A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib
Open accessAbstract
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.
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References 41 · Cited by 694
- Authors
- 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.
- Affiliations
- Harvard University (US)
- Corresponding author
- Anderson, Kenneth C.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2005-11
- Volume
- 8
- Issue
- 5
- Pages
- 407-419
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W1987583882
- Cited by
- 694
- References
- 41
- Citations by year
- 2026: 5 · 2025: 16 · 2024: 10 · 2023: 13 · 2022: 14 · 2021: 20 · 2020: 22 · 2019: 27 · 2018: 15 · 2017: 31 · 2016: 26 · 2015: 36 · 2014: 41 · 2013: 48 · 2012: 53
- FWCI
- 31.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research Institute
- Multiple Myeloma Research Foundation
- Moffitt Cancer Center
- National Institutes of Health (CA100707)
- National Cancer Institute (P0-1 CA78373, R01- CA50947, P50CA100707, R01CA050947)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- NPI-0052, proteasome inhibitors, multiple myeloma, apoptosis, bortezomib, drug resistance, oral bioavailability, combination therapy, tumor recurrence, toxicity profile
- MeSH terms
- Bortezomib, Administration, Oral, Animals, Antineoplastic Agents, Boronic Acids, Cell Movement, Drug Synergism, Humans, Lactones, Lymphocytes, Mitochondria, Multiple Myeloma, Plasmacytoma, Protease Inhibitors, Pyrazines, Pyrroles, Tumor Cells, Cultured, NF-kappa B, Apoptosis, Genes, bcl-2, Caspases, Proteasome Endopeptidase Complex, Cell Proliferation, Mice
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