Chlorogenic acid inhibits Bcr-Abl tyrosine kinase and triggers p38 mitogen-activated protein kinase–dependent apoptosis in chronic myelogenous leukemic cells

作者：Gautam Kumar Bandyopadhyay, Tanusree Biswas, Keshab C. Roy, Swapan Mandal, Chhabinath Mandal, Bikas Chandra Pal, Samir Bhattacharya, Srabanti Rakshit, Dilip Kumar Bhattacharya, Utpal Chaudhuri, Aditya Konar, Santu K. Bandyopadhyay · 发表于：Blood · 年份：2004 · DOI：10.1182/blood-2003-11-4065 · 被引用次数：104 · 研究领域：Chronic Myeloid Leukemia Treatments、Chronic Lymphocytic Leukemia Research、Quinazolinone synthesis and applications

We report that chlorogenic acid (Chl) induces apoptosis of several Bcr-Abl-positive chronic myelogenous leukemia (CML) cell lines and primary cells from CML patients in vitro and destroys Bcr-Abl-positive K562 cells in vivo. In contrast, this compound has no effect on the growth and viability of Bcr-Abl-negative lymphocytic and myeloid cell lines and primary CML cells. Sodium chlorogenate (NaChl) exhibits 2-fold higher efficiency in killing K562 cells compared with Chl. NaChl also induces growth inhibition of squamous cell carcinoma (HSC-2) and salivary gland tumor cells (HSG), although at 50-fold higher concentration. NaChl inhibits autophosphorylation of p210(Bcr-Abl) fusion protein rapidly. We demonstrate that p38 phosphorylation is increased in Bcr-Abl-positive cells after treatment with NaChl and closely paralleled the inhibition of Bcr-Abl phosphorylation. NaChl did not increase phosphorylation of p38 in Bcr-Abl-negative cells including HSC-2 and HSG that are responsive to this compound, indicating that p38 activation by NaChl is dependent on Bcr-Abl kinase inhibition. Inhibition of p38 activity by SB203580 significantly reduced NaChl-induced apoptosis of K562 cells, whereas activation of p38 by anisomycin augmented the apoptosis. These findings indicate that inhibition of Bcr-Abl kinase leading to activation of p38 mitogen-activated protein (MAP) kinase may play an important role in the anti-CML activity of Chl.