title: 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.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Bai
authors.forename: Yihui
authors.initials: Y
authors.lastname: Ma
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Wang
authors.forename: Chang-Fang
authors.initials: CF
authors.lastname: Chiu
authors.forename: Frank
authors.initials: F
authors.lastname: Frissora
authors.forename: Rajeswaran
authors.initials: R
authors.lastname: Mani
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.forename: David
authors.initials: D
authors.lastname: Jarjoura
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000201:enzymology / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000077022:Survivin; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; C559193:OSU-DY7 compound; D000077022:Survivin; D014443:Tyrosine; D011065:Poly(ADP-ribose) Polymerases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3