Simvastatin mediates inhibition of exosome synthesis, localization and secretion via multicomponent interventions

Kulshreshtha, Ankur; Singh, Swati; Ahmad, Mohd Kamil; Khanna, Kritika; Ahmad, Tanveer; Agrawal, Anurag; Ghosh, Balaram

doi:10.1038/s41598-019-52765-7

Cited by 48 publications

(39 citation statements)

References 28 publications

(30 reference statements)

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“…Simvastatin, which is often used to decrease elevated lipid levels and the risk of heart problems in those at high risk, also exhibited the ability to inhibit the secretion of exosome 51 . Data showed that epithelial cells and monocytes treated with different concentrations of simvastatin for 24 h exhibited a significant reduction in the level of secreted exosomes, and a significant reduction of about 40% was noted at the 0.3 µM dose of simvastatin, so its exosome inhibitory effect was significant.…”

Section: Exosome Inhibitorsmentioning

confidence: 99%

Advances in the discovery of exosome inhibitors in cancer

Zhang

Lü

Liu

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Exosomes are small membrane vesicles released by most eukaryotic cells. They are considered to play an essential role in cell-to-cell communication, and It is also found that they serve as functional mediators in many severe diseases, including progression of various types of cancers. Inhibition of exosome release may slow the progression of some cancers; thus, exosome has been an attractive target for cancer treatment. Over the years, considerable efforts have been made to discover novel, highly potent and excellently selective exosome inhibitors. Most of these inhibitors are derived from synthetic compounds, some of which are currently existed drugs and found to have the potential to inhibit exosome release. In this review, we briefly discussed the development of exosome inhibitors that are currently discovered and provided guidance for the future development of inhibitors.

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Section: Exosome Inhibitorsmentioning

confidence: 99%

Advances in the discovery of exosome inhibitors in cancer

Zhang

Lü

Liu

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Last, simvastatin was recently identified as an inhibitor of EV secretion based on the rationale that cholesterol is necessary for the formation of vesicle membranes. However, simvastatin's function as an HMG-CoA reductase inhibitor does not entirely explain the mechanism, as supplementation with mevalonate did not fully restore EV output to baseline levels (111). Given that different mechanisms of EV biogenesis exist, we may utilize this knowledge to selectively target (inhibit) specific populations of EVs while leaving other subsets of EVs untouched.…”

Section: Modulating Ev Secretion As a Mechanism To Control Cytokine Rmentioning

confidence: 99%

Modulating Cytokine Production via Select Packaging and Secretion From Extracellular Vesicles

Barnes

Somerville

2020

Front. Immunol.

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Cytokines are soluble factors that play vital roles in systemic function due to their ability to initiate and mediate cell-to-cell communication. Another important mechanism of intercellular communication that has gained significant attention in the past 10 years is the release of extracellular vesicles (EVs). EVs are released by all cells during normal physiology, in states of resting and activation, as well as during disease. Accumulating evidence indicates that cytokines may be packaged into EVs, and the packaging of cytokines into EVs, along with their ultimate secretion, may also be regulated by cytokines. Importantly, the repertoire of biomolecules packaged into EVs is shaped by the biological state of the cell (resting vs. activated and healthy vs. disease) and the EV biogenesis pathway involved, thus providing mechanisms by which EV packaging and secretion may be modulated. Given the critical role of cytokines in driving acute and chronic inflammatory and autoimmune diseases, as well as their role in establishing the tumor immune microenvironment, in this review, we will focus on these disease settings and summarize recent progress and mechanisms by which cytokines may be packaged within and modulated by EVs, as a therapeutic option for regulating innate and adaptive immunity.

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“…Modulating exosome release appears to be an attractive therapeutic intervention ( McAndrews and Kalluri, 2019 ), especially in immuno-oncology because of the critical roles of exosomes in tumor progression and immune evasion ( Hoshino et al, 2015 ; Chen et al, 2018 ; Poggio et al, 2019 ; Wortzel et al, 2019 ; Daassi et al, 2020 ). Despite various drug discovery attempts from empirical study to drug repurposing and high throughput screening ( Trajkovic et al, 2008 ; Chalmin et al, 2010 ; Ostrowski et al, 2010 ; Datta et al, 2018 ; Kosgodage et al, 2018 ; Im et al, 2019 ; Kulshreshtha et al, 2019 ), targeting exosomes for the treatment of disease has been challenging due to exosome’s complex biogenesis, dynamic contents, heterogeneous origins, and diverse functions ( Jeppesen et al, 2019 ; Pegtel and Gould, 2019 ; Kalluri and LeBleu, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

A Small Vimentin-Binding Molecule Blocks Cancer Exosome Release and Reduces Cancer Cell Mobility

Xie

Liu

et al. 2021

Front. Pharmacol.

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Vimentin is an intermediate filament protein with diverse roles in health and disease far beyond its structural functions. Exosomes or small extracellular vesicles (sEVs) are key mediators for intercellular communication, contributing to tissue homeostasis and the progression of various diseases, especially the metastasis of cancers. In this study, we evaluated a novel vimentin-binding compound (R491) for its anti-cancer activities and its roles in cancer exosome release. The compound R491 induced a rapid and reversible intracellular vacuolization in various types of cancer cells. This phenotype did not result in an inhibition of cancer cell growth, which was consistent with our finding from a protein array that R491 did not reduce levels of major oncoproteins in cancer cells. Morphological and quantitative analyses on the intracellular vacuoles and extracellular exosomes revealed that in response to R491 treatment, the exosomes released from the cells were significantly reduced, while the exosomes retained as intra-luminal vesicles inside the cells were subsequently degraded. Vim+/− cells had lower amounts of vimentin and accordingly, lower amounts of both the retained and the released exosomes than Vim+/+ cells had, while the vimentin-binding compound R491 inhibited only the release of exosomes. Further functional tests showed that R491 significantly reduced the migration and invasion of cancer cells in vitro and decreased the amount of exosome in the blood in mice. Our study suggests that vimentin promotes exosome release, and small-molecule compounds that target vimentin are able to both block cancer exosome release and reduce cancer cell motility, and therefore could have potential applications for inhibiting cancer invasive growth.

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Simvastatin mediates inhibition of exosome synthesis, localization and secretion via multicomponent interventions

Cited by 48 publications

References 28 publications

Advances in the discovery of exosome inhibitors in cancer

Advances in the discovery of exosome inhibitors in cancer

Modulating Cytokine Production via Select Packaging and Secretion From Extracellular Vesicles

A Small Vimentin-Binding Molecule Blocks Cancer Exosome Release and Reduces Cancer Cell Mobility

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