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PMID: 18006697 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma.

Blood ·Vol. 111 ·No. 3 ·2008-02-01 ·Pages 1654-64

Chauhan D, Singh A, Brahmandam M, Podar K, Hideshima T, Richardson P, Munshi N, Palladino MA, Anderson KC

Abstract

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.

MeSH Terms
Animals Boronic Acids/toxicity Bortezomib Cell Line, Tumor Cell Movement/drug effects Cell Survival/drug effects Endoplasmic Reticulum/metabolism Heat-Shock Proteins/metabolism Humans Lactones/toxicity Mice Multiple Myeloma/blood supply,enzymology,pathology NF-kappa B/metabolism Neovascularization, Pathologic Protease Inhibitors/toxicity Proteasome Endopeptidase Complex/metabolism Pyrazines/toxicity Pyrroles/toxicity Xenograft Model Antitumor Assays
Chemicals
Boronic Acids Heat-Shock Proteins Lactones NF-kappa B Protease Inhibitors Pyrazines Pyrroles Bortezomib marizomib Proteasome Endopeptidase Complex
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Chauhan Dharminder
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
Brahmandam Mohan
Podar Klaus
Hideshima Teru
Richardson Paul
Munshi Nikhil
Palladino Michael A
Anderson Kenneth C
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2007-08-105601
Email
dharminder_chauhan@dfci.harvard.edu
Published
2008-02-01
Epub
2007-00-15
Pages
1654-64
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2214767
Subset
IM
Grants
NCI NIH HHS · R01 CA050947 · United States
NCI NIH HHS · CA 50947 · United States
NCI NIH HHS · CA 10070 · United States
NCI NIH HHS · CA 78373 · United States
External Links
PubMed source DOI: 10.1182/blood-2007-08-105601 PMC Full Text View journal details
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