JSI‐124 (cucurbitacin I) inhibits Janus kinase‐3/signal transducer and activator of transcription‐3 signalling, downregulates nucleophosmin‐anaplastic lymphoma kinase (ALK), and induces apoptosis in ALK‐positive anaplastic large cell lymphoma cells

Summary JSI‐124 (cucurbitacin I) has been recently described as a specific inhibitor of signal transducer and activator of transcription‐3 (STAT3). As STAT3 activation is pathogenetically important in anaplastic lymphoma kinase‐positive anaplastic large cell lymphoma (ALK+ ALCL), we investigated whether JSI‐124 can mediate significant inhibitory effects in this cell type. In two ALK+ ALCL cell lines (Karpas 299 and SU‐DHL‐1), JSI‐124 significantly reduced the number of viable cells to 50% of that of negative controls at a dose of 5–10 μ mol/l at 24 h and 1–1·25 μ mol/l at 48 h. This decrease in viability was associated with apoptosis, as confirmed by the increase in the subG 0/1 fraction, poly(ADP‐ribose)polymerase cleavage and expression of active caspase 3. JSI‐124 decreased the phosphorylated‐STAT3 and ‐Janus kinase‐3 (JAK3) levels in a dose‐dependent fashion, and these changes were coupled with significant decreases in several STAT3 downstream targets, including mcl‐1, bcl‐2, bcl‐xL and cyclin D3. Interestingly, JSI‐124 also dramatically decreased the protein levels of JAK3 and nucleophosmin (NPM)‐ALK, and these effects were reversible by MG132. Our data support that JSI‐124 is a potentially useful therapeutic agent for ALK+ ALCL. In addition to its role as a tyrosine kinase inhibitor, JSI‐124 appears to be involved in regulating proteosome degradation for proteins such as JAK3 and NPM‐ALK.