Author/Authors :
Chauhan، نويسنده , , Dharminder and Catley، نويسنده , , Laurence and Li، نويسنده , , Guilan and Podar، نويسنده , , Klaus and Hideshima، نويسنده , , Teru and Velankar، نويسنده , , Mugdha and Mitsiades، نويسنده , , Constantine S. Mitsiades، نويسنده , , Nicolas and Yasui، نويسنده , , Hiroshi and Letai، نويسنده , , Anthony and Ovaa، نويسنده , , Huib and Berkers، نويسنده , , Celia and Nicholson، نويسنده , , Benjamin and Chao، نويسنده , , Ta-Hsiang and Neuteboom، نويسنده , , Saskia T.C. and Richardson، نويسنده , , Paul and Palladino، نويسنده , , Michael A. and Anderson، نويسنده , , Kenneth C.، نويسنده ,
Abstract :
Summary
omib 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.
