NF-κB as a Therapeutic Target in Multiple Myeloma

Abstract

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

CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells

“…The suppression of NF-κB occurred through inhibition of IκBα kinase activation [1]. Activation of NF-κB has been shown to promote IL-6 expression in tumor cells [4,13]. Our results show CDDO-Me inhibits IL-6 secretion, Jak2 and Src phosphorylation; therefore, CDDO-Me likely inhibits the IL-6-Stat3 pathway at multiple points.…”

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

“…Inhibition of NF-kB activity by specific IKK inhibitor downregulates IL-6 secretion in BMSC and related plasma cell growth (Hideshima et al, 2002a). Furthermore, inhibition of either p38MAPK or TFG-b by specific inhibitors downregulates IL-6 secretion in BMSC Hideshima et al, 2004).…”

“…Transforming growth factor-beta is secreted by plasma cells and triggers IL-6 production by BMSC , further enhancing paracrine plasma cell growth and angiogenesis. Most IL-6 is secreted by BMSC and its transcription and secretion are further enhanced by secretion of TGF-b, TNF-a, VEGF and IL-1 within the bone marrow microenvironment Costes et al, 1998;Dankbar et al, 2000;Gupta et al, 2001;Hideshima et al, 2001b). Tumor necrosis factor-alpha is a more potent stimulus of IL-6 secretion in BMSC than VEGF or TGF-b (Hideshima et al, 2001b).…”

“…Targeting inhibition of Ras/Raf/MEK/ERK signaling by using the farnesyltransferase inhibitors SCH66336 and R115777 abrogates plasma cell growth (Ochiai et al, 2003). The proteasome inhibitor bortezomib (formerly PS-341) can overcome the protective effect of IL-6 against dex-induced apoptosis in MM by inducing caspase-8/-9/-3 activation, which results in caspase-dependent gp130 cleavage (Hideshima et al, 2001b(Hideshima et al, , 2003b. Moreover, bortezomib inhibits DNA repair and may restore the sensitivity of MM cells to DNA-damaging chemotherapeutic agents, suggesting that its combination with conventional chemotherapy may augment clinical effectiveness and overcome resistance in patients with relapsed or refractory MM .…”

Inhibitors of NF-κB signaling: 785 and counting

“…Although bortezomib is clearly an efficient blocker of NF-kB in many in vitro systems including myeloma cells (Cusack et al, 2001;Hideshima et al, 2002), it is not entirely clear whether its antimyeloma effects are mediated entirely, or even in part, through inhibition of NF-kB. For example, bortezomib has non-NF-kB effects on cancer cell growth and additional cancer-related protein targets are affected by its proteasome inhibitory activity (Hideshima et al, 2002;Adams, 2004;Zheng et al, 2004;Takigawa et al, 2006); moreover, in some cases bortezomib can activate, rather than inhibit, NF-kB (Ne´meth et al, 2004). Thus, whether the therapeutic effect of bortezomib in the treatment of multiple myeloma (and other cancers) is entirely or in part due to its effect on NF-kB is not clear.…”