Aminopeptidase inhibition as a targeted treatment strategy in myeloma

• Published in: Molecular cancer therapeutics 2009-04, Vol.8 (4), p.762-770
• Main Authors: Moore, Hannah E, Davenport, Emma L, Smith, Emma M, Muralikrishnan, Srikanth, Dunlop, Alan S, Walker, Brian A, Krige, David, Drummond, Alan H, Hooftman, Leon, Morgan, Gareth J, Davies, Faith E
• Format: Article
• Language: English
• Subjects: aminopeptidase inhibition; aminopeptidases; Aminopeptidases - antagonists & inhibitors; Aminopeptidases - metabolism; Apoptosis - drug effects; Biomarkers, Tumor - metabolism; Bone Marrow Cells - enzymology; Bone Marrow Cells - pathology; Caspases - metabolism; Cell Cycle - drug effects; Cell Proliferation - drug effects; Glycine - analogs & derivatives; Glycine - pharmacology; Humans; Hydroxamic Acids - pharmacology; Immunoblotting; multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - enzymology; novel treatments; proteasome inhibition; Stromal Cells - enzymology; Stromal Cells - pathology; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-0735

Myeloma cells are highly dependent on the unfolded protein response to assemble folded immunoglobulins correctly. Therefore, targeting protein handling within a myeloma cell by inhibiting the aminopeptidase enzyme system, which catalyses the hydrolysis of amino acids from the proteins NH 2 terminus, represents a therapeutic approach. CHR-2797, a novel aminopeptidase inhibitor, is able to inhibit proliferation and induce growth arrest and apoptosis in myeloma cells, including cells resistant to conventional chemotherapeutics. It causes minimal inhibition of bone marrow stromal cell (BMSC) proliferation but is able to overcome the microenvironmental protective effects, inhibiting the proliferation of myeloma cells bound to BMSCs and the increase in vascular endothelial growth factor levels seen when myeloma cells and BMSCs are bound together. Additive and synergistic effects are seen with bortezomib, melphalan, and dexamethasone. Apoptosis occurs via both caspase-dependent and non-caspase-dependent pathways with an increase in Noxa, cleavage of Mcl-1, and activation of the unfolded protein response. Autophagy is also seen. CHR-2797 causes an up-regulation of genes involved in the proteasome/ubiquitin pathway, as well as aminopeptidases, and amino acid deprivation response genes. In conclusion, inhibiting protein turnover using the aminopeptidase inhibitor CHR-2797 results in myeloma cell apoptosis and represents a novel therapeutic approach that warrants further investigation in the clinical setting. [Mol Cancer Ther 2009;8(4):762–70]