Modulating protein ubiquitination via proteasome inhibition represents a promising target for cancer therapy, owing to the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome which down-modulates the NF-κB activity and the expression of several NF-κB downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib- treated MM patients. In vitro, CEP-18770 has a strong anti-angiogenic activity and potently represses RANKL–induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally-active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition.
|Titolo:||CEP-18770 : a novel orally-active proteasome inhibitor with a tumor-selective pharmacological profile competitive with bortezomib|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Data di pubblicazione:||2008|
|Digital Object Identifier (DOI):||10.1182/blood-2007-07-100651|
|Appare nelle tipologie:||01 - Articolo su periodico|