Histone deacetylase inhibitor ITF2357 is effective on the P39 cells. A gene expression study

18024 Background: ITF2357 is a histone deacetylase inhibitor that has been reported to induce apoptosis in myeloma and acute leukemia. We assessed if ITF2357 would exert an anti-proliferative and pro-apoptotic effect on a myelo-monocytic cell line (the P39). Methods: Samples were hybridized on Whole Human Genome Microarray (Agilent). The genes identified as de-regulated by bortezomib were then analyzed for network and gene ontology by Ingenuity Pathway Analysis software. Results have been confirmed by using the TaqMan Low Density Array Human Apoptosis Panel. Results: With an IC50 of 0.8 mcM, ITF2357 was able to inhibit proliferation and induce apoptosis of P39 cells. ITF2357 blocked cell cycle in the G1 phase at low dose (0.5 mcM) and in the G2 phase at higher dose (0.8 mcM). The production of reactive oxygen species (ROS) was significantly increased after exposure to this histone deacetylase inhibitor. In the untreated P39, 84 of the 93 genes involved in the apoptotic pathway and represented in the Taqman Low-Density Arrays were expressed. After 12h-treatment, ITF2357 down-regulated 9 genes and up-regulated 11 genes. After 24 hours, ITF2357 down-regulated 48 genes and up-regulated 3 genes only. Among down-regulated genes, BAD, BCLXL, BCL2, BCL2L10, whereas APAF1 was significantly up-regulated. IL6, IL10, inflammation, NF-kB, PDGF, TGFbeta and apoptosis were the pathways more significantly modified. Among the down-regulated genes, JUN, NF-kB, TNFalpha, IL1beta could be clinically relevant. Indeed, IL1beta has been reported to induce activation of NF-kB, with consequent cell proliferation in acute leukemia; consequently, a down-regulation of IL1beta expression, in addition to the direct down-regulation of NF-kB, could suggest an anti-proliferative effect in MDS. Moreover, TNFalpha plays a well-known pathogenetic role in MDS: it induces apoptosis in the maturing cells causing pancytopenia, but also stimulates the proliferation of the primitive progenitors, accounting for the hypercellular bone marrow frequently observed in MDS. The ability of ITF2357 of down-regulating TNFalpha expression would be also relevant. Conclusions: In summary, biological results and gene expression assays suggest the possible use of histone deacetylase inhibitors in treatment of high-risk MDS. No significant financial relationships to disclose.