The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma
Open accessAbstract
We have shown that the proteasome inhibitor bortezomib (formerly known as PS-341) triggers significant antitumor activity in multiple myeloma (MM) in both preclinical models and patients with relapsed refractory disease. Recent studies have shown that unfolded and misfolded ubiquitinated proteins are degraded not only by proteasomes, but also by aggresomes, dependent on histone deacetylase 6 (HDAC6) activity. We therefore hypothesized that inhibition of both mechanisms of protein catabolism could induce accumulation of ubiquitinated proteins followed by significant cell stress and cytotoxicity in MM cells. To prove this hypothesis, we used bortezomib and tubacin to inhibit the proteasome and HDAC6, respectively. Tubacin specifically triggers acetylation of α-tubulin as a result of HDAC6 inhibition in a dose- and time-dependent fashion. It induces cytotoxicity in MM cells at 72 h with an IC 50 of 5–20 μM, which is mediated by caspase-dependent apoptosis; no toxicity is observed in normal peripheral blood mononuclear cells. Tubacin inhibits the interaction of HDAC6 with dynein and induces marked accumulation of ubiquitinated proteins. It synergistically augments bortezomib-induced cytotoxicity by c-Jun NH 2 -terminal kinase/caspase activation. Importantly, this combination also induces significant cytotoxicity in plasma cells isolated from MM patient bone marrow. Finally, adherence of MM cells to bone marrow stromal cells confers growth and resistance to conventional treatments; in contrast, the combination of tubacin and bortezomib triggers toxicity even in adherent MM cells. Our studies therefore demonstrate that tubacin combined with bortezomib mediates significant anti-MM activity, providing the framework for clinical evaluation of combined therapy to improve patient outcome in MM.
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A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma
Richardson, P. G., Barlogie, B., Berenson, J., Singhal, S., Jagannath, S., Irwin, D., Rajkumar, S. V., Srkalovic, G., Alsina, M., Alexanian, R., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa030288 · Cited by 2,632
Self-citationAggresomes, inclusion bodies and protein aggregation
Kopito, R. R. (2000) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)01852-3 · Cited by 1,921
Kawaguchi, Y., Kovacs, J. J., McLaurin, A., Vance, J. M., Ito, A., & Yao, T.-P. (2003) · Cell · doi:10.1016/s0092-8674(03)00939-5 · Cited by 1,524
Hideshima, T., Richardson, P. G. G., Chauhan, D., Palombella, V. J., Elliott, P. J., Adams, J., & Anderson, K. C. (2001) · PubMed · Cited by 1,508
Self-citationHaggarty, S. J., Koeller, K. M., Wong, J. C., Grozinger, C. M., & Schreiber, S. L. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0430973100 · Cited by 1,066
Self-citationSingle versus Double Autologous Stem-Cell Transplantation for Multiple Myeloma
Attal, M., Harousseau, J.-L., Facon, T., Guilhot, F., Doyen, C., Fuzibet, J.-G., Monconduit, M., Hulin, C., Caillot, D., Bouabdallah, R., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa032290 · Cited by 984
NF-κB as a Therapeutic Target in Multiple Myeloma
Hideshima, T., Chauhan, D., Richardson, P., Mitsiades, C., Mitsiades, N., Hayashi, T., Munshi, N., Dang, L., Castro, A., Palombella, V., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200360200 · Cited by 893
Self-citationSingle versus Double Autologous Stem-Cell Transplantation for Multiple Myeloma
(2004) · New England Journal of Medicine · doi:10.1056/nejm200406173502526 · Cited by 817
Molecular sequelae of proteasome inhibition in human multiple myeloma cells
Mitsiades, N., Mitsiades, C. S., Poulaki, V., Chauhan, D., Fanourakis, G., Gu, X., Bailey, C., Joseph, M., Libermann, T. A., Treon, S. P., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.202445099 · Cited by 741
Self-citationMitsiades, N., Mitsiades, C. S., Richardson, P. G., Poulaki, V., Tai, Y.-T., Chauhan, D., Fanourakis, G., Gu, X., Bailey, C., Joseph, M., et al. (2003) · Blood · doi:10.1182/blood-2002-06-1768 · Cited by 697
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Cited by
Anticancer activities of histone deacetylase inhibitors
Bolden, J. E., Peart, M. J., & Johnstone, R. W. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2133 · Cited by 2,919
New and emerging HDAC inhibitors for cancer treatment
West, A. C., & Johnstone, R. W. (2014) · Journal of Clinical Investigation · doi:10.1172/jci69738 · Cited by 1,404
HDAC family: What are the cancer relevant targets?
Witt, O., Deubzer, H. E., Milde, T., & Oehme, I. (2009) · Cancer Letters · doi:10.1016/j.canlet.2008.08.016 · Cited by 1,069
Proteasome inhibitors in cancer therapy
Manasanch, E. E., & Orlowski, R. Z. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.206 · Cited by 1,024
Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets
Hideshima, T., Mitsiades, C., Tonon, G., Richardson, P. G., & Anderson, K. C. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2189 · Cited by 932
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Metadata
- Authors
- Hideshima, T., Bradner, J. E., Wong, J., Chauhan, D., Richardson, P., Schreiber, S. L., & Anderson, K. C.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2005-06-03
- Volume
- 102
- Issue
- 24
- Pages
- 8567-8572
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2166427186
- Cited by
- 593
- References
- 30
- FWCI
- 20.17
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Hideshima, T., Bradner, J. E., Wong, J., Chauhan, D., Richardson, P., Schreiber, S. L., & Anderson, K. C. (2005). Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0503221102
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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