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

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

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

645 Citations (Scopus)

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.

Original language	English
Pages (from-to)	407-419
Number of pages	13
Journal	Cancer Cell
Volume	8
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2005.10.013
Publication status	Published - Nov 2005
Externally published	Yes

Keywords

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

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10.1016/j.ccr.2005.10.013

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Chauhan, D., Catley, L., Li, G., Podar, K., Hideshima, T., Velankar, M., Mitsiades, C., Mitsiades, N., Yasui, H., Letai, A., Ovaa, H., Berkers, C., Nicholson, B., Chao, T.-H., Neuteboom, S. T. C., Richardson, P., Palladino, M. A., & Anderson, K. C. (2005). A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell, 8(5), 407-419. https://doi.org/10.1016/j.ccr.2005.10.013

@article{d78e07240c81481a9dd06b16d4a9f4ba,

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

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.",

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

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

year = "2005",

month = nov,

doi = "10.1016/j.ccr.2005.10.013",

language = "English",

volume = "8",

pages = "407--419",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

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Chauhan, D, Catley, L, Li, G, Podar, K, Hideshima, T, Velankar, M, Mitsiades, C, Mitsiades, N, Yasui, H, Letai, A, Ovaa, H, Berkers, C, Nicholson, B, Chao, T-H, Neuteboom, STC, Richardson, P, Palladino, MA & Anderson, KC 2005, 'A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib', Cancer Cell, vol. 8, no. 5, pp. 407-419. https://doi.org/10.1016/j.ccr.2005.10.013

TY - JOUR

T1 - A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib

AU - Chauhan, Dharminder

AU - Catley, Laurence

AU - Li, Guilan

AU - Podar, Klaus

AU - Hideshima, Teru

AU - Velankar, Mugdha

AU - Mitsiades, Constantine

AU - Mitsiades, Nicolas

AU - Yasui, Hiroshi

AU - Letai, Anthony

AU - Ovaa, Huib

AU - Berkers, Celia

AU - Nicholson, Benjamin

AU - Chao, Ta-Hsiang

AU - Neuteboom, Saskia T C

AU - Richardson, Paul

AU - Palladino, Michael A

AU - Anderson, Kenneth C

PY - 2005/11

Y1 - 2005/11

N2 - 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.

AB - 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.

KW - Administration, Oral

KW - Animals

KW - Antineoplastic Agents/pharmacology

KW - Apoptosis/drug effects

KW - Boronic Acids/pharmacology

KW - Bortezomib

KW - Caspases/metabolism

KW - Cell Movement/drug effects

KW - Cell Proliferation/drug effects

KW - Drug Synergism

KW - Genes, bcl-2

KW - Humans

KW - Lactones/administration & dosage

KW - Lymphocytes/drug effects

KW - Mice

KW - Mitochondria/drug effects

KW - Multiple Myeloma/drug therapy

KW - NF-kappa B/metabolism

KW - Plasmacytoma/drug therapy

KW - Protease Inhibitors/pharmacology

KW - Proteasome Endopeptidase Complex/pharmacology

KW - Pyrazines/pharmacology

KW - Pyrroles/administration & dosage

KW - Tumor Cells, Cultured

UR - http://www.scopus.com/inward/record.url?scp=27644562277&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2005.10.013

DO - 10.1016/j.ccr.2005.10.013

M3 - Journal article

C2 - 16286248

SN - 1535-6108

VL - 8

SP - 407

EP - 419

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

Abstract

Keywords

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