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

• Published in: Blood 2004-10, Vol.104 (8), p.2514-2522
• Main Authors: Bandyopadhyay, Gautam, Biswas, Tanusree, Roy, Keshab C., Mandal, Swapan, Mandal, Chhabinath, Pal, Bikas C., Bhattacharya, Samir, Rakshit, Srabanti, Bhattacharya, Dilip K., Chaudhuri, Utpal, Konar, Aditya, Bandyopadhyay, Santu
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Chlorogenic Acid - pharmacology; Enzyme Activation; Enzyme Inhibitors - pharmacology; Fusion Proteins, bcr-abl; Hematologic and hematopoietic diseases; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; MAP Kinase Signaling System - drug effects; Medical sciences; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Phosphorylation - drug effects; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; src-Family Kinases - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-11-4065

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 p210Bcr-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.