Mangiferin Has an Additive Effect on the Apoptotic Properties of Hesperidin in Cyclopia sp. Tea Extracts

A variety of biological pro-health activities have been reported for mangiferin and hesperidin, two major phenolic compounds of Honeybush (Cyclopia sp.) tea extracts. Given their increasing popularity, there is a need for understanding the mechanisms underlying the biological effects of these compounds. In this study, we used real-time cytotoxicity cellular analysis of the Cyclopia sp. extracts on HeLa cells and found that the higher hesperidin content in non-fermented "green" extracts correlated with their higher cytotoxicity compared to the fermented extracts. We also found that mangiferin had a modulatory effect on the apoptotic effects of hesperidin. Quantitative PCR analysis of hesperidin-induced changes in apoptotic gene expression profile indicated that two death receptor pathway members, TRADD and TRAMP, were up regulated. The results of this study suggest that hesperidin mediates apoptosis in HeLa cells through extrinsic pathway for programmed cell death.

[1]  A. Taga,et al.  Mangiferin induces apoptosis by suppressing Bcl-xL and XIAP expressions and nuclear entry of NF-κB in HL-60 cells , 2011, Archives of pharmacal research.

[2]  D. Goeddel,et al.  The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. , 1995, Cell.

[3]  Krishnendu Sinha,et al.  Mangiferin, a Natural Xanthone, Protects Murine Liver in Pb(II) Induced Hepatic Damage and Cell Death via MAP Kinase, NF-κB and Mitochondria Dependent Pathways , 2013, PloS one.

[4]  K. Srinivasan,et al.  Effect of mangiferin on hyperglycemia and atherogenicity in streptozotocin diabetic rats. , 2005, Journal of ethnopharmacology.

[5]  B. Periyasamy,et al.  Effect of flavonone hesperidin on the apoptosis of human mammary carcinoma cell line MCF-7 , 2011 .

[6]  G. Zdunić,et al.  Radioprotective activity of Gentiana lutea extract and mangiferin , 2010, Phytotherapy research : PTR.

[7]  I. Nishigaki,et al.  Immunomodulatory Effect of Mangiferin in Experimental Animals with Benzo(a)Pyrene-induced Lung Carcinogenesis , 2013, International journal of biomedical science : IJBS.

[8]  A. Kotani,et al.  Determination of hesperidin in Pericarpium Citri Reticulatae by semi-micro HPLC with electrochemical detection. , 2006, Journal of pharmaceutical and biomedical analysis.

[9]  K. Knutson,et al.  Determining optimal cytotoxic activity of human Her2neu specific CD8 T cells by comparing the Cr51 release assay to the xCELLigence system. , 2012, Journal of visualized experiments : JoVE.

[10]  M. van de Venter,et al.  Combination treatment with oxaliplatin and mangiferin causes increased apoptosis and downregulation of NFκB in cancer cell lines. , 2011, African journal of traditional, complementary, and alternative medicines : AJTCAM.

[11]  C. Teng,et al.  Vasorelaxation of rat thoracic aorta caused by norathyriol isolated from Gentianaceae. , 1991, European journal of pharmacology.

[12]  T. Dzieciątkowski,et al.  The xCELLigence system for real-time and label-free analysis of neuronal and dermal cell response to equine herpesvirus type 1 infection. , 2012, Polish journal of veterinary sciences.

[13]  J. Irelan,et al.  Label-free monitoring of T cell activation by the impedance-based xCELLigence system. , 2013, Molecular bioSystems.

[14]  Y. E. Chin,et al.  Stat1 as a Component of Tumor Necrosis Factor Alpha Receptor 1-TRADD Signaling Complex To Inhibit NF-κB Activation , 2000, Molecular and Cellular Biology.

[15]  F. Ondrey,et al.  Peroxisome Proliferator-Activated Receptor γ Pathway Targeting in Carcinogenesis: Implications for Chemoprevention , 2009, Clinical Cancer Research.

[16]  K. Bauer,et al.  Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-κB , 1996, Current Biology.

[17]  Z. Lu,et al.  Antiviral effect of mangiferin and isomangiferin on herpes simplex virus. , 1990, Chinese medical journal.

[18]  J. Das,et al.  Mangiferin exerts hepatoprotective activity against D-galactosamine induced acute toxicity and oxidative/nitrosative stress via Nrf2-NFκB pathways. , 2012, Toxicology and applied pharmacology.

[19]  Xin-yang Wang,et al.  Silencing livin gene by siRNA leads to apoptosis induction, cell cycle arrest, and proliferation inhibition in malignant melanoma LiBr cells , 2007, Acta Pharmacologica Sinica.

[20]  Stefan Wiemann,et al.  MicroRNA-200c Represses Migration and Invasion of Breast Cancer Cells by Targeting Actin-Regulatory Proteins FHOD1 and PPM1F , 2011, Molecular and Cellular Biology.

[21]  Gilles Caraux,et al.  PermutMatrix: a graphical environment to arrange gene expression profiles in optimal linear order , 2005, Bioinform..

[22]  J-H Chung,et al.  Apoptotic effect of hesperidin through caspase3 activation in human colon cancer cells, SNU-C4. , 2008, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[23]  D. Goeddel,et al.  The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation , 1995, Cell.

[24]  Rafał Bartoszewski,et al.  CFTR expression regulation by the unfolded protein response. , 2011, Methods in enzymology.

[25]  D. Ferreira,et al.  Polyphenols from Honeybush tea (Cyclopia intermedia). , 2003, Journal of agricultural and food chemistry.

[26]  Jessica Tang,et al.  Hesperidin suppressed proliferations of both Human breast cancer and androgen‐dependent prostate cancer cells , 2010, Phytotherapy research : PTR.

[27]  S. Kao,et al.  The inhibitory effect of hesperidin on tumor cell invasiveness occurs via suppression of activator protein 1 and nuclear factor-kappaB in human hepatocellular carcinoma cells. , 2010, Toxicology letters.

[28]  F. Hoppe-Seyler,et al.  Induction of apoptosis in tumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene , 2003, Oncogene.

[29]  Wei Cheng,et al.  Mangiferin exerts antitumor activity in breast cancer cells by regulating matrix metalloproteinases, epithelial to mesenchymal transition, and β-catenin signaling pathway. , 2013, Toxicology and applied pharmacology.

[30]  Hong-Bing Shu,et al.  TRADD–TRAF2 and TRADD–FADD Interactions Define Two Distinct TNF Receptor 1 Signal Transduction Pathways , 1996, Cell.

[31]  J. Wan,et al.  Anti-inflammatory effects of mangiferin on sepsis-induced lung injury in mice via up-regulation of heme oxygenase-1. , 2013, The Journal of nutritional biochemistry.

[32]  S. Garg,et al.  Chemistry and pharmacology of the citrus bioflavonoid hesperidin , 2001, Phytotherapy research : PTR.

[33]  M. Venter,et al.  COMBINATION TREATMENT WITH OXALIPLATIN AND MANGIFERIN CAUSES INCREASED APOPTOSIS AND DOWNREGULATION OF NFΚB IN CANCER CELL LINES , 2011 .

[34]  Zheng‐gang Liu,et al.  The Adaptor Protein TRADD Is Essential for TNF-Like Ligand 1A/Death Receptor 3 Signaling , 2011, The Journal of Immunology.

[35]  M. Manley,et al.  Rapid screening methods for estimation of mangiferin and xanthone contents of Cyclopia subternata plant material , 2012 .

[36]  Andreas Krause,et al.  A standard curve based method for relative real time PCR data processing , 2005, BMC Bioinformatics.

[37]  E. Joubert,et al.  Reversed-phase HPLC determination of mangiferin, isomangiferin and hesperidin in Cyclopia and the effect of harvesting date on the phenolic composition of C. genistoides , 2003 .

[38]  Jiake Xu,et al.  Mangiferin attenuates osteoclastogenesis, bone resorption, and RANKL‐induced activation of NF‐κB and ERK , 2011, Journal of cellular biochemistry.

[39]  A. Buciński,et al.  Micropropagation of Cyclopia genistoides, an Endemic South African Plant of Economic Importance , 2012, Zeitschrift fur Naturforschung. C, Journal of biosciences.

[40]  J. Tschopp,et al.  TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95). , 1997, Immunity.

[41]  L. Busund,et al.  Cancer-associated fibroblasts from human NSCLC survive ablative doses of radiation but their invasive capacity is reduced , 2012, Radiation Oncology.

[42]  Thomas D. Schmittgen,et al.  Analyzing real-time PCR data by the comparative CT method , 2008, Nature Protocols.

[43]  J. Das,et al.  D(+) galactosamine induced oxidative and nitrosative stress-mediated renal damage in rats via NF-κB and inducible nitric oxide synthase (iNOS) pathways is ameliorated by a polyphenol xanthone, mangiferin , 2012, Free radical research.

[44]  M. Jeddi-Tehrani,et al.  Inactivation of nuclear factor-κB by citrus flavanone hesperidin contributes to apoptosis and chemo-sensitizing effect in Ramos cells. , 2011, European journal of pharmacology.

[45]  C. Teng,et al.  Novel inhibitory actions on platelet thromboxane and inositolphosphate formation by xanthones and their glycosides. , 1989, Biochemical Pharmacology.

[46]  S. Guha,et al.  Antitumor, immunomodulatory and anti-HIV effect of mangiferin, a naturally occurring glucosylxanthone. , 1996, Chemotherapy.

[47]  J. V. Vanden Heuvel Peroxisome proliferator-activated receptors (PPARS) and carcinogenesis. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[48]  Eric O'Neill,et al.  Use of the xCELLigence system for real-time analysis of changes in cellular motility and adhesion in physiological conditions. , 2013, Methods in molecular biology.

[49]  M. Jeddi-Tehrani,et al.  The citrus flavonoid hesperidin induces p53 and inhibits NF-κB activation in order to trigger apoptosis in NALM-6 cells: involvement of PPARγ-dependent mechanism , 2012, European Journal of Nutrition.