Alhosin Mahmoud, León-González Antonio J, Dandache Israa, Lelay Agnès, Rashid Sherzad K, Kevers Claire, Pincemail Joël, Fornecker Luc-Matthieu, Mauvieux Laurent, Herbrecht Raoul, Schini-Kerth Valérie B
CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch, France.
1] CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch, France [2] Oncologie et Hématologie, Hôpitaux Universitaires de Strasbourg, Avenue Molière, 67100 Strasbourg, France.
Sci Rep. 2015 Mar 11;5:8996. doi: 10.1038/srep08996.
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.
细胞凋亡缺陷被认为是B细胞慢性淋巴细胞白血病（B-CLL）中观察到的化疗耐药的主要原因。本研究评估了富含花青素的越橘膳食提取物（Antho 50）对30例患者的B-CLL细胞和健康受试者外周血单核细胞（PBMC）的促凋亡作用，并确定了其潜在机制。Antho 50在B-CLL细胞中诱导浓度和时间依赖性的促凋亡作用，但对PBMC几乎没有影响。在越橘提取物的主要酚类化合物中，飞燕草素-3-O-葡萄糖苷和飞燕草素-3-O-芸香糖苷诱导了促凋亡作用。Antho 50诱导的细胞凋亡与半胱天冬酶3的激活、UHRF1的下调、Akt和Bad的快速去磷酸化以及Bcl-2的下调有关。Antho 50在B-CLL细胞中显著诱导了聚乙二醇过氧化氢酶敏感的活性氧形成。聚乙二醇过氧化氢酶阻止了Antho 50诱导的细胞凋亡和相关信号传导。目前的研究结果表明，Antho 50通过涉及Bad/Bcl-2途径失调的氧化还原敏感的半胱天冬酶3激活相关机制，在B-CLL细胞中表现出强大的促凋亡活性。Antho 50的这种活性涉及飞燕草素的葡萄糖苷和芸香糖苷衍生物。它们进一步表明，Antho 50通过选择性靶向B-CLL细胞具有化疗潜力。
