A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib.
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.
Chauhan
Dharminder
D
The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Catley
Laurence
L
Li
Guilan
G
Podar
Klaus
K
Hideshima
Teru
T
Velankar
Mugdha
M
Mitsiades
Constantine
C
Mitsiades
Nicolas
N
Yasui
Hiroshi
H
Letai
Anthony
A
Ovaa
Huib
H
Berkers
Celia
C
Nicholson
Benjamin
B
Chao
Ta-Hsiang
TH
Neuteboom
Saskia T C
ST
Richardson
Paul
P
Palladino
Michael A
MA
Anderson
Kenneth C
KC
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D019254:Genes, bcl-2; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy*; D016328:NF-kappa B / Q000378:metabolism; D010954:Plasmacytoma / Q000188:drug therapy; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001897:Boronic Acids; D007783:Lactones; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D011758:Pyrroles; D000069286:Bortezomib; C475865:marizomib; D020169:Caspases; D046988:Proteasome Endopeptidase Complex