title: 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.
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 NH(2)-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.
authors: Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine-University, Düsseldorf, Germany.
authors: Raminder
authors: R
authors: Singh
authors: Ron-Patrick
authors: RP
authors: Cadeddu
authors: Julia
authors: J
authors: Fröbel
authors: Christian Matthias
authors: CM
authors: Wilk
authors: Ingmar
authors: I
authors: Bruns
authors: Luiz Fernando
authors: LF
authors: Zerbini
authors: Tanja
authors: T
authors: Prenzel
authors: Sonja
authors: S
authors: Hartwig
authors: Daniela
authors: D
authors: Brünnert
authors: Thomas
authors: T
authors: Schroeder
authors: Stefan
authors: S
authors: Lehr
authors: Rainer
authors: R
authors: Haas
authors: Akos
authors: A
authors: Czibere
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D003001:Cloning, Molecular; D004008:Diclofenac / Q000627:therapeutic use*; D005434:Flow Cytometry; D051921:Fos-Related Antigen-2 / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D018922:HL-60 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034622:RNA Interference; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D013467:Sulindac / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D000097642:GADD45 Proteins
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D053148:Caspase 3; D018797:Cell Cycle Proteins; D004008:Diclofenac; D051921:Fos-Related Antigen-2; D048031:JNK Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D013467:Sulindac; D018808:Transcription Factor AP-1; C497872:FOSL2 protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C025462:sulindac sulfide; C505407:CASP3 protein, human