Histone deacetylase (HDAC) inhibitors represent an encouraging class of antitumor drugs. HDAC inhibitors induce a series
of molecular and biological responses and minimal toxicity to normal cells. Citarinostat (Acy-241) is a second generation,
orally administered, HDAC6-selective inhibitor. Momelotinib (CYT387) is an orally administered inhibitor of Janus kinase/
signal transducer of transcription-3 (JAK/STAT3) signaling. Momelotinib showed efcacy in patients with myelofbrosis. We
hypothesized that both HDAC and JAK/STAT pathways were important in lymphoproliferative disorders, and that inhibiting
JAK/STAT3 and HDAC simultaneously might enhance the efcacy of momelotinib and citarinostat without increasing toxicity. Accordingly, we tested the citarinostat+momelotinib combination in lymphoid cell lines. Citarinostat+momelotinib
showed strong cytotoxicity; it signifcantly reduced mitochondrial membrane potential, down-regulated Bcl-2 and Bcl-xL,
and activated caspases 9 and 3. Caspase-8 was upregulated in only two lymphoid cell lines, which indicated activation of
the extrinsic apoptotic pathway. We identifed a lymphoid cell line that was only slightly sensitive to the combination treatment. We knocked down thioredoxin expression by transfecting with small interfering RNA that targeted thioredoxin. This
knockdown increased cell sensitivity to the combination-induced cell death. The combination treatment reduced Bcl-2
expression, activated caspase 3, and signifcantly inhibited cell viability and clonogenic survival.