The class‐I HDAC inhibitor MGCD0103 induces apoptosis in Hodgkin lymphoma cell lines and synergizes with proteasome inhibitors by an HDAC6‐independent mechanism

Abstract

Summary Inhibition of histone deacetylase 6 (HDAC6)-dependent aggresome function by pan HDAC inhibitors was recently reported to be a key mechanism underlying the synergistic activity between proteasome inhibitors and HDAC inhibitors in a variety of tumour types. Because these combinations induce significant thrombocytopenia in vivo, we examined whether less toxic, isotype-selective HDAC inhibitors may still synergize with proteasome inhibitors, and if so, by what mechanisms. Here, we showed that the class I HDAC inhibitor, MGCD0103, has a potent antiproliferative activity in Hodgkin lymphoma (HL) cell lines. Furthermore, MGCD0103 induced tumour necrosis factor α (TNF-α) expression and secretion, which was associated with nuclear factor (NF)-κB activation. Selective inhibition of TNF- α expression by short interfering mRNA, or inhibition of MGCD0103-induced NF-kB activation by proteasome inhibitors enhanced MGCD0103-induced cell death. Thus, our results demonstrate that MGCD0103 may synergize with proteasome inhibitors by HDAC6-independent mechanisms, providing mechanistic rationale for exploring this potentially less toxic combination for the treatment of lymphoma.

Class I and IIa Histone Deacetylases Have Opposite Effects on Sclerostin Gene Regulation

“…In contrast, the pan-HDI TSA (46,47) (46,47,49,50). In contrast to TSA and apicidin, MS-275 did not inhibit SOST expression, but showed a bell-shaped about 2-fold stimulation with a maximum at 1 M. A similar response was obtained with MGCD0103 (51,52), another potent HDAC1 inhibitor (data not shown). As the class I HDAC8 is not expressed in UMR106 cells (Fig.…”

The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines

“…We demonstrated that panobinostat is among the most active HDAC inhibitors against HL cell lines in vitro, with IC 50 in the nanomolar ranges. 20 The antiproliferative activity involved regulation of several oncogenic pathways, including caspase activation and induction of apoptosis, inhibition of the activation of STAT5 and STAT6, and inhibition of tumor angiogenesis and regulation of glucose uptake. Our data also provide a mechanistic rationale for combining panobinostat with everolimus for the treatment of patients with HL.…”

Isoform-Selective HDAC Inhibition in Autoimmune DiseaseNicole L Regna1* and Christopher M Reilly2

“…Previous studies indicate that MGCD10103 increases caspase-dependent apoptosis while inhibiting autophagy through the activation of the PI3K/AKT/mTOR pathway [81,82]. Furthermore, MGD10103 increased NF-κB activation and resulted in increased TNF-α expression and production [80]. For these reasons, MGCD0103 may not be optimal for treatment for autoimmune diseases, including SLE and RA, which are characterized by increased PI3K/AKT/mTOR signaling and NF-κB activation [83][84][85].…”

“…MGCD0103 has been demonstrated to have antiproliferative activity in Hodgkin lymphoma cell lines and B-cell chronic lymphocytic leukemia [79][80][81]. Previous studies indicate that MGCD10103 increases caspase-dependent apoptosis while inhibiting autophagy through the activation of the PI3K/AKT/mTOR pathway [81,82].…”