Abstract
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 efficacy in patients with myelofibrosis. 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 efficacy of momelotinib and citarinostat without increasing toxicity. Accordingly, we tested the citarinostat + momelotinib combination in lymphoid cell lines. Citarinostat + momelotinib showed strong cytotoxicity; it significantly 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 identified 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 significantly inhibited cell viability and clonogenic survival.
Highlights
Histone deacetylases (HDACs) are master regulators of chromatin remodeling
We found that combinations of citarinostat (2 and 4 μM) and momelotinib (0.5 and 1 μM) exerted strong synergy in all the samples studied (n = 5)
Attention has been focused on the development of selective HDAC inhibitors (HDACis), based on the principle that selective agents might be more tolerable than pan-HDACis
Summary
Histone deacetylases (HDACs) are master regulators of chromatin remodeling. HDACs can epigenetically control gene expression [1, 2], and they are considered promising therapeutic targets. Selective HDAC inhibitors (HDACis), alone or in combination with other anti-cancer agents, have shown encouraging results in cancer treatment strategies [3,4,5,6]. Attention has focused on the HDAC6 isoform, due to its critical role in many biological functions. Selective inhibition of HDAC6 might reduce the toxicity associated with off-target effects of pan-HDACis [7]. Ricolinostat is a first-in-class HDAC6 selective inhibitor. Pharmacodynamic evidence has shown that, in patients, ricolinostat could inhibit both HDAC6 and Class I HDACs. Citarinostat is a second generation, orally available, selective HDAC6 inhibitor [17]. Compared to nonselective HDACis, citarinostat was well-tolerated, showed reduced potency against Class I HDACs, but had similar anticancer effectiveness [18]
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