Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 151, Issue 4, Pages 387-396Publisher
WILEY
DOI: 10.1111/j.1365-2141.2010.08342.x
Keywords
Hodgkin lymphoma; new drugs for lymphoma; MGCD0103; Bortezomib
Categories
Funding
- NCI [1 R21 CA117070-01]
- Lymphoma SPORE grant [1P50CA136411-01A1]
- Clay Chiles Lymphoma Fund
- Jack L. Stotsky Memorial Fund
- Pharmion
- Methylgene
Ask authors/readers for more resources
P>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 alpha (TNF-alpha) expression and secretion, which was associated with nuclear factor (NF)-kappa B activation. Selective inhibition of TNF-alpha 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available