Proteasome inhibition as therapy
Abstract No: 3122
Author(s): D. Chauhan, L. Catley, G. Li, T. Hideshima, P. Richardson, M. Palladino, K. C. Anderson
Abstract:
Multiple Myeloma (MM) remains fatal despite all available therapies, and novel approaches which target mechanisms regulating MM cell growth, survival, and apoptosis are urgently needed. Proteasome is a promising target in the treatment of MM. The proteasome inhibitor Bortezomib/PS-341/Velcade has shown potent preclinical activity in vitro as well as therapeutic activity in MM and is the first treatment in more than a decade to be FDA approved for patients with MM. However, prolonged exposure is associated with attendant toxicity and development of bortezomib-resistance. Here we demonstrate that novel proteasome inhibitor NPI-0052, distinct in its chemical structure from bortezomib, induces apoptosis even in MM cells resistant to bortezomib, dexamethasone (Dex), melphalan and thalidomide without significantly affecting the viability of normal cells. NPI-0052 overcomes growth/survival and drug-resistance in MM cells conferred by bone marrow (BM) microenvironment, and/or altered expression of anti-apoptotic proteins Bcl2, Hsp27, and IAPs. Mechanistic studies demonstrate that NPI-0052-triggered MM apoptosis is associated with loss of mitochondrial membrane potential; Superoxide generation; release of mitochondrial proteins cytochrome-c/Smac; and activation of caspase-8/9/3. Alternatively, pretreatment of MM cells with the pan-caspase inhibitor Z-VAD-fmk blocks NPI-0052-induced cell death. In vivo studies in animal models show that oral administration of NPI-0052 decreased proteasome activity in packed whole blood lysates in a dose dependent fashion. Moreover, studies using a human plasmacytoma xenograft mouse model show that NPI-0052 is orally active and has significant anti-MM activity at doses that are not only well tolerated, but also inhibit MM cell growth and prolong survival. Collectively, these data provide the framework for clinical evaluation of NPI-0052 to trigger apoptosis in MM cells, reduce bortezomib-associated toxicity, overcome bortezomib-resistance, and improve patient outcome in MM.
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