Can NF-κB Be Considered a Valid Drug Target in Neoplastic Diseases? Our Point of View

Labbozzetta, Manuela; Notarbartolo, Monica; Poma, Paola

doi:10.3390/ijms21093070

Cited by 47 publications

(35 citation statements)

References 142 publications

(160 reference statements)

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“…Phosphorylation of IκBα by IκB kinase (IKK) triggers its dissociation from the cytoplasmic NF-κB-IκB complex allowing it to be targeted for degradation. As a result, activated NF-κB translocates to the nucleus and induces the transcription of a series of genes involved in cell survival or apoptosis, immune responses, and inflammation [ 53 , 54 , 55 ]. In order to reveal the involvement of NF-κB in the anti-inflammatory and anti-migratory effects of HSR2104, we tested its effects on the nuclear translocation of NF-κB and phosphorylation of IκBα in LPS-treated BV2 cells.…”

Section: Discussionmentioning

confidence: 99%

A Novel 1,8-Naphthyridine-2-Carboxamide Derivative Attenuates Inflammatory Responses and Cell Migration in LPS-Treated BV2 Cells via the Suppression of ROS Generation and TLR4/Myd88/NF-κB Signaling Pathway

Nguyen

Bui

Lee

et al. 2021

IJMS

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Novel 1,8-naphthyridine-2-carboxamide derivatives with various substituents (HSR2101-HSR2113) were synthesized and evaluated for their effects on the production of pro-inflammatory mediators and cell migration in lipopolysaccharide (LPS)-treated BV2 microglial cells. Among the tested compounds, HSR2104 exhibited the most potent inhibitory effects on the LPS-stimulated production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-α, and interleukin-6. Therefore, this compound was chosen for further investigation. We found that HSR2104 attenuated levels of inducible NO synthase and cyclooxygenase 2 in LPS-treated BV2 cells. In addition, it markedly suppressed LPS-induced cell migration as well as the generation of intracellular reactive oxygen species (ROS). Moreover, HSR2104 abated the LPS-triggered nuclear translocation of nuclear factor-κB (NF-κB) through inhibition of inhibitor kappa Bα phosphorylation. Furthermore, it reduced the expressions of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) in LPS-treated BV2 cells. Similar results were observed with TAK242, a specific inhibitor of TLR4, suggesting that TLR4 is an upstream regulator of NF-κB signaling in BV2 cells. Collectively, our findings demonstrate that HSR2104 exhibits anti-inflammatory and anti-migratory activities in LPS-treated BV2 cells via the suppression of ROS and TLR4/MyD88/NF-κB signaling pathway. Based on our observations, HSR2104 may have a beneficial impact on inflammatory responses and microglial cell migration involved in the pathogenesis of various neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

A Novel 1,8-Naphthyridine-2-Carboxamide Derivative Attenuates Inflammatory Responses and Cell Migration in LPS-Treated BV2 Cells via the Suppression of ROS Generation and TLR4/Myd88/NF-κB Signaling Pathway

Nguyen

Bui

Lee

et al. 2021

IJMS

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“…Cytokine signaling results in the activation of transcription factors, in particular nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT)-1/3, which are points of convergence for several pathways promoting malignancy, as evidenced in many studies [ 10 , 11 , 12 , 13 ]. In particular, NF-κB is a coordinator of innate immunity and inflammation and has emerged as an important endogenous tumor promoter [ 14 , 15 ]. NF-κB also enhances expression of IL-6, that further elicits cell proliferation and inhibits apoptosis via STAT-3 signaling pathway [ 16 , 17 ].…”

Section: Signaling Pathways In Cancer and Molecular Targets Suscepmentioning

confidence: 99%

Anti-Tumor Activity of Hypericum perforatum L. and Hyperforin through Modulation of Inflammatory Signaling, ROS Generation and Proton Dynamics

2020

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In this paper we review the mechanisms of the antitumor effects of Hypericum perforatum L. (St. John’s wort, SJW) and its main active component hyperforin (HPF). SJW extract is commonly employed as antidepressant due to its ability to inhibit monoamine neurotransmitters re-uptake. Moreover, further biological properties make this vegetal extract very suitable for both prevention and treatment of several diseases, including cancer. Regular use of SJW reduces colorectal cancer risk in humans and prevents genotoxic effects of carcinogens in animal models. In established cancer, SJW and HPF can still exert therapeutic effects by their ability to downregulate inflammatory mediators and inhibit pro-survival kinases, angiogenic factors and extracellular matrix proteases, thereby counteracting tumor growth and spread. Remarkably, the mechanisms of action of SJW and HPF include their ability to decrease ROS production and restore pH imbalance in tumor cells. The SJW component HPF, due to its high lipophilicity and mild acidity, accumulates in membranes and acts as a protonophore that hinders inner mitochondrial membrane hyperpolarization, inhibiting mitochondrial ROS generation and consequently tumor cell proliferation. At the plasma membrane level, HPF prevents cytosol alkalization and extracellular acidification by allowing protons to re-enter the cells. These effects can revert or at least attenuate cancer cell phenotype, contributing to hamper proliferation, neo-angiogenesis and metastatic dissemination. Furthermore, several studies report that in tumor cells SJW and HPF, mainly at high concentrations, induce the mitochondrial apoptosis pathway, likely by collapsing the mitochondrial membrane potential. Based on these mechanisms, we highlight the SJW/HPF remarkable potentiality in cancer prevention and treatment.

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“…Similarly, Suh et al [34] also reported that setin induced cell apoptosis in CRC by inhibiting the activation and transcriptional activity of NF-κB. However, the role of NF-κB in cancer remains contradictory [35,36]. For example, several studies have demonstrated that activation of NF-κB signaling pathway promotes in ammation-associated cancer, and inhibition of it in hepatocytes attenuates the onset of HCC related to in ammation [37,38].…”

Section: Discussionmentioning

confidence: 99%

Fisetin Exerts Anti-tumorigenic Activity via Inhibition of Trypsin Activity in Colorectal Cancer

L¹,

Wang²,

et al. 2021

Preprint

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Background: Colorectal cancer (CRC) is a malignant tumor with high incidence and bad prognosis. Therapies, which are more safety and effective, are urgent needed in clinical. Trypsin is proved to be crucial to cancer proliferation and migration, therefore, it’s possible to control cancers through modulating the activity of trypsin. Fisetin is a flavone with excellent trypsin inhibition that screened from more than 45 compounds derived from traditional Chinese medicine. However, the effects and the mechanisms of fisetin on CRC have not been well investigated. Methods: In this study, we firstly evaluated the expression of trypsin on CRC cells. The effects of fisetin on proliferation and migration of CRC cells were also investigated in vitro. The inhibitory effects on cell cycle and apoptosis were assayed using flow cytometry. The therapeutic activity and toxicity were evaluated in vivo. Results: Fisetin remarkably inhibited CRC cell proliferation and migration, as well as induced cell apoptosis and Go/G1 phase arrest in a dose‐dependent manner. Mechanistic studies revealed these effects were mediated partially through signaling pathways involving cell cycle regulators p21, p27, cyclinD1 and NF kappa B (NF-κB) p65. Administration of fisetin also significantly suppressed the tumor growth in tumor-bearing NOG mice inoculated with human HCT116 cells. Fisetin at the given dosage did not induce significant acute or chronic toxicity in rats.Conclusions: Fisetin can inhibit the growth and migration of CRC by inhibiting the trypsin both in vitro and in vivo. Our results revealed fisetin is a potent therapy for CRC.

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Can NF-κB Be Considered a Valid Drug Target in Neoplastic Diseases? Our Point of View

Cited by 47 publications

References 142 publications

A Novel 1,8-Naphthyridine-2-Carboxamide Derivative Attenuates Inflammatory Responses and Cell Migration in LPS-Treated BV2 Cells via the Suppression of ROS Generation and TLR4/Myd88/NF-κB Signaling Pathway

A Novel 1,8-Naphthyridine-2-Carboxamide Derivative Attenuates Inflammatory Responses and Cell Migration in LPS-Treated BV2 Cells via the Suppression of ROS Generation and TLR4/Myd88/NF-κB Signaling Pathway

Anti-Tumor Activity of Hypericum perforatum L. and Hyperforin through Modulation of Inflammatory Signaling, ROS Generation and Proton Dynamics

Fisetin Exerts Anti-tumorigenic Activity via Inhibition of Trypsin Activity in Colorectal Cancer

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