Chauhan, Dharminder, Catley, Laurence, Li, Guilan, Podar, Klaus, Hideshima, Teru, Velankar, Mugdha, Mitsiades, Constantine, Mitsiades, Nicolas, Yasui, Hiroshi, Letai, Anthony, Ovaa, Huib, Berkers, Celia, Nicholson, Benjamin, Chao, Ta-Hsiang, Neuteboom, Saskia T.C., Richardson, Paul, Palladino, Michael A., and Anderson, Kenneth C.
Summary: 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. [Copyright &y& Elsevier]