The BioInvestigationIndex (BII)

Title:

2 AML (acute myeloid leukemia) cell lines treated with the NSAID diclofenac, vs. control. [original 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]

Organism(s):

Homo sapiens

Description:

Acute myeloid leukemia is a heterogeneous disease with regard to the underlying genetic and molecular pathophysiology. Non-steroidal anti-inflammatory drugs (NSAIDs) exert significant anti-proliferative effects in various malignant cells in vitro and in vivo. Hence, these agents can be utilized to study potential disease specific anti-proliferative pathways. In this study, a total number of 42 bone marrow derived CD34+ cells from de novo AML patients and the AML cell lines THP-1 and HL-60 were treated with the NSAIDs Sulindac sulfide and Diclofenac. We examined viability, apoptosis, differentiation and addressed the molecular mechanisms involved. We found a consistent induction of apoptosis and to some extent myeloid differentiation in NSAID treated AML cells. Comprehensive protein and gene expression profiling of Diclofenac treated AML cells revealed transcriptional activation of GADD45alpha and its downstream MAPK/JNK pathway as well as increased protein levels of the Caspase-3 precursor. This points towards a role of the c-Jun NH2-terminal kinase (JNK) in NSAID mediated apoptosis. This was 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. Re-expression of these transcription factors led to activation of GADD45alpha 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 GADD45alpha expression with consecutive activation of JNK and induction of apoptosis. HL-60 and THP-1 AML cells were treated with 100 M Diclofenac or DMSO as control for 48 hours. Each experiment was performed in duplicate. After this treatment total RNA of the cells was harvested and analysed by means of gene expression profiling with the Affymetrix HU-133A array.

Design(s):

transcription profiling by array

Experimental factor(s):

treatment 2 recorded
diclofenac control condition
cell line 4 recorded
THP-1 cell THP-1 HL-60 cell HL60
disease state 4 recorded
monocytic leukemia monocytic leukemia cell line Promyelocytic Leukemia promyelocytic leukemia cell line

Publication(s):

Sample attribute(s):

cell line 2 recorded
THP-1 cell HL-60 cell
Label 1 recorded
biotin
disease state 2 recorded
monocytic leukemia cell line promyelocytic leukemia cell line
organism 1 recorded
Homo sapiens