Exisulind Selectively Induces Apoptosis Via C-Jun Kinase Activation in MDS and sAML/MDS.

Treatment of patients suffering from myelodysplastic syndromes (MDS) is difficult and frustrating, particularly when in progression or already progressed to secondary acute myeloid leukemia (sAML). In these cases, the bone marrow contains an increasing number of immature cells, which are characterized by reduced apoptotic and increased proliferative activity. Therefore, pro-apoptosis has recently been proposed as a novel therapeutic approach. Exisulind is a potentially pro-apoptotic agent, and therefore, we investigated its influence on proliferation, differentiation, cell cycle and apoptosis in peripheral blood-derived CD34⁺ stem cells (PBSC) obtained from 10 patients suffering from refractory anaemia with excess of blasts in transformation (RAEB-T), two sAML/MDS cell lines, one de-novo AML cell line and healthy CD34⁺ bone marrow cells. Incubation 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-, S-, G2-, M-phase, but reduced proliferation and induced apoptosis in this cell type. Likewise, in 8 out of 10 RAEB-T samples Exisulind significantly inhibited proliferation and increased the rate of apoptotic cells. 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 and RAEB-T cells partly abrogated apoptosis, thus proving that Exisulind-mediated apoptosis in sAML/MDS and RAEB-T cells is dependent on JNK activation. We conclude that JNK is one mediator of apoptosis in 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 RAEB-T and sAML/MDS.