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

Sci Rep. 2015 Mar 11;5:8996. doi: 10.1038/srep08996.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anthocyanins / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Caspase 3 / metabolism*
  • Cell Line, Tumor
  • Female
  • Glucosides / pharmacology
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Male
  • Middle Aged
  • Oxidation-Reduction*
  • Phosphorylation
  • Plant Extracts / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects*
  • Vaccinium myrtillus / chemistry*
  • bcl-Associated Death Protein / metabolism*

Substances

  • Anthocyanins
  • Apoptosis Regulatory Proteins
  • Glucosides
  • Plant Extracts
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • bcl-Associated Death Protein
  • delphinidin 3-O-glucopyranoside
  • Caspase 3