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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

Antho 50 induces dephosphorylation of Akt at Ser473, Bad at Ser112 and down-regulation of Bcl-2 in B CLL cells.Cells were incubated with Antho 50 at 75 μg/mL for the indicated times. The expression of the p-Akt, p-Bad and Bcl-2 was studied by Western blot (A, upper panel) and their expression levels were analyzed by densitometry and represented as percentage compared with control (A, lower panel). Cell viability was assessed by cell counting using the trypan blue dye exclusion assay (B). The control (Ctr) represents untreated cells harvested at 6 h. The data are representative of cells from three CLL patients.
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f4: Antho 50 induces dephosphorylation of Akt at Ser473, Bad at Ser112 and down-regulation of Bcl-2 in B CLL cells.Cells were incubated with Antho 50 at 75 μg/mL for the indicated times. The expression of the p-Akt, p-Bad and Bcl-2 was studied by Western blot (A, upper panel) and their expression levels were analyzed by densitometry and represented as percentage compared with control (A, lower panel). Cell viability was assessed by cell counting using the trypan blue dye exclusion assay (B). The control (Ctr) represents untreated cells harvested at 6 h. The data are representative of cells from three CLL patients.

Mentions: The Bcl-2 family plays a key regulatory role in cellular responses to treatment via its pro- and anti-apoptotic properties27. The anti-apoptotic protein Bcl-2 is overexpressed in several hematological malignancies including CLL and this overexpression is considered primarily responsible for defective apoptosis in CLL28. We therefore evaluated the effect of Antho 50 treatment on the expression of two major members of the Bcl-2 family, Bcl-2 and p-Bad in cells from 3 CLL patients. As shown in Fig. 4A, a reduced Bcl-2 level was observed in CLL cells as a function of the treatment time with Antho 50. The down-regulation of Bcl-2 was accompanied by a reduction of cell viability starting at 1 h (Fig. 4B).


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)

Antho 50 induces dephosphorylation of Akt at Ser473, Bad at Ser112 and down-regulation of Bcl-2 in B CLL cells.Cells were incubated with Antho 50 at 75 μg/mL for the indicated times. The expression of the p-Akt, p-Bad and Bcl-2 was studied by Western blot (A, upper panel) and their expression levels were analyzed by densitometry and represented as percentage compared with control (A, lower panel). Cell viability was assessed by cell counting using the trypan blue dye exclusion assay (B). The control (Ctr) represents untreated cells harvested at 6 h. The data are representative of cells from three CLL patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Antho 50 induces dephosphorylation of Akt at Ser473, Bad at Ser112 and down-regulation of Bcl-2 in B CLL cells.Cells were incubated with Antho 50 at 75 μg/mL for the indicated times. The expression of the p-Akt, p-Bad and Bcl-2 was studied by Western blot (A, upper panel) and their expression levels were analyzed by densitometry and represented as percentage compared with control (A, lower panel). Cell viability was assessed by cell counting using the trypan blue dye exclusion assay (B). The control (Ctr) represents untreated cells harvested at 6 h. The data are representative of cells from three CLL patients.
Mentions: The Bcl-2 family plays a key regulatory role in cellular responses to treatment via its pro- and anti-apoptotic properties27. The anti-apoptotic protein Bcl-2 is overexpressed in several hematological malignancies including CLL and this overexpression is considered primarily responsible for defective apoptosis in CLL28. We therefore evaluated the effect of Antho 50 treatment on the expression of two major members of the Bcl-2 family, Bcl-2 and p-Bad in cells from 3 CLL patients. As shown in Fig. 4A, a reduced Bcl-2 level was observed in CLL cells as a function of the treatment time with Antho 50. The down-regulation of Bcl-2 was accompanied by a reduction of cell viability starting at 1 h (Fig. 4B).

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