Abstract
There is a growing body of evidence supporting the use of epigenetic therapies in the treatment of multiple myeloma. We show the novel HDAC inhibitor CHR-3996 induces apoptosis in myeloma cells at concentrations in the nanomolar range and with apoptosis mediated by p53 and caspase pathways. In addition, HDAC inhibitors are highly synergistic, both in vitro and in vivo, with the aminopeptidase inhibitor tosedostat (CHR-2797). We demonstrate that the basis for this synergy is a consequence of changes in the levels of NFκB regulators BIRC3/cIAP2, A20, CYLD, and IκB, which were markedly affected by the combination. When co-administered the HDAC and aminopeptidase inhibitors caused rapid nuclear translocation of NFκB family members p65 and p52, following activation of both canonical and non-canonical NFκB signalling pathways. The subsequent up-regulation of inhibitors of NFκB activation (most significantly BIRC3/cIAP2) turned off the cytoprotective effects of the NFκB signalling response in a negative feedback loop. These results provide a rationale for combining HDAC and aminopeptidase inhibitors clinically for the treatment of myeloma patients and support the disruption of the NFκB signalling pathway as a therapeutic strategy.
Highlights
Despite the recent introduction of novel therapies for the treatment of the plasma cell malignancy multiple myeloma, it remains an almost incurable disease with a high rate of relapse
HDAC6 has been shown to regulate the processing of misfolded proteins via the aggresome www.impactjournals.com/oncotarget pathway [13, 14], a process that is important to myeloma cells which have to cope with a significant load of unfolded immunoglobulin[15, 16]
CHR3996 demonstrates Histone deacetylases (HDACs) inhibitory activity at low concentrations with minimal activity against HDAC6 function and the aggresome pathway [21]. We show that this HDAC inhibitor is highly efficacious against myeloma cells, inducing apoptosis via its effects on the acetylome, and go on to demonstrate that it is highly synergistic when combined with the aminopeptidase inhibitor tosedostat (CHR-2797) [22], which we have previously shown to have potent anti-myeloma activity in vitro and in vivo [23, 24]
Summary
Despite the recent introduction of novel therapies for the treatment of the plasma cell malignancy multiple myeloma, it remains an almost incurable disease with a high rate of relapse. At relapse the clonal cells are often resistant to standard therapies and there is a clinical need to develop novel therapeutic combinations Epigenetic processes such as DNA methylation and regulation of chromatin structure are considered to make an important contribution to gene regulation, oncogenic transformation and survival of neoplastic cells in a wide range of malignancies including myeloma [1, 2]. HDAC6 has been shown to regulate the processing of misfolded proteins via the aggresome www.impactjournals.com/oncotarget pathway [13, 14], a process that is important to myeloma cells which have to cope with a significant load of unfolded immunoglobulin[15, 16] These diverse roles of HDACs imply that cell death resulting from their inhibition is likely to be multi-factorial and depend upon the selective activity of the inhibitor used against the different HDAC family members
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