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.

Sulfated Polysaccharide Isolated from the Sea Cucumber Stichopus japonicus Against PC12 Hypoxia/Reoxygenation Injury by Inhibition of the MAPK Signaling Pathway

“…Bcl-2 is an anti-apoptotic protein and promotes cell survival. Bcl-2 is necessary to regulate caspase-3-mediated apoptosis (Alhosin et al 2015). Cytosolic cyto-c likely activates caspase-3 that feeds back to the mitochondria (Laethem et al 2004).…”

Pro-oxidant activity of polyphenols and its implication on cancer chemoprevention and chemotherapy

“…There is some controversy whether ROS are a cause or consequence of apoptosis induced by polyphenols. Some studies point that ROS accumulation occurs as an early step in the pathway toward polyphenol-induced apoptosis (1 h), and that pre-incubation with NAC, Tiron, or antioxidant enzymes such as PEG-Cat can effectively reduce their pro-apoptotic effects [72][73][74]. Other researchers have observed that NAC reduced the apoptosis in cutaneous…”

UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics

“…96,97 Bilberry extract (Antho 50) rich in polyphenols caused reactive oxygen species (ROS)-dependent but p53-/p73-independent UHRF1 downregulation in chronic lymphocytic leukemia cells. 98 UHRF1 has shown to regulate Keap-1-Nrf2 pathway which provides protection to cells from oxidative stress by inducing expression of antioxidant response element genes. 99 These studies underline the potential of natural compounds to control tumor growth by targeting UHRF1.…”