Proteosome inhibitors and HDAC inhibitors

Proteasome inhibitors

Bortezomib modulates protein expression post-translationally by blocking the degradation of a subset of proteins by the proteasome. Although this agent has proved effective in myeloma treatment and CLL cells are sensitive to bortezomib in vitro, poor anti-tumour responses are observed in CLL. Apoptosis induction may be dependent on the post-translational upregulation of the pro-apoptotic NOXA or BAX proteins.

Histone deacetylase inhibitors

Inhibitors of histone deacetylases (HDACs) are a novel class of candidate anti-tumor agent that induce apoptosis by reprogramming patterns of gene expression via modification of the acetylation state of histones. HDAC inhibitor treatment of CLL cells results in upregulation of the pro-apoptotic NOXA and BIM proteins and in apoptosis. NOXA neutralized the antiapoptotic function of the MCL-1 protein and downregulation of MCL-1 expression by CDK inhibitors, including roscovitine-potentiated apoptosis induction by HDAC inhibitors. However, these agents are likely to have a very broad spectrum of targets, which may limit their clinical utility.
Responses were disappointing in phase I trials of the hydroxamate HDAC inhibitor belinostat (no partial or complete remissions) and depsipeptide (no responses by NCI criteria despite substantially increased histone acetylation) and in a phase II trial of the orally available Class I HDAC inhibitor MGCD0103 (no responses). The dose of HDAC inhibitors is likely to be limited by constitutional symptoms including fatigue and nausea. Improved scheduling or combination of HDAC inhibitors with other agents could improve the clinical efficacy of these inhibitors.