title: Chlorogenic acid inhibits Bcr-Abl tyrosine kinase and triggers p38 mitogen-activated protein kinase-dependent apoptosis in chronic myelogenous leukemic cells.
abstract: 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.
authors.affiliation: Division of Immunology, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Rd, Kolkata-, India.
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.forename: Tanusree
authors.initials: T
authors.lastname: Biswas
authors.forename: Keshab C
authors.initials: KC
authors.lastname: Roy
authors.forename: Swapan
authors.initials: S
authors.lastname: Mandal
authors.forename: Chhabinath
authors.initials: C
authors.lastname: Mandal
authors.forename: Bikas C
authors.initials: BC
authors.lastname: Pal
authors.forename: Samir
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Srabanti
authors.initials: S
authors.lastname: Rakshit
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Bhattacharya
authors.forename: Utpal
authors.initials: U
authors.lastname: Chaudhuri
authors.forename: Aditya
authors.initials: A
authors.lastname: Konar
authors.forename: Santu
authors.initials: S
authors.lastname: Bandyopadhyay
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002726:Chlorogenic Acid / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D002726:Chlorogenic Acid; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases