OSU-DY7, a novel D-tyrosinol derivative, mediates cytotoxicity in chronic lymphocytic leukaemia and Burkitt lymphoma through p38 mitogen-activated protein kinase pathway.

Abstract

Drug resistance and associated immune deregulation limit use of current therapies in chronic lymphocytic leukaemia (CLL), thus warranting alternative therapy development. Herein we demonstrate that OSU-DY7, a novel D-tyrosinol derivative targeting p38 mitogen-activated protein kinase (MAPK), mediates cytotoxicity in lymphocytic cell lines representing CLL (MEC-1), acute lymphoblastic leukaemia (697 cells), Burkitt lymphoma (Raji and Ramos) and primary B cells from CLL patients in a dose- and time-dependent manner. The OSU-DY7-induced cytotoxicity is dependent on caspase activation, as evidenced by induction of caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage and rescue of cytotoxicity by Z-VAD-FMK. Interestingly, OSU-DY7-induced cytotoxicity is mediated through activation of p38 MAPK, as evidenced by increased phosphorylation of p38 MAPK and downstream target protein MAPKAPK2. Pretreatment of B-CLL cells with SB202190, a specific p38 MAPK inhibitor, results in decreased MAPKAPK2 protein level with concomitant rescue of the cells from OSU-DY7-mediated cytotoxicity. Furthermore, OSU-DY7-induced cytotoxicity is associated with down regulation of p38 MAPK target BIRC5, that is rescued at protein and mRNA levels by SB202190. This study provides evidence for a role of OSU-DY7 in p38 MAPK activation and BIRC5 down regulation associated with apoptosis in B lymphocytic cells, thus warranting development of this alternative therapy for lymphoid malignancies.

• Authors: Li-Yuan Bai, Yihui Ma, Samuel K Kulp, Shu-Huei Wang, Chang-Fang Chiu, Frank Frissora, Rajeswaran Mani, Xiaokui Mo, David Jarjoura, John C Byrd, Ching-Shih Chen, Natarajan Muthusamy
• Journal: British journal of haematology (Br J Haematol) Vol. 153 Issue 5 Pg. 623-33 (Jun 2011) ISSN: 1365-2141 [Electronic] England
• PMID: 21470196 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Blackwell Publishing Ltd.

Chemical References

• Antineoplastic Agents
• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• OSU-DY7 compound
• Survivin
• Tyrosine
• Poly(ADP-ribose) Polymerases
• p38 Mitogen-Activated Protein Kinases
• Caspase 3

Topics

• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• B-Lymphocytes (drug effects)
• Burkitt Lymphoma (enzymology, pathology)
• Caspase 3 (metabolism)
• Cell Death (drug effects)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Drug Evaluation, Preclinical (methods)
• Enzyme Activation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Inhibitor of Apoptosis Proteins (biosynthesis, genetics)
• Leukemia, Lymphocytic, Chronic, B-Cell (enzymology, pathology)
• MAP Kinase Signaling System (drug effects, physiology)
• Phosphorylation (drug effects)
• Poly(ADP-ribose) Polymerases (metabolism)
• Survivin
• Tumor Cells, Cultured
• Tyrosine (administration & dosage, analogs & derivatives, pharmacology)
• p38 Mitogen-Activated Protein Kinases (physiology)