Targeting NF-κB Signaling for Multiple Myeloma

Wong, Ada Hang‐Heng; Shin, Eun Myoung; Tergaonkar, Vinay; Chng, Wee‐Joo

doi:10.3390/cancers12082203

Cited by 31 publications

(26 citation statements)

References 135 publications

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“…In addition, the NF-κB pathway is abnormally activated in hematopoietic diseases (multiple myeloma and AML) accompanied by a wide range of inflammatory factors, which build a terrific tumor microenvironment to promote the development of blood tumors [45,46]. Therefore, we believe that the hyperactivated NF-κB signaling pathway is related to the abnormal proliferation of AML.…”

Section: Discussionmentioning

confidence: 98%

Effect of MT2A on apoptosis and proliferation in HL60 cells

et al. 2021

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Although accumulating evidence has revealed that metallothioneins (MTs) and its family member MT2A are strongly linked to the risk of various solid tumors, researches on the occurrence and development of acute myeloid leukemia (AML) have rarely been investigated. Here, we constructed a lentiviral vector with MT2A over-expression and the interfering plasmids with MT2A expression inhibition to study the influence of MT2A on the bioactivities of HL60 cells. After cells were infected with a lentiviral vector containing the MT2A gene, both transcription and translation levels of MT2A were significantly increased in the over-expressed group in comparison with control groups. In vitro experiments, all results demonstrated that cell reproductive capacity was inhibited, but cell apoptosis rate was significantly increased. Together, the expression of apoptosis-related protein Bcl2 was remarkably reduced, while a high expression level of Bax protein was detected. Further experiments revealed that up-regulation of MT2A induced cell apoptosis and promoted G2/M phase arrest. The mechanism may be associated with down-regulated p-IκB-α and cyclinD1 expression and up-regulated IκB-α expression in the nuclear factor-kappaB (NF-κB) pathway. On the contrary, MT2A expression was down-regulated by interfering plasmids. We found that cell proliferative potential was notably increased in the interfering group compared with the negative and untreated group. What's more, MT2A may be closely related to AML cell proliferation and function via the NF-κB signal pathway.

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Section: Discussionmentioning

confidence: 98%

Effect of MT2A on apoptosis and proliferation in HL60 cells

et al. 2021

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“…Expression of the growth factors IL-6 or BAFF in MM is regulated by the pathway NF-κB as well as the expression of regulators of the cell cycle—cyclin D, cyclin E, c-Myc, and E2F3α [ 37 ]. NF-κB signaling, in combination with other important transcription factors, such as STAT3, also plays an important role in the regulation of apoptosis [ 38 ]. Mutations of NF-κB, typically generated in the MM tumors, mostly activate the non-canonical pathway (NIK, TRAF3, TRAF2, CD40, etc.…”

Section: Characteristic Of Multiple Myelomamentioning

confidence: 99%

“…Nowadays, the most frequently used drugs for the treatment of MM are still the proteasome inhibitors (bortezomib, carfilzomib, and ixazomib) [ 38 ]. The suppression of the proteasome function blocks the ERAD mechanism, leading to accumulation of misfolded proteins.…”

Section: Disulfirammentioning

confidence: 99%

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Possible Therapeutic Potential of Disulfiram for Multiple Myeloma

Drozdkova

Trtková

2021

Current Oncology

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Multiple myeloma (MM) is a malignant disease of the plasma cells representing approximately 10% of all hemato-oncological diseases. Detection of the disease is most probable at around 65 years of age, and the average survival of patients is estimated to be 5–10 years, specifically due to frequent relapses and resistance to the therapy used. Thus, the search for new therapeutic approaches is becoming a big challenge. Disulfiram (DSF), a substance primarily known as a medication against alcoholism, has often been mentioned in recent years in relation to cancer treatment for its secondary anti-cancer effects. Recent studies performed on myeloma cell lines confirm high inhibition of the cell growth activity if a complex of disulfiram and copper is used. Its significant potential is now being seen in the cure of haematological malignities.

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“…Following the milestone approval of imatinib mesylate for CML, pathway-directed therapies have become a major focus of drug development also in MM in order to not only inhibit tumor cell proliferation, survival, migration, and drug resistance, but also to overcome immunoparesis, bone marrow angiogenesis, and bone disease ( Figure 1 a). While several recent articles excellently review the functional basics of signaling pathways [ 30 ], kinases in general [ 31 ], as well as STAT3- [ 32 ], and NFκB- [ 33 ] pathways in MM pathogenesis, we here focus on novel therapeutic strategies that specifically target the RAS/RAF/MEK/ERK- and the PI3K/AKT-pathways and PIM-kinase as well as selected downstream transcription factors. Figure 1 shows an overview of important signaling pathways in MM and drugs targeting those pathways.…”

Section: Introductionmentioning

confidence: 99%

Pathway-Directed Therapy in Multiple Myeloma

John

Krauth

Podar

et al. 2021

Cancers

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Multiple Myeloma (MM) is a malignant plasma cell disorder with an unmet medical need, in particular for relapsed and refractory patients. Molecules within deregulated signaling pathways, including the RAS/RAF/MEK/ERK, but also the PI3K/AKT-pathway belong to the most promising evolving therapeutic targets. Rationally derived compounds hold great therapeutic promise to target tumor-specific abnormalities rather than general MM-associated vulnerabilities. This paradigm is probably best depicted by targeting mutated BRAF: while well-tolerated, remarkable responses have been achieved in selected patients by inhibition of BRAFV600E alone or in combination with MEK. Targeting of AKT has also shown promising results in a subset of patients as monotherapy or to resensitize MM-cells to conventional treatment. Approaches to target transcription factors, convergence points of signaling cascades such as p53 or c-MYC, are emerging as yet another exciting strategy for pathway-directed therapy. Informed by our increasing knowledge on the impact of signaling pathways in MM pathophysiology, rationally derived Precision-Medicine trials are ongoing. Their results are likely to once more fundamentally change treatment strategies in MM.

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Targeting NF-κB Signaling for Multiple Myeloma

Cited by 31 publications

References 135 publications

Effect of MT2A on apoptosis and proliferation in HL60 cells

Effect of MT2A on apoptosis and proliferation in HL60 cells

Possible Therapeutic Potential of Disulfiram for Multiple Myeloma

Pathway-Directed Therapy in Multiple Myeloma

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