NF-κB localization in multiple myeloma plasma cells and mesenchymal cells

Conticello, Concetta; Giuffrida, Raffaella; Adamo, Luana; Anastasi, Gabriele; Martinetti, Daniela; Salomone, Edvige; Colarossi, Cristina; Amato, G.; Gorgone, Ausilia; Romano, Alessandra; Iannolo, Gioacchin; Maria, Ruggero De; Giustolisi, Rosario; Gulisano, Massimo; Raimondo, Francesco Di

doi:10.1016/j.leukres.2010.06.023

Cited by 12 publications

(13 citation statements)

References 41 publications

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“…39 Both of these pathways are important players in myeloma pathogenesis and development of chemoresistance. 40, 41, 42 We treated UM3 cells with 1 μ niclosamide for 2 h and then stimulated them for 15 min with 100 ng/ml tumour necrosis factorα (TNFα). Sub-cellular localisation of the p65 NF-κB subunit was assessed using immunofluorescence staining and fluorescence microscopy.…”

Section: Resultsmentioning

confidence: 99%

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production

Khanim

Merrick

Giles

et al. 2011

Blood Cancer Journal

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Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-κB and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity.

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Section: Resultsmentioning

confidence: 99%

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production

Khanim

Merrick

Giles

et al. 2011

Blood Cancer Journal

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“…Our group has recently described that the majority of MM cells from BM specimens at different stages of disease almost exclusively express the cytoplasmic (inactive) form of NF- κ B while, in mesenchymal cells from MM-patients, NF- κ B is present in the nuclear active form, further underlining the relevance of BM mesenchymal cells [37]. In addition, the proteasome inhibitor bortezomib, which was described in the past as a NF- κ B antagonist, had a consistent antitumor activity against both chemoresistant and chemosensitive MM cells, regardless of the NF- κ B localization, thus suggesting the existence of other molecular targets of proteasome inhibitors in MM [29, 35, 37].…”

Section: The MM Nichementioning

confidence: 99%

“…In addition, the proteasome inhibitor bortezomib, which was described in the past as a NF- κ B antagonist, had a consistent antitumor activity against both chemoresistant and chemosensitive MM cells, regardless of the NF- κ B localization, thus suggesting the existence of other molecular targets of proteasome inhibitors in MM [29, 35, 37]. The overexpression and activation of several molecules involved in NF- κ B signaling give rise to promising targets for novel anti-MM therapy [38].…”

Section: The MM Nichementioning

confidence: 99%

Immunological Dysregulation in Multiple Myeloma Microenvironment

Romano

Conticello

Cavalli

et al. 2014

BioMed Research International

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109

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Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.

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“…Most remarkably, these cells exhibit a high sensitivity to bortezomib, regardless of NF-kB localization, suggesting the existence of other molecular targets of this proteasome inhibitor in MM [29];…”

Section: Mechanisms Of Action: Open Questionsmentioning

confidence: 95%

“…Proteasome inhibitor PS-1145 that selectively blocks IkB induces a weak inhibition of plasma cell proliferation in comparison with bortezomib, thus indicating that bortezomib has a different mechanism of action [29,30]; It has been demonstrated that plasma cells from MM patients at diagnosis and relapse almost exclusively present the cytoplasmic inactive form of NF-kB. Most remarkably, these cells exhibit a high sensitivity to bortezomib, regardless of NF-kB localization, suggesting the existence of other molecular targets of this proteasome inhibitor in MM [29];…”

Section: Mechanisms Of Action: Open Questionsmentioning

confidence: 99%

Bortezomib for the Treatment of Previously Untreated Multiple Myeloma

2013

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Management of multiple myeloma (MM) has been drastically changed in the last 10 years thanks to the introduction of novel agents, which, combined with the backbone of classical chemotherapy, have led to a significant improvement in disease control. Bortezomib is the first reversible proteasome inhibitor approved for the treatment of MM, with wide synergism in vitro and in vivo with a plethora of drugs active for MM. In patients eligible for autologous stem cell transplantation (ASCT), the achievement of complete response or very good partial response before ASCT is associated with prolonged progression-free and overall survival. Thus, the goal of induction regimens should include, at least for younger patients, a continued improvement of the quality and depth of the achieved response. This article is focused on reviewing the major efforts in frontline therapy for MM, including bortezomib-containing induction regimens in patients either eligible or ineligible for ASCT.

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NF-κB localization in multiple myeloma plasma cells and mesenchymal cells

Cited by 12 publications

References 41 publications

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production

Immunological Dysregulation in Multiple Myeloma Microenvironment

Bortezomib for the Treatment of Previously Untreated Multiple Myeloma

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