title: Aronia melanocarpa juice induces a redox-sensitive p73-related caspase 3-dependent apoptosis in human leukemia cells.
abstract: Polyphenols are natural compounds widely present in fruits and vegetables, which have antimutagenic and anticancer properties. The aim of the present study was to determine the anticancer effect of a polyphenol-rich Aronia melanocarpa juice (AMJ) containing 7.15 g/L of polyphenols in the acute lymphoblastic leukemia Jurkat cell line, and, if so, to clarify the underlying mechanism and to identify the active polyphenols involved. AMJ inhibited cell proliferation, which was associated with cell cycle arrest in G(2)/M phase, and caused the induction of apoptosis. These effects were associated with an upregulation of the expression of tumor suppressor p73 and active caspase 3, and a downregulation of the expression of cyclin B1 and the epigenetic integrator UHRF1. AMJ significantly increased the formation of reactive oxygen species (ROS), decreased the mitochondrial membrane potential and caused the release of cytochrome c into the cytoplasm. Treatment with intracellular ROS scavengers prevented the AMJ-induced apoptosis and upregulation of the expression of p73 and active caspase 3. The fractionation of the AMJ and the use of identified isolated compounds indicated that the anticancer activity was associated predominantly with chlorogenic acids, some cyanidin glycosides, and derivatives of quercetin. AMJ treatment also induced apoptosis of different human lymphoblastic leukemia cells (HSB-2, Molt-4 and CCRF-CEM). In addition, AMJ exerted a strong pro-apoptotic effect in human primary lymphoblastic leukemia cells but not in human normal primary T-lymphocytes. Thus, the present findings indicate that AMJ exhibits strong anticancer activity through a redox-sensitive mechanism in the p53-deficient Jurkat cells and that this effect involves several types of polyphenols. They further suggest that AMJ has chemotherapeutic properties against acute lymphoblastic leukemia by selectively targeting lymphoblast-derived tumor cells.
authors.affiliation: UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
authors.forename: Tanveer
authors.initials: T
authors.lastname: Sharif
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Alhosin
authors.forename: Cyril
authors.initials: C
authors.lastname: Auger
authors.forename: Carole
authors.initials: C
authors.lastname: Minker
authors.forename: Jong-Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Nelly
authors.initials: N
authors.lastname: Etienne-Selloum
authors.forename: Pierre
authors.initials: P
authors.lastname: Bories
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: Annelise
authors.initials: A
authors.lastname: Lobstein
authors.forename: Christian
authors.initials: C
authors.lastname: Bronner
authors.forename: Guy
authors.initials: G
authors.lastname: Fuhrmann
authors.forename: Valérie B
authors.initials: VB
authors.lastname: Schini-Kerth
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000378:metabolism*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D046936:Photinia / Q000737:chemistry*; D010936:Plant Extracts / Q000494:pharmacology*; D059808:Polyphenols / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010936:Plant Extracts; D059808:Polyphenols; D017382:Reactive Oxygen Species; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D045304:Cytochromes c; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases; D053148:Caspase 3