A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib

Dharminder Chauhan; Laurence Catley; Guilan Li; Klaus Podar; Teru Hideshima; Mugdha Velankar; Constantine Mitsiades; Nicolas Mitsiades; Hiroshi Yasui; Anthony Letai; Huib Ovaa; Celia Berkers; Benjamin Nicholson; Ta-Hsiang Chao; Saskia T C Neuteboom; Paul Richardson; Michael A Palladino; Kenneth C Anderson

doi:10.1016/j.ccr.2005.10.013

A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib

Cancer Cell. 2005 Nov;8(5):407-19. doi: 10.1016/j.ccr.2005.10.013.

Authors

Dharminder Chauhan¹, Laurence Catley, Guilan Li, Klaus Podar, Teru Hideshima, Mugdha Velankar, Constantine Mitsiades, Nicolas Mitsiades, Hiroshi Yasui, Anthony Letai, Huib Ovaa, Celia Berkers, Benjamin Nicholson, Ta-Hsiang Chao, Saskia T C Neuteboom, Paul Richardson, Michael A Palladino, Kenneth C Anderson

Affiliation

¹ The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

PMID: 16286248
DOI: 10.1016/j.ccr.2005.10.013

Abstract

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.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Boronic Acids / pharmacology*
Boronic Acids / therapeutic use
Bortezomib
Caspases / metabolism
Cell Movement / drug effects
Cell Proliferation / drug effects
Drug Synergism
Genes, bcl-2
Humans
Lactones / administration & dosage
Lactones / chemistry
Lactones / pharmacology*
Lymphocytes / drug effects
Mice
Mitochondria / drug effects
Mitochondria / metabolism
Multiple Myeloma / drug therapy*
NF-kappa B / metabolism
Plasmacytoma / drug therapy
Protease Inhibitors / pharmacology*
Proteasome Endopeptidase Complex / pharmacology
Pyrazines / pharmacology*
Pyrazines / therapeutic use
Pyrroles / administration & dosage
Pyrroles / chemistry
Pyrroles / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Boronic Acids
Lactones
NF-kappa B
Protease Inhibitors
Pyrazines
Pyrroles
Bortezomib
marizomib
Caspases
Proteasome Endopeptidase Complex

Abstract

Publication types

MeSH terms

Substances

Grants and funding