NF-κB as a Therapeutic Target in Multiple Myeloma*
By T. Hideshima, D. Chauhan, P. Richardson, C. Mitsiades, N. Mitsiades, Toshiaki Hayashi, N. Munshi, L. Dang, Alfredo C Castro, V. Palombella and 2 more. Journal of Biological Chemistry, 2002
869 citations recorded by the source corpus.
We have shown that thalidomide (Thal) and its immunomodulatory derivatives (IMiDs), proteasome inhibitor PS-341, and As2O3 act directly on multiple myeloma (MM) cells and in the bone marrow (BM) milieu to overcome drug resistance. Although Thal/IMiDs, PS-341, and As2O3 inhibit nuclear factor (NF)-κB activation, they also have multiple and varied other actions. In this study, we therefore specifically address the role of NF-κB blockade in mediating anti-MM activity. To characterize the effect of specific NF-κB blockade on MM cell growth and survival in vitro, we used an IκB kinase (IKK) inhibitor (PS-1145). Our studies demonstrate that PS-1145 and PS-341 block TNFα-induced NF-κB activation in a dose- and time-dependent fashion in MM cells through inhibition of IκBα phosphorylation and degradation of IκBα, respectively. Dexamethasone (Dex), which up-regulates IκBα protein, enhances blockade of NF-κB activation by PS-1145. Moreover, PS-1145 blocks the protective effect of IL-6 against Dex-induced apotosis. TNFα-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-κB blockade cannot account for all of the anti-MM activity of PS-341. Importantly, however, TNFα induces MM cell toxicity in the presence of PS-1145. These studies demonstrate that specific targeting of NF-κB 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-κB.
Subfields: Cancer Research, Hematology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/a5f6e54f527405f40872f0f9713218671addc311
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Citations in the corpus
- A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. (2005, background): “NPI-0052 targets nuclear factor-κB A major rationale for using Bortezomib therapeutically is its ability to inhibit nuclear factor-κB (NF-κB) activation (Adams, 2002; Hideshima et al., 2002; Russo et al., 2001).”
- The proteasome: a suitable antineoplastic target (2004, neutral): “Bortezomib blocks TNF-α-induced NF-κB activation in a dose- and time-dependent fashion in multiple-myeloma cells through degradation of IκB&alpha”
- The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. (2003, methodology): “MM.1S cells were therefore (1) pretreated with doxorubicin for 24 hours and then treated with PS-341 for an additional 24 hours, ( 2 ) pretreated with PS-341 for 24 hours and then treated with doxorubicin for an additional 24 hours, or (3) treated concomitantly with PS-341 and doxorubicin for 24 hou”
- Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. (2007, background): “…new therapeutic strategies targeting defined pathogenetic events in MM. Previous studies suggested the importance of NF-kB signaling in MM, by the nuclear presence of NF-kB in MM cells and the sensitivity of some MM cell lines to NF-kB inhibition (Hideshima et al., 2002; Hideshima et al., 2006).”