The combination of HDAC and aminopeptidase inhibitors is highly synergistic in myeloma and leads to disruption of the NF?B signalling pathway.

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 NF?B regulators BIRC3/cIAP2, A20, CYLD, and I?B, which were markedly affected by the combination. When co-administered the HDAC and aminopeptidase inhibitors caused rapid nuclear translocation of NF?B family members p65 and p52, following activation of both canonical and non-canonical NF?B signalling pathways. The subsequent up-regulation of inhibitors of NF?B activation (most significantly BIRC3/cIAP2) turned off the cytoprotective effects of the NF?B 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 NF?B signalling pathway as a therapeutic strategy.

SUBMITTER: Smith EM 

PROVIDER: S-EPMC4627310 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature