A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib
Dharminder Chauhan, Laurence Catley, Guilan Li, Klaus Podar, Teru Hideshima, Mugdha Velankar, Constantine Mitsiades, Nicolas Mitsiades, Hiroshi Yasui, Anthony Letai, Huib Ovaa, Celia Berkers, Benjamin Nicholson, Ta-Hsiang Chao, Saskia T C Neuteboom, Paul Richardson, Michael A Palladino, Kenneth C Anderson, Dharminder Chauhan, Laurence Catley, Guilan Li, Klaus Podar, Teru Hideshima, Mugdha Velankar, Constantine Mitsiades, Nicolas Mitsiades, Hiroshi Yasui, Anthony Letai, Huib Ovaa, Celia Berkers, Benjamin Nicholson, Ta-Hsiang Chao, Saskia T C Neuteboom, Paul Richardson, Michael A Palladino, Kenneth C Anderson
Abstract
Bortezomib therapy has proven successful for the treatment of relapsed and/or refractory multiple myeloma (MM); however, prolonged treatment is associated with toxicity and development of drug resistance. Here, we show that the novel proteasome inhibitor NPI-0052 induces apoptosis in MM cells resistant to conventional and Bortezomib therapies. NPI-0052 is distinct from Bortezomib in its chemical structure, effects on proteasome activities, mechanisms of action, and toxicity profile against normal cells. Moreover, NPI-0052 is orally bioactive. In animal tumor model studies, NPI-0052 is well tolerated and prolongs survival, with significantly reduced tumor recurrence. Combining NPI-0052 and Bortezomib induces synergistic anti-MM activity. Our study therefore provides the rationale for clinical protocols evaluating NPI-0052, alone and together with Bortezomib, to improve patient outcome in MM.
Source: PubMed