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The non-steroidal anti-inflammatory drugs Sulindac sulfide and Diclofenac induce apoptosis and differentiation in human acute myeloid leukemia cells through an AP-1 dependent pathway

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Abstract

Acute myeloid leukemia is a heterogeneous disease with varying genetic and molecular pathologies. Non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to possess significant anti-proliferative potential in various cancer cells in vitro and in vivo. Hence, treatment with these agents can be utilized to study disease specific 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 sulfide 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 profiling of Diclofenac treated AML cells revealed transcriptional activation of GADD45α 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 specific 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 GADD45α 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 sufficient to induce GADD45α expression with consecutive activation of JNK and induction of apoptosis.

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Acknowledgments

We would like to thank Annemarie Koch and Waltraud Passlack for excellent technical assistance. A.C. and I.B. are supported by grants from Leukämie Liga e.V. Düsseldorf, Germany and the Forschungskommission of the Heinrich-Heine-University, Düsseldorf, Germany. A.C. is further supported by the Deutsche Krebshilfe through a Dr. Mildred Scheel fellowship award and by a research fellowship award from the European Association of Hematology (EHA). L.F.Z is supported by Department of Defense grants PC051217 and OC0060439.

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Authors and Affiliations

  1. Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine-University, Düsseldorf, Germany

    Raminder Singh, Ron-Patrick Cadeddu, Julia Fröbel, Christian Matthias Wilk, Ingmar Bruns, Daniela Brünnert, Thomas Schroeder, Rainer Haas & Akos Czibere

  2. Department of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center GDC, Düsseldorf, Germany

    Julia Fröbel, Tanja Prenzel, Sonja Hartwig & Stefan Lehr

  3. International Center for Genetic Engineering and Biotechnology (ICGEB), Medical Biochemistry Division, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Luiz Fernando Zerbini

  4. Beth Israel Deaconess Medical Center, Harvard Medical School, Center for Life Sciences, 3 Blackfan Circle, Boston, MA, 02215, USA

    Akos Czibere

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  1. Raminder Singh
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Correspondence to Akos Czibere.

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Singh, R., Cadeddu, RP., Fröbel, J. et al. The non-steroidal anti-inflammatory drugs Sulindac sulfide and Diclofenac induce apoptosis and differentiation in human acute myeloid leukemia cells through an AP-1 dependent pathway. Apoptosis 16, 889–901 (2011). https://doi.org/10.1007/s10495-011-0624-y

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