Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

Mercogliano, María F.; Bruni, Sofía; Elizalde, Patricia V.; Schillaci, Roxana

doi:10.3389/fonc.2020.00584

Cited by 116 publications

(98 citation statements)

References 278 publications

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“…These data fueled our initial hypothesis that using clinically available TNF-α inhibitors would be a smart approach to alter the secretion profile of invasive breast cancer cells, and thus motivated us to assess the inhibitory effect of Etanercept, a TNF-α inhibitor, to suppress proliferation and survival of breast cancer cells. Our hypothesis is also supported by the findings of other studies indicating the efficacy of Etanercept, a soluble receptor, to capture and neutralize circulating TNF-α in breast cancer treatment [18,27]. The present study showed that inhibition of TNF-α signaling by Etanercept results in a reduction in the activity of NFKB transcription factor, leading to reduced survival rates of MDA-MB-231 cells, and induced cell cycle arrest and apoptosis.…”

Section: Discussionsupporting

confidence: 91%

The efficacy of etanercept as anti-breast cancer treatment is attenuated by residing macrophages

Shirmohammadi¹,

Ebrahimi²,

Farshchi³

et al. 2020

BMC Cancer

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Background: Interaction between microenvironment and breast cancer cells often is not considered at the early stages of drug development leading to failure of many drugs at later clinical stages. Etanercept is a TNF-alpha inhibitor that has been investigated for potential antitumor effect in breast cancer with conflicting results. Methods: Secretome data on MDA-MB-231 cancer cell-line were from public repositories and subjected to gene enrichment analyses. Since MDA-MB-231 cells secrete high levels of Granulocyte-Monocyte Colony Stimulating Factor, which activates macrophages to promote tumor growth, the effect of macrophage co-culturing on anticancer efficacy of Etanercept in breast cancer was evaluated using the Boolean network modeling and in vitro experiments including invasion, cell cycle, Annexin PI, and tetrazolium based viability assays and NFKB activity. Results: The secretome profile of MDA-MB-231 cells was similar to the expression of genes following treatment of breast cancer cells with TNF-α. Accordingly, inhibition of TNF-α by Etanercept decreased MDA-MB-231 cell survival, induced apoptosis and cell cycle arrest in vitro and inhibited NFKB activation. The inhibitory effect of Etanercept on cell viability, cell cycle progression, invasion and induction of apoptosis decreased following co-culturing of the cancer cells with macrophages. The Boolean network modeling of the changes in the dynamics of intracellular signaling pathways revealed NFKB activation by secretome of macrophages, leading to a decreased efficacy of Etanercept, suggesting NFKB inhibition as an alternative approach to inhibit cancer cell growth in the presence of macrophage crosstalk. Conclusion: This study indicates that the effect of Etanercept may be influenced by residing macrophages in tumor microenvironment, and suggests a method to predict the effect of drugs in the presence of stromal cells to guide experimental designs in drug development.

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Section: Discussionsupporting

confidence: 91%

The efficacy of etanercept as anti-breast cancer treatment is attenuated by residing macrophages

Shirmohammadi¹,

Ebrahimi²,

Farshchi³

et al. 2020

BMC Cancer

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“…Abnormalities of crucial cellular function, such as senescence, apoptosis, and cell cycle, are the important pathological processes of BC [ 155 – 160 ]. The TNF signaling pathway is a mediator of the inflammatory process, and its activity is closely linked with the progression, metastasis, and poor prognosis of BC [ 161 , 162 ]. The estrogen signaling pathway functions as the most critical regulator of tumor initiation and malignant progression in BC, and therapeutic modulation of its activity serves as a primary treatment strategy [ 163 – 167 ].…”

Section: Resultsmentioning

confidence: 99%

A Network Pharmacology Study on the Molecular Mechanisms of FDY003 for Breast Cancer Treatment

Lee¹,

Kang

Park³

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Herbal medicines have drawn considerable attention with regard to their potential applications in breast cancer (BC) treatment, a frequently diagnosed malignant disease, considering their anticancer efficacy with relatively less adverse effects. However, their mechanisms of systemic action have not been understood comprehensively. Based on network pharmacology approaches, we attempted to unveil the mechanisms of FDY003, an herbal drug comprised of Lonicera japonica Thunberg, Artemisia capillaris Thunberg, and Cordyceps militaris, against BC at a systemic level. We found that FDY003 exhibited pharmacological effects on human BC cells. Subsequently, detailed data regarding the biochemical components contained in FDY003 were obtained from comprehensive herbal medicine-related databases, including TCMSP and CancerHSP. By evaluating their pharmacokinetic properties, 18 chemical compounds in FDY003 were shown to be potentially active constituents interacting with 140 BC-associated therapeutic targets to produce the pharmacological activity. Gene ontology enrichment analysis using g:Profiler indicated that the FDY003 targets were involved in the modulation of cellular processes, involving the cell proliferation, cell cycle process, and cell apoptosis. Based on a KEGG pathway enrichment analysis, we further revealed that a variety of oncogenic pathways that play key roles in the pathology of BC were significantly enriched with the therapeutic targets of FDY003; these included PI3K-Akt, MAPK, focal adhesion, FoxO, TNF, and estrogen signaling pathways. Here, we present a network-perspective of the molecular mechanisms via which herbal drugs treat BC.

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“… 251 – 253 The current anti-TNF-α antibodies approved by FDA include infliximab, adalimumab and golimumab. 254 Infliximab is proved to be well tolerated without dose-limiting toxic effects in advanced cancer by clinical studies, 255 and seven in forty-one patients treated with infliximab show disease stabilization. 255 …”

Section: Canonical Nf-κb In Cancermentioning

confidence: 99%

Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study

Lin

Zhang

et al. 2020

Sig Transduct Target Ther

797

568

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NF-κB pathway consists of canonical and non-canonical pathways. The canonical NF-κB is activated by various stimuli, transducing a quick but transient transcriptional activity, to regulate the expression of various proinflammatory genes and also serve as the critical mediator for inflammatory response. Meanwhile, the activation of the non-canonical NF-κB pathway occurs through a handful of TNF receptor superfamily members. Since the activation of this pathway involves protein synthesis, the kinetics of non-canonical NF-κB activation is slow but persistent, in concordance with its biological functions in the development of immune cell and lymphoid organ, immune homeostasis and immune response. The activation of the canonical and non-canonical NF-κB pathway is tightly controlled, highlighting the vital roles of ubiquitination in these pathways. Emerging studies indicate that dysregulated NF-κB activity causes inflammation-related diseases as well as cancers, and NF-κB has been long proposed as the potential target for therapy of diseases. This review attempts to summarize our current knowledge and updates on the mechanisms of NF-κB pathway regulation and the potential therapeutic application of inhibition of NF-κB signaling in cancer and inflammatory diseases.

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Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

Cited by 116 publications

References 278 publications

The efficacy of etanercept as anti-breast cancer treatment is attenuated by residing macrophages

The efficacy of etanercept as anti-breast cancer treatment is attenuated by residing macrophages

A Network Pharmacology Study on the Molecular Mechanisms of FDY003 for Breast Cancer Treatment

Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study

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