title: Bilberry extract (Antho 50) selectively induces redox-sensitive caspase 3-related apoptosis in chronic lymphocytic leukemia cells by targeting the Bcl-2/Bad pathway.
abstract: Defect in apoptosis has been implicated as a major cause of resistance to chemotherapy observed in B cell chronic lymphocytic leukaemia (B CLL). This study evaluated the pro-apoptotic effect of an anthocyanin-rich dietary bilberry extract (Antho 50) on B CLL cells from 30 patients and on peripheral blood mononuclear cells (PBMCs) from healthy subjects, and determined the underlying mechanism. Antho 50 induced concentration- and time-dependent pro-apoptotic effects in B CLL cells but little or no effect in PBMCs. Among the main phenolic compounds of the bilberry extract, delphinidin-3-O-glucoside and delphinidin-3-O-rutinoside induced a pro-apoptotic effect. Antho 50-induced apoptosis is associated with activation of caspase 3, down-regulation of UHRF1, a rapid dephosphorylation of Akt and Bad, and down-regulation of Bcl-2. Antho 50 significantly induced PEG-catalase-sensitive formation of reactive oxygen species in B CLL cells. PEG-catalase prevented the Antho 50-induced induction of apoptosis and related signaling. The present findings indicate that Antho 50 exhibits strong pro-apoptotic activity through redox-sensitive caspase 3 activation-related mechanism in B CLL cells involving dysregulation of the Bad/Bcl-2 pathway. This activity of Antho 50 involves the glucoside and rutinoside derivatives of delphinidin. They further suggest that Antho 50 has chemotherapeutic potential by targeting selectively B CLL cells.
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch, France.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Alhosin
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch, France.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: León-González
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch, France.
authors.forename: Israa
authors.initials: I
authors.lastname: Dandache
authors.affiliation: 1] CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch, France [2] Oncologie et Hématologie, Hôpitaux Universitaires de Strasbourg, Avenue Molière, 67100 Strasbourg, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Lelay
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch, France.
authors.forename: Sherzad K
authors.initials: SK
authors.lastname: Rashid
authors.affiliation: University of Liège, Plant Molecular Biology and Biotechnology Unit, B22, Sart Tilman, B-4000 Liège, Belgium.
authors.forename: Claire
authors.initials: C
authors.lastname: Kevers
authors.affiliation: Dept. of Cardiovascular Surgery and CREDEC, Pathology Tower B23, Sart Tilman, B-4000 Liège, Belgium.
authors.forename: Joël
authors.initials: J
authors.lastname: Pincemail
authors.affiliation: 1] Oncologie et Hématologie, Hôpitaux Universitaires de Strasbourg, Avenue Molière, 67100 Strasbourg, France [2] Université de Strasbourg, Faculté de Médecine, Strasbourg, France.
authors.forename: Luc-Matthieu
authors.initials: LM
authors.lastname: Fornecker
authors.affiliation: 1] Université de Strasbourg, Faculté de Médecine, Strasbourg, France [2] Laboratoire d'Hématologie, Hôpitaux Universitaires de Strasbourg, Avenue Molière, 67100 Strasbourg, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mauvieux
authors.affiliation: 1] Oncologie et Hématologie, Hôpitaux Universitaires de Strasbourg, Avenue Molière, 67100 Strasbourg, France [2] Université de Strasbourg, Faculté de Médecine, Strasbourg, France.
authors.forename: Raoul
authors.initials: R
authors.lastname: Herbrecht
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch, France.
authors.forename: Valérie B
authors.initials: VB
authors.lastname: Schini-Kerth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000872:Anthocyanins / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D005960:Glucosides / Q000494:pharmacology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D029800:Vaccinium myrtillus / Q000737:chemistry*; D051025:bcl-Associated Death Protein / Q000378:metabolism*
chemical_list: D000872:Anthocyanins; D051017:Apoptosis Regulatory Proteins; D005960:Glucosides; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051025:bcl-Associated Death Protein; C494120:delphinidin 3-O-glucopyranoside; D053148:Caspase 3