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Apoptosis (2011) 16:889901 DOI 10.1007/s10495-011-0624-y
ORIGINAL PAPER
The non-steroidal anti-inammatory drugs Sulindac suldeand Diclofenac induce apoptosis and differentiation in human acute myeloid leukemia cells through an AP-1 dependent pathway
Raminder Singh Ron-Patrick Cadeddu Julia Frbel Christian Matthias Wilk
Ingmar Bruns Luiz Fernando Zerbini Tanja Prenzel Sonja Hartwig
Daniela Brnnert Thomas Schroeder Stefan Lehr Rainer Haas Akos Czibere
Published online: 8 July 2011 Springer Science+Business Media, LLC 2011
Abstract Acute myeloid leukemia is a heterogeneous disease with varying genetic and molecular pathologies. Non-steroidal anti-inammatory drugs (NSAIDs) have been proven to possess signicant anti-proliferative potential in various cancer cells in vitro and in vivo. Hence, treatment with these agents can be utilized to study disease specic anti-proliferative pathways. In this study, a total number of 42 bone marrow derived CD34? selected de novo AML patient samples and the AML cell lines THP-1 and HL-60 were treated with the NSAIDs Sulindac sulde and Diclofenac. We analyzed viability, apoptosis, differentiation and addressed the molecular mechanisms involved. We found a consistent induction of apoptosis and to some extent an increased myeloid differentiation capacity in NSAID treated AML cells. Comprehensive
protein and gene expression proling of Diclofenac treated AML cells revealed transcriptional activation of GADD45a and its downstream MAPK/JNK pathway as well as increased protein levels of the caspase-3 precursor. This pointed towards a role of the c-Jun NH2-terminal kinase (JNK) in NSAID mediated apoptosis that we found indeed to be dependent on JNK activity as addition of a specic JNK-inhibitor abrogated apoptosis. Furthermore, the AP-1 transcription factor family members c-Jun, JunB and Fra-2 were transcriptionally activated in NSAID treated AML cells and re-expression of these transcription factors led to activation of GADD45a with induction of apoptosis.
Mechanistically, we demonstrate that NSAIDs induce apoptosis in AML through a novel pathway involving increased expression of AP-1 heterodimers, which by itself is sufcient to induce GADD45a expression with consecutive activation of JNK and induction of apoptosis.
Keywords AML NSAID GADD45a Growth arrest
Apoptosis AP-1
Introduction
Acute myeloid leukemia (AML) represents a heterogeneous group of myeloid neoplasias which are driven by varying genetic and/or molecular alterations in clonally evolving hematopoietic stem and progenitor cells (HSPCs) [13]. As a consequence of this diversity, treatment regimens are nowadays rened and tailored towards the specic genetic/molecular alterations...