title: The nonsteroidal anti-inflammatory drug Exisulind selectively induces apoptosis via JNK in secondary acute myeloid leukemia after myelodysplastic syndrome.
abstract: 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.
authors.affiliation: BIDMC Genomics Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA. aczibere@bidmc.harvard.edu
authors.forename: Akos
authors.initials: A
authors.lastname: Czibere
authors.forename: Wolf C
authors.initials: WC
authors.lastname: Prall
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Zerbini
authors.forename: Franck
authors.initials: F
authors.lastname: Grall
authors.forename: Eve C
authors.initials: EC
authors.lastname: Craigie
authors.forename: Slif D
authors.initials: SD
authors.lastname: Ulrich
authors.forename: Aristoteles A N
authors.initials: AA
authors.lastname: Giagounidis
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
authors.forename: Manuel
authors.initials: M
authors.lastname: Aivado
mesh_terms: 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
chemical_list: 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