TNF alpha signaling is associated with therapeutic responsiveness to vascular disrupting agents in endocrine tumors

Hantel, Constanze; Ozimek, Alexandra; Lira, Régia Caroline Peixoto; Ragazzon, Bruno; Jäckel, Carsten; Frantsev, Roman; Reincke, Martín; Bertherat, Jérôme; Mussack, Thomas; Beuschlein, Felix

doi:10.1016/j.mce.2015.12.009

Cited by 17 publications

(16 citation statements)

References 42 publications

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“…5,6-Dimethylxanthenone-4-acetic Acid (DMXAA, Vadimezan, ASA404) appears to be the most thoroughly tested drug in this group. The drug is effective in inhibiting the growth of murine glioma, acute myeloid leukaemia, B16.F10 melanoma, endocrine tumors, non-small cell lung cancer 6 – 8 , 12 , 23 . Our results confirm the effectiveness of inhibition of B16-F10 murine melanoma tumors growth after the administration of DMXAA in a dose of 25 mg/kg body weight.…”

Section: Discussionmentioning

confidence: 99%

“…It activates the TANK-binding kinase 1/interferon regulatory factor 3 (TBK1/IRF3) signaling pathway in leukocytes, inducing type-I-interferon (IFN-I) production 4 , 5 . DMXAA vascular disrupting properties are partly mediated by TNF-α signaling 6 . DMXAA activates the mitochondria- and endoplasmic reticulum-associated protein known as stimulator of interferon genes (STING) 7 , 8 .…”

Section: Introductionmentioning

confidence: 99%

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Combination of anti-vascular agent - DMXAA and HIF-1α inhibitor - digoxin inhibits the growth of melanoma tumors

Smolarczyk

Cichoń

Pilny

et al. 2018

Sci Rep

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Vascular disrupting agents as DMXAA inhibit tumor growth only for a short period of time followed by rapid tumor regrowth. Among others, hypoxia and presence of transcription factor HIF-1α are responsible for tumors regrowth. The aim of our study was to investigate the inhibition of murine melanoma growth by combining two agents: anti-vascular - DMXAA and the HIF-1α inhibitor - digoxin and explaining the mechanism of action of this combination. After DMXAA treatment tumor size was reduced only for a limited time. After 7 days regrowth of tumors was observed and number of vessels was increased especially in tumor’s peripheral areas. DMXAA also induced an influx of immune cells: macrophages, CD8+ cytotoxic lymphocytes, NK cells, CD4+ lymphocytes. Administration of digoxin alone inhibited the growth of tumors. Administration of both agents in the proper sequence significantly inhibited the regrowth of tumors better than either agents alone. Combination therapy reduced number of newly formed vessels. In tumors of mice treated with combination therapy, the number of macrophages M1, CD8+ cytotoxic lymphocytes, NK cells and to a lesser extent CD4+ cells was increased. The combination of anti-vascular agents with HIF-1α inhibitors appears to be an effective therapeutic option.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combination of anti-vascular agent - DMXAA and HIF-1α inhibitor - digoxin inhibits the growth of melanoma tumors

Smolarczyk

Cichoń

Pilny

et al. 2018

Sci Rep

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“…According to the KEGG pathway analysis, coexpressed genes in the green module mainly participate in the TNF, IL‐17, NOD‐like receptor, and MAPK signalling pathways. These pathways are mainly involved in inflammation and the progression of OA . The MAPK signalling pathway, one of intracellular serine‐threonine protein kinase superfamily members, is the centre of multiple signal transduction pathways .…”

Section: Discussionmentioning

confidence: 99%

Identification and functional analysis of long non‐coding RNAs in the synovial membrane of osteoarthritis patients

Shui

Xie

Chen

et al. 2020

Cell Biochemistry & Function

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Osteoarthritis (OA), the most common chronic joint disease in the elderly, has become a significant economic burden for families and societies worldwide. Although treatments are continually improving, current drugs only target joint pain, with no effective therapies modifying OA progression. Long noncoding RNAs (lncRNAs), which have received increasing attention in recent years, are abnormally expressed in OA cartilage. In the present study, weighted coexpression network analysis (WGCNA) was applied to identify modules related to certain OA clinical traits. In total, 4404 coding genes and 161 lncRNAs were differentially expressed based on two OA expression profile data sets and normal control samples. Subsequently, 11 independent modules were acquired, and the green module, with a total of 49 hub genes, was identified as the most relevant to OA. These hub genes were validated using the GSE12021 data set. There was only one lncRNA among the hub genes, namely, NONHSAG034351. Thus, we further explored the function of NONHSAG034351‐related genes in the network. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that NONHSAG034351‐associated genes are involved in the response to lipopolysaccharide, angiogenesis, tumour necrosis factor (TNF) signalling, and mitogen‐activated protein kinase (MAPK) signalling pathways. In conclusion, we identified modules through WGCNA related to OA clinical traits. NONHSAG034351, the only hub‐lncRNA, was downregulated in OA synovial tissue and might play a significant role in the pathological progression of this disease. Our findings have important clinical implications and could provide novel biomarkers that indicate the molecular mechanisms of OA and act as potential therapeutic targets. Significance of this study Long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in osteoarthritis (OA), which is the most common chronic joint disease among the elderly. In the present study, we report the expression profiles of lncRNAs in OA and the identification of modules through WGCNA related to OA clinical traits. NONHSAG034351, the only hub‐lncRNA identified to be downregulated in the synovial tissue of OA patients, might play a significant role in the pathological progression of OA. Furthermore, our findings provide novel biomarkers associated with the molecular mechanisms underlying OA pathogenesis, thus implying potential therapeutic targets with important clinical implications.

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“…Induction of 'long lasting immune protection' [35] Intratumoral injection inhibits growth of distant metastatic lesions in B16F10 mice [35] ML-RR-S2-CDG Similar antitumor potency than ML-RR-S2-CDA in B16F10 models but associated with side effects (open wounds) and decreased overall survival [35] Active through type I IFN induction against HSV2 both in vitro in human cells and in vivo in mice [101] Non-CDN agonists Flavone 8-acetic acid (FAA) Potent antitumor activity associated with tumor regression in various mouse models but dropped in Phase I trials [124] DMXAA First discovered as a vascular disrupting agent through TNF-a induction. Related to FAA [105][106][107][108][109] Potent antitumor activity associated with tumor regression on various in vivo models [35,[112][113][114] in a STING-dependent fashion [30] mSting agonist with no affinity for hSTING both in vitro [62,63] and in vivo [35] 2 0 ,3 0 -cGAMP (the endogenous product of cGAS) demonstrated potent activity after intratumoral injection in the CT26 murine colon adenocarcinoma model, reducing tumor size and increasing survival [94]. Delayed and reduced tumor growth was also observed after intratumoral injection of cGAMP in 4T1-luc (mouse breast cancer), B16F10, mSCC1 (murine squamous cell carcinoma), and CT26 tumors [95].…”

Section: Ml-rr-s2-cgampmentioning

confidence: 99%

“…Its failure is explained by the fact that it specifically activates the STING-IRF-3 pathway [111] as a competitive and selective mSting agonist, but has poor affinity for hSTING [62,63]. In animals, DMXAA has shown growth inhibitory effects on the gastroenteropancreatic BON model [112], the murine glioma GL261 model, for which it largely prolonged survival [113], the murine acute myeloid leukemia C1498.SIY (with a STING-dependent increase in survival) [30], and the murine lung cancer model 344SQ-ELuc [114]. Intratumoral injection of DMXAA in mice bearing B16 melanoma tumors induces potent tumor regression and a striking total rejection in most of the treated mice, while STING knockout mice were unresponsive to the compound [35].…”

Section: Pharmacological Modulation Of Sting -Non-cdn Agonistsmentioning

confidence: 99%

Pharmacological Modulation of the STING Pathway for Cancer Immunotherapy

Berger

Marloye

Lawler

2019

Trends in Molecular Medicine

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The advent of immunotherapy in recent years has shown the potential to revolutionize the treatment of cancer. Unleashing antitumor T cell responses via immune checkpoint blockade has led to remarkable responses in previously untreatable tumors. The master regulator of interferon-mediated antiviral responsesstimulator of interferon genes (STING)has now emerged as a critical mediator of innate immune sensing of cancer, and is a promising target for local immunostimulation, promoting intratumoral inflammation, and facilitating antitumor T cell responses. Pharmacological activation of the STING pathway can lead to T cell-mediated tumor regression in preclinical tumor models, and novel STING activating small molecules are now being tested in clinical trials. Here we will introduce the STING pathway and review the current state of drug development. Cancer Immunotherapy The concept of immunity against disease was first proposed by Thucydides in the 5th century BC, while the earliest recognized attempt to intentionally induce immunity was in the 10th century in China. It is, however, only recently that the close link between cancer and the immune system has become evident, although the benefit of infecting tumors with pathogenic organisms (e.g., Coley's toxins) was reported in the 19th century. Highlights The host STING pathway has been identified as a crucial mechanism of innate sensing of cancer and tumor growth. Activation of the cGAS-STING-IRF-3 cascade leads to the priming and infiltration of CD8 + T cells through type I IFN production and triggers potent antitumor immunity.

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TNF alpha signaling is associated with therapeutic responsiveness to vascular disrupting agents in endocrine tumors

Cited by 17 publications

References 42 publications

Combination of anti-vascular agent - DMXAA and HIF-1α inhibitor - digoxin inhibits the growth of melanoma tumors

Combination of anti-vascular agent - DMXAA and HIF-1α inhibitor - digoxin inhibits the growth of melanoma tumors

Identification and functional analysis of long non‐coding RNAs in the synovial membrane of osteoarthritis patients

Pharmacological Modulation of the STING Pathway for Cancer Immunotherapy

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