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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 affects cleaved caspase 3 and UHRF1 proteins through a ROS-dependent mechanism.B CLL cells were exposed to either PEG-catalase (500 U/mL), catalase (500 U/mL), or SOD (500 U/mL) for 30 min before the addition of Antho 50 (75 μg/mL) for the indicated times. The expression of cleaved caspase 3 and UHRF1 was studied using Western blot and their expression levels were analyzed by densitometry and represented as percentage compared with control (Ctr). The control represents untreated cells harvested at 6 h. The data are representative of three CLL patients.
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f7: Antho 50 affects cleaved caspase 3 and UHRF1 proteins through a ROS-dependent mechanism.B CLL cells were exposed to either PEG-catalase (500 U/mL), catalase (500 U/mL), or SOD (500 U/mL) for 30 min before the addition of Antho 50 (75 μg/mL) for the indicated times. The expression of cleaved caspase 3 and UHRF1 was studied using Western blot and their expression levels were analyzed by densitometry and represented as percentage compared with control (Ctr). The control represents untreated cells harvested at 6 h. The data are representative of three CLL patients.

Mentions: To determine whether the intracellular formation of ROS is a key event in the Bad/Bcl-2 deregulation leading to activation of the caspase 3-related pro-apoptotic signaling pathway in response to Antho 50, the effect of various antioxidants were tested. Exposure of cells isolated from patient 11, 26, 20 and 18 with PEG-catalase markedly reduced the Antho 50-induced dephosphorylation of Bad and down-regulation of Bcl-2 at 6 h (Fig. 6). Native SOD and catalase affected only slightly or had no such effect on p-Bad and Bcl-2 (Fig. 6). The Antho 50-induced activation of caspase 3 was inhibited in CLL cells CLL11, 6 and 20 (Fig. 7) and CLL9 and 10 (data not shown) in the presence of PEG-catalase as well as the down-regulation of UHRF1 in CLL11, 6 and 20 (Fig. 7). In contrast, native SOD and catalase affected only slightly or not at all both signals (Fig. 7). Altogether, these findings indicate that Antho 50 triggers apoptosis in CLL cells through a redox-sensitive activation of the caspase 3-related pro-apoptotic pathway possibly through Bad dephosphorylation and Bcl-2 down-regulation.


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 affects cleaved caspase 3 and UHRF1 proteins through a ROS-dependent mechanism.B CLL cells were exposed to either PEG-catalase (500 U/mL), catalase (500 U/mL), or SOD (500 U/mL) for 30 min before the addition of Antho 50 (75 μg/mL) for the indicated times. The expression of cleaved caspase 3 and UHRF1 was studied using Western blot and their expression levels were analyzed by densitometry and represented as percentage compared with control (Ctr). The control represents untreated cells harvested at 6 h. The data are representative of three CLL patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: Antho 50 affects cleaved caspase 3 and UHRF1 proteins through a ROS-dependent mechanism.B CLL cells were exposed to either PEG-catalase (500 U/mL), catalase (500 U/mL), or SOD (500 U/mL) for 30 min before the addition of Antho 50 (75 μg/mL) for the indicated times. The expression of cleaved caspase 3 and UHRF1 was studied using Western blot and their expression levels were analyzed by densitometry and represented as percentage compared with control (Ctr). The control represents untreated cells harvested at 6 h. The data are representative of three CLL patients.
Mentions: To determine whether the intracellular formation of ROS is a key event in the Bad/Bcl-2 deregulation leading to activation of the caspase 3-related pro-apoptotic signaling pathway in response to Antho 50, the effect of various antioxidants were tested. Exposure of cells isolated from patient 11, 26, 20 and 18 with PEG-catalase markedly reduced the Antho 50-induced dephosphorylation of Bad and down-regulation of Bcl-2 at 6 h (Fig. 6). Native SOD and catalase affected only slightly or had no such effect on p-Bad and Bcl-2 (Fig. 6). The Antho 50-induced activation of caspase 3 was inhibited in CLL cells CLL11, 6 and 20 (Fig. 7) and CLL9 and 10 (data not shown) in the presence of PEG-catalase as well as the down-regulation of UHRF1 in CLL11, 6 and 20 (Fig. 7). In contrast, native SOD and catalase affected only slightly or not at all both signals (Fig. 7). Altogether, these findings indicate that Antho 50 triggers apoptosis in CLL cells through a redox-sensitive activation of the caspase 3-related pro-apoptotic pathway possibly through Bad dephosphorylation and Bcl-2 down-regulation.

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