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Bilberry extract (Antho 50) selectively induces redox-sensitive caspase 3-related apoptosis in chronic lymphocytic leukemia cells by targeting the Bcl-2/Bad pathway.

Alhosin M, León-González AJ, Dandache I, Lelay A, Rashid SK, Kevers C, Pincemail J, Fornecker LM, Mauvieux L, Herbrecht R, Schini-Kerth VB - Sci Rep (2015)

Bottom Line: 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.This activity of Antho 50 involves the glucoside and rutinoside derivatives of delphinidin.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch, France.

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.

No MeSH data available.


Related in: MedlinePlus

Chemical structures of anthocyanins present in Antho 50 (A): cyanidin-3-O-glucoside (1), cyanidin-3-O-galactoside (2), cyanidin-3-O-rutinoside (3), delphinidin-3-O-glucoside (4), delphinidin-3-O-galactoside (5) and delphinidin-3-O-rutinoside (6).B CLL cells were exposed to 30 or 100 μM of the indicated anthocyanin for 24 h. Then apoptosis rate was determined by flow cytometry using annexin V-FITC/PI assay (B). The control (Ctr) represents untreated cells. The data are representative of cells from four CLL patients. Values are shown as means ± S.E.M. (n = 4); ***, P < 0.001 versus control.
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f2: Chemical structures of anthocyanins present in Antho 50 (A): cyanidin-3-O-glucoside (1), cyanidin-3-O-galactoside (2), cyanidin-3-O-rutinoside (3), delphinidin-3-O-glucoside (4), delphinidin-3-O-galactoside (5) and delphinidin-3-O-rutinoside (6).B CLL cells were exposed to 30 or 100 μM of the indicated anthocyanin for 24 h. Then apoptosis rate was determined by flow cytometry using annexin V-FITC/PI assay (B). The control (Ctr) represents untreated cells. The data are representative of cells from four CLL patients. Values are shown as means ± S.E.M. (n = 4); ***, P < 0.001 versus control.

Mentions: In order to determine the pro-apoptotic activity of pure anthocyanins, B CLL cells were incubated for 24 h with 30 or 100 μM of six commercially available anthocyanins: cyanidin-3-O-glucoside (1), cyanidin-3-O-galactoside (2), cyanidin-3-O-rutinoside (3), delphinidin-3-O-glucoside (4), delphinidin-3-O-galactoside (5) and delphinidin-3-O-rutinoside (6) (Fig. 2A). Then, the level of apoptosis was determined by flow cytometry. Treatment of B CLL cells with glucoside and rutinoside delphinidin derivatives increased the percentage of apoptotic cells, whereas delphinidin-3-O-galactoside and the cyanidin derivatives had only minor effects (Fig. 2B).


Bilberry extract (Antho 50) selectively induces redox-sensitive caspase 3-related apoptosis in chronic lymphocytic leukemia cells by targeting the Bcl-2/Bad pathway.

Alhosin M, León-González AJ, Dandache I, Lelay A, Rashid SK, Kevers C, Pincemail J, Fornecker LM, Mauvieux L, Herbrecht R, Schini-Kerth VB - Sci Rep (2015)

Chemical structures of anthocyanins present in Antho 50 (A): cyanidin-3-O-glucoside (1), cyanidin-3-O-galactoside (2), cyanidin-3-O-rutinoside (3), delphinidin-3-O-glucoside (4), delphinidin-3-O-galactoside (5) and delphinidin-3-O-rutinoside (6).B CLL cells were exposed to 30 or 100 μM of the indicated anthocyanin for 24 h. Then apoptosis rate was determined by flow cytometry using annexin V-FITC/PI assay (B). The control (Ctr) represents untreated cells. The data are representative of cells from four CLL patients. Values are shown as means ± S.E.M. (n = 4); ***, P < 0.001 versus control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4355738&req=5

f2: Chemical structures of anthocyanins present in Antho 50 (A): cyanidin-3-O-glucoside (1), cyanidin-3-O-galactoside (2), cyanidin-3-O-rutinoside (3), delphinidin-3-O-glucoside (4), delphinidin-3-O-galactoside (5) and delphinidin-3-O-rutinoside (6).B CLL cells were exposed to 30 or 100 μM of the indicated anthocyanin for 24 h. Then apoptosis rate was determined by flow cytometry using annexin V-FITC/PI assay (B). The control (Ctr) represents untreated cells. The data are representative of cells from four CLL patients. Values are shown as means ± S.E.M. (n = 4); ***, P < 0.001 versus control.
Mentions: In order to determine the pro-apoptotic activity of pure anthocyanins, B CLL cells were incubated for 24 h with 30 or 100 μM of six commercially available anthocyanins: cyanidin-3-O-glucoside (1), cyanidin-3-O-galactoside (2), cyanidin-3-O-rutinoside (3), delphinidin-3-O-glucoside (4), delphinidin-3-O-galactoside (5) and delphinidin-3-O-rutinoside (6) (Fig. 2A). Then, the level of apoptosis was determined by flow cytometry. Treatment of B CLL cells with glucoside and rutinoside delphinidin derivatives increased the percentage of apoptotic cells, whereas delphinidin-3-O-galactoside and the cyanidin derivatives had only minor effects (Fig. 2B).

Bottom Line: 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.This activity of Antho 50 involves the glucoside and rutinoside derivatives of delphinidin.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch, France.

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.

No MeSH data available.


Related in: MedlinePlus