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

Dharminder Chauhan, Ajita Singh, Mohan Brahmandam, Klaus Podar, Teru Hideshima, Paul Richardson, Nikhil Munshi, Michael A Palladino, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

202 Citations (Scopus)


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-κB 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.

Original languageEnglish
Pages (from-to)1654-1664
Number of pages11
Issue number3
Publication statusPublished - 01 Feb 2008
Externally publishedYes


  • 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
  • NF-kappa B/metabolism
  • Neovascularization, Pathologic
  • Protease Inhibitors/toxicity
  • Proteasome Endopeptidase Complex/metabolism
  • Pyrazines/toxicity
  • Pyrroles/toxicity
  • Xenograft Model Antitumor Assays

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology


Dive into the research topics of 'Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma'. Together they form a unique fingerprint.

Cite this