Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma.
Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells, and importantly, that is distinct from bortezomib (Velcade) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138(+) MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 plus bortezomib-induced synergistic apoptosis is associated with: (1) activation of caspase-8, caspase-9, caspase-3, and PARP; (2) induction of endoplasmic reticulum (ER) stress response and JNK; (3) inhibition of migration of MM cells and angiogenesis; (4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) proteolytic activities; and (5) blockade of NF-kappaB signaling. Studies in a xenograft model show that low dose combination of NPI-0052 and bortezomib is well tolerated and triggers synergistic inhibition of tumor growth and CT-L, C-L, and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 plus bortezomib-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM.
Chauhan
Dharminder
D
The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Myeloma Research, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. dharminder_chauhan@dfci.harvard.edu
Singh
Ajita
A
Brahmandam
Mohan
M
Podar
Klaus
K
Hideshima
Teru
T
Richardson
Paul
P
Munshi
Nikhil
N
Palladino
Michael A
MA
Anderson
Kenneth C
KC
D000818:Animals; D001897:Boronic Acids / Q000633:toxicity*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000633:toxicity*; D051379:Mice; D009101:Multiple Myeloma / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D011480:Protease Inhibitors / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011719:Pyrazines / Q000633:toxicity*; D011758:Pyrroles / Q000633:toxicity*; D023041:Xenograft Model Antitumor Assays
D001897:Boronic Acids; D006360:Heat-Shock Proteins; D007783:Lactones; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D011758:Pyrroles; D000069286:Bortezomib; C475865:marizomib; D046988:Proteasome Endopeptidase Complex