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The Marine Natural Product Pseudopterosin Blocks Cytokine Release of Triple-Negative Breast Cancer and Monocytic Leukemia Cells by Inhibiting NF-?B Signaling.

ABSTRACT: Pseudopterosins are a group of marine diterpene glycosides which possess an array of biological activities including anti-inflammatory effects. However, despite the striking in vivo anti-inflammatory potential, the underlying in vitro molecular mode of action remains elusive. To date, few studies have examined pseudopterosin effects on cancer cells. However, to our knowledge, no studies have explored their ability to block cytokine release in breast cancer cells and the respective bidirectional communication with associated immune cells. The present work demonstrates that pseudopterosins have the ability to block the key inflammatory signaling pathway nuclear factor ?B (NF-?B) by inhibiting the phosphorylation of p65 and I?B (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor) in leukemia and in breast cancer cells, respectively. Blockade of NF-?B leads to subsequent reduction of the production of the pro-inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF?) and monocyte chemotactic protein 1 (MCP-1). Furthermore, pseudopterosin treatment reduces cytokine expression induced by conditioned media in both cell lines investigated. Interestingly, the presence of pseudopterosins induces a nuclear translocation of the glucocorticoid receptor. When knocking down the glucocorticoid receptor, the natural product loses the ability to block cytokine expression. Thus, we hypothesize that pseudopterosins inhibit NF-?B through activation of the glucocorticoid receptor in triple negative breast cancer.

SUBMITTER: Sperlich J

PROVIDER: S-EPMC5618401 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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The Marine Natural Product Pseudopterosin Blocks Cytokine Release of Triple-Negative Breast Cancer and Monocytic Leukemia Cells by Inhibiting NF-κB Signaling.

Sperlich Julia J Kerr Russell R Teusch Nicole N

Marine drugs 20170823 9

Pseudopterosins are a group of marine diterpene glycosides which possess an array of biological activities including anti-inflammatory effects. However, despite the striking in vivo anti-inflammatory potential, the underlying in vitro molecular mode of action remains elusive. To date, few studies have examined pseudopterosin effects on cancer cells. However, to our knowledge, no studies have explored their ability to block cytokine release in breast cancer cells and the respective bidirectional ...[more]

PMID: 28832545

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Project description:BackgroundInflammation-mediated lung injury is a major cause of health problems in many countries and has been the leading cause of morbidity/mortality in intensive care units. In the current COVID-19 pandemic, the majority of the patients experienced serious pneumonia resulting from inflammation (Acute respiratory distress syndrome/ARDS). Pathogenic infections cause cytokine release syndrome (CRS) by hyperactivation of immune cells, which in turn release excessive cytokines causing ARDS. Currently, there are no standard therapies for viral, bacterial or pathogen-mediated CRS.PurposeThis study aimed to investigate and validate the protective effects of Dehydrozingerone (DHZ) against LPS induced lung cell injury by in-vitro and in-vivo models and to gain insights into the molecular mechanisms that mediate these therapeutic effects.MethodsThe therapeutic activity of DHZ was determined in in-vitro models by pre-treating the cells with DHZ and exposed to LPS to stimulate the inflammatory cascade of events. We analysed the effect of DHZ on LPS induced inflammatory cytokines, chemokines and cell damage markers expression/levels using various cell lines. We performed gene expression, ELISA, and western blot analysis to elucidate the effect of DHZ on inflammation and its modulation of MAPK and NF-κB pathways. Further, the prophylactic and therapeutic effect of DHZ was evaluated against the LPS induced ARDS model in rats.ResultsDHZ significantly (p < 0.01) attenuated the LPS induced ROS, inflammatory cytokine, chemokine gene expression and protein release in macrophages. Similarly, DHZ treatment protected the lung epithelial and endothelial cells by mitigating the LPS induced inflammatory events in a dose-dependent manner. In vivo analysis showed that DHZ treatment significantly (p < 0.001) mitigated the LPS induced ARDS pathophysiology of increase in the inflammatory cells in BALF, inflammatory cytokine and chemokines in lung tissues. LPS stimulated neutrophil-mediated events, apoptosis, alveolar wall thickening and alveolar inflammation were profoundly reduced by DHZ treatment in a rat model.ConclusionThis study demonstrates for the first time that DHZ has the potential to ameliorate LPS induced ARDS by inhibiting cytokine storm and oxidative through modulating the MAPK and NF-κB pathways. This data provides pre-clinical support to develop DHZ as a potential therapeutic agent against ARDS.

Dataset Information

The Marine Natural Product Pseudopterosin Blocks Cytokine Release of Triple-Negative Breast Cancer and Monocytic Leukemia Cells by Inhibiting NF-?B Signaling.

Publications

The Marine Natural Product Pseudopterosin Blocks Cytokine Release of Triple-Negative Breast Cancer and Monocytic Leukemia Cells by Inhibiting NF-κB Signaling.

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