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OSU‐DY7, a novel D ‐tyrosinol derivative, mediates cytotoxicity in chronic lymphocytic leukaemia and Burkitt lymphoma through p38 mitogen‐activated protein kinase pathway
Author(s) -
Bai LiYuan,
Ma Yihui,
Kulp Samuel K.,
Wang ShuHuei,
Chiu ChangFang,
Frissora Frank,
Mani Rajeswaran,
Mo Xiaokui,
Jarjoura David,
Byrd John C.,
Chen ChingShih,
Muthusamy Natarajan
Publication year - 2011
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2010.08443.x
Subject(s) - cytotoxicity , p38 mitogen activated protein kinases , mapk/erk pathway , protein kinase a , cancer research , biology , chronic lymphocytic leukemia , kinase , immunology , microbiology and biotechnology , leukemia , biochemistry , in vitro
Summary 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.