The nonsteroidal anti-inflammatory drug Exisulind selectively induces apoptosis via JNK in secondary acute myeloid leukemia after myelodysplastic syndrome.
Treatment of patients suffering from myelodysplastic syndromes and secondary acute myeloid leukemia after MDS is often unsuccessful. Pro-apoptosis with arsenic trioxide has recently been proposed as a novel therapeutic approach. Exisulind is another potentially pro-apoptotic agent, and therefore, we investigated its influence on proliferation, differentiation, cell cycle and apoptosis in two sAML/MDS cell lines, one de-novo AML cell line and healthy CD34+ bone marrow cells. Treatment of sAML/MDS cells with Exisulind clearly inhibited colony formation in the CFU-assays. Interestingly, Exisulind did not alter the percentages of sAML/MDS cells in G1-, G2-, M- or S-phase, but reduced proliferation and induced apoptosis in this cell type. Exisulind had no effect on de-novo AML or normal CD34+ cells. We detected increased c-Jun NH2-terminal kinase activity in sAML/MDS cells treated with Exisulind. Adding a specific JNK-inhibitor to Exisulind-treated sAML/MDS cells partly abrogated apoptosis, thus proving that Exisulind-mediated apoptosis in sAML/MDS cells is dependent on JNK activation. We conclude that JNK is one mediator of apoptosis in sAML/MDS cells treated with Exisulind. Moreover, our data strongly suggests to explore the potential use of Exisulind as a novel, pro-apoptotic therapy for patients with MDS and sAML/MDS.
Czibere
Akos
A
BIDMC Genomics Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA. aczibere@bidmc.harvard.edu
Prall
Wolf C
WC
Zerbini
Luiz F
LF
Grall
Franck
F
Craigie
Eve C
EC
Ulrich
Slif D
SD
Giagounidis
Aristoteles A N
AA
Haas
Rainer
R
Libermann
Towia A
TA
Aivado
Manuel
M
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000209:etiology*; D009190:Myelodysplastic Syndromes / Q000150:complications*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D000097642:GADD45 Proteins
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018952:Antigens, CD34; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D013467:Sulindac; D000097642:GADD45 Proteins; C025463:sulindac sulfone