The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
NF-κB as a Therapeutic Target in Multiple Myeloma
Open accessAbstract
We have shown that thalidomide (Thal) and its immunomodulatory derivatives (IMiDs), proteasome inhibitor PS-341, and As(2)O(3) act directly on multiple myeloma (MM) cells and in the bone marrow (BM) milieu to overcome drug resistance. Although Thal/IMiDs, PS-341, and As(2)O(3) inhibit nuclear factor (NF)-kappaB activation, they also have multiple and varied other actions. In this study, we therefore specifically address the role of NF-kappaB blockade in mediating anti-MM activity. To characterize the effect of specific NF-kappaB blockade on MM cell growth and survival in vitro, we used an IkappaB kinase (IKK) inhibitor (PS-1145). Our studies demonstrate that PS-1145 and PS-341 block TNFalpha-induced NF-kappaB activation in a dose- and time-dependent fashion in MM cells through inhibition of IkappaBalpha phosphorylation and degradation of IkappaBalpha, respectively. Dexamethasone (Dex), which up-regulates IkappaBalpha protein, enhances blockade of NF-kappaB activation by PS-1145. Moreover, PS-1145 blocks the protective effect of IL-6 against Dex-induced apotosis. TNFalpha-induced intracellular adhesion molecule (ICAM)-1 expression on both RPMI8226 and MM.1S cells is also inhibited by PS-1145. Moreover, PS-1145 inhibits both IL-6 secretion from BMSCs triggered by MM cell adhesion and proliferation of MM cells adherent to BMSCs. However, in contrast to PS-341, PS-1145 only partially (20-50%) inhibits MM cell proliferation, suggesting that NF-kappaB blockade cannot account for all of the anti-MM activity of PS-341. Importantly, however, TNFalpha induces MM cell toxicity in the presence of PS-1145. These studies demonstrate that specific targeting of NF-kappaB can overcome the growth and survival advantage conferred both by tumor cell binding to BMSCs and cytokine secretion in the BM milieu. Furthermore, they provide the framework for clinical evaluation of novel MM therapies based upon targeting NF-kappaB.
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Cites
THE NF-κB AND IκB PROTEINS: New Discoveries and Insights
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Antitumor Activity of Thalidomide in Refractory Multiple Myeloma
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Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB
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Self-citationControl of oncogenesis and cancer therapy resistance by the transcription factor NF-κB
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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-citationThe IKK NF-κB system: a treasure trove for drug development
Karin, M., Yamamoto, Y., & Wang, Q. M. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1279 · Cited by 1,364
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
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Self-citationChauhan, D., Catley, L., Li, G., Podar, K., Hideshima, T., Velankar, M., Mitsiades, C., Mitsiades, N., Yasui, H., Letai, A., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.10.013 · Cited by 694
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Metadata
- Authors
- Hideshima, T., Chauhan, D., Richardson, P., Mitsiades, C., Mitsiades, N., Hayashi, T., Munshi, N., Dang, L., Castro, A., Palombella, V., Adams, J., & Anderson, K. C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-05
- Volume
- 277
- Issue
- 19
- Pages
- 16639-16647
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1759028523
- Cited by
- 893
- References
- 45
- FWCI
- 27.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
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