Aronia melanocarpa Juice Induces a Redox-Sensitive p73-Related Caspase 3-Dependent Apoptosis in Human Leukemia Cells

Tanveer Sharif,Christian Bronner,Jong-Hun Kim,Guy Fuhrmann,Mahmoud Alhosin,Annelise Lobstein,Nelly Etienne-Selloum,Cyril Auger,Valérie B Schini-Kerth,Hinrich Gronemeyer,Carole Minker,Pierre Bories,Rakesh K Srivastava

doi:10.1371/journal.pone.0032526

Abstract

Polyphenols are natural compounds widely present in fruits and vegetables, which have antimutagenic and anticancer properties. The aim of the present study was to determine the anticancer effect of a polyphenol-rich Aronia melanocarpa juice (AMJ) containing 7.15 g/L of polyphenols in the acute lymphoblastic leukemia Jurkat cell line, and, if so, to clarify the underlying mechanism and to identify the active polyphenols involved. AMJ inhibited cell proliferation, which was associated with cell cycle arrest in G2/M phase, and caused the induction of apoptosis. These effects were associated with an upregulation of the expression of tumor suppressor p73 and active caspase 3, and a downregulation of the expression of cyclin B1 and the epigenetic integrator UHRF1. AMJ significantly increased the formation of reactive oxygen species (ROS), decreased the mitochondrial membrane potential and caused the release of cytochrome c into the cytoplasm. Treatment with intracellular ROS scavengers prevented the AMJ-induced apoptosis and upregulation of the expression of p73 and active caspase 3. The fractionation of the AMJ and the use of identified isolated compounds indicated that the anticancer activity was associated predominantly with chlorogenic acids, some cyanidin glycosides, and derivatives of quercetin. AMJ treatment also induced apoptosis of different human lymphoblastic leukemia cells (HSB-2, Molt-4 and CCRF-CEM). In addition, AMJ exerted a strong pro-apoptotic effect in human primary lymphoblastic leukemia cells but not in human normal primary T-lymphocytes. Thus, the present findings indicate that AMJ exhibits strong anticancer activity through a redox-sensitive mechanism in the p53-deficient Jurkat cells and that this effect involves several types of polyphenols. They further suggest that AMJ has chemotherapeutic properties against acute lymphoblastic leukemia by selectively targeting lymphoblast-derived tumor cells.

Highlights

Natural products derived from plants have received considerable attention as potential cancer chemopreventive and chemotherapeutic agents over few decades
Aronia melanocarpa juice (AMJ) inhibited the growth of acute lymphoblastic leukemia Jurkat cells by promoting their cell cycle arrest in G2/M phase
AMJ induces apoptosis and modulates the expression of proteins related to cell cycle and apoptosis in Jurkat cells

Summary

Introduction

Natural products derived from plants have received considerable attention as potential cancer chemopreventive and chemotherapeutic agents over few decades. Natural products rich in polyphenols, such as green tea and red wine, have been shown to have strong chemopreventive and chemotherapeutic properties in different types of cancer cells [2,3,4]. Aronia melanocarpa juice (AMJ) is one of the richest sources of natural polyphenols; one liter of juice can contain up to 7 g of polyphenols [8]. Several in vitro and in vivo studies indicate that Aronia melanocarpa extracts have anti-proliferative effects against several colon cancer cells [9,10,11]. AMJ inhibited the growth and triggered apoptosis of human colon cancer HT-29 cells but had little effect on non-tumorigenic colonic NCM460 cells [9]. Cell proliferation inhibition of human colorectal carcinoma cell line (Caco-2) is associated with G2/M cell cycle arrest and a sharp upregulation of the tumor suppressor carcinoembryonic antigenrelated cell adhesion molecule 1 (CEACAM1) [11]

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