phosphorylation of Akt, suggesting an alternate mechanism for EGCG-mediated anti-inflammatory action in mesangial cells. Taken together, these studies show that EGCG attenuated inflammation in MRL/lpr mouse mesangial cells via the PI3K/Akt/mTOR pathway. Our findings suggest a potential therapeutic role for the use of EGCG to regulate inflammation and control autoimmune disease.
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Monteiro R, Assunção M, Andrade JP, Neves D, Calhau C, Azevedo I. Chronic green tea consumption decreases body mass, induces aromatase expression, and changes proliferation and apoptosis in adult male rat adipose tissue. J Nutr 2008; 138:2156-63. [PMID: 18936213 DOI: 10.1093/jn/138.11.2156] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Green tea (GT) and its components have been shown to possess antiobesity properties and the corresponding mechanisms of action are being investigated, given the epidemic proportions of obesity incidence. In the current work, we used 12-mo-old male Wistar rats to test the effect of 6 mo of treatment with GT as the sole drinking beverage (52.8 +/- 6.4 mL/d) on adipose tissue (AT). AT aromatase expression was determined by Western blotting, plasma concentrations of 17beta-estradiol and testosterone were determined by RIA, and adipocyte size determined by measuring diameter in tissue sections. Proliferation and apoptosis were also assessed by Ki67 immunostaining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling, respectively. Evaluations were made in subcutaneous (sc) AT and visceral (v) AT. Body weight increased over time in both groups (P < 0.001), but the increase was more pronounced in controls (P < 0.001) and food and fluid intake did not influence that effect. At the end of the experiment, aromatase expression increased in the AT (318.5 +/- 60.6% of control in scAT, P < 0.05, and 285.5 +/- 82.9% of control in vAT, P < 0.01). AT of GT-treated rats had a higher percentage of proliferating cells (204.1 +/- 19.5% of control in scAT, P < 0.01, and 246.6 +/- 50.2% of control in vAT, P < 0.01) and smaller adipocytes (78.3 +/- 1.7% of control in scAT, P < 0.001, and 87.9 +/- 3.2% of control in vAT, P < 0.05). GT also increased the number of apoptotic cells in vAT (320.4 +/- 21.9% of control; P < 0.001). These results suggest new mechanisms for GT on body weight and highlight its potential benefit to prevent or treat obesity and the metabolic syndrome.
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Affiliation(s)
- Rosário Monteiro
- Department of Biochemistry, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
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