The eIF4A inhibitor silvestrol sensitizes T-47D ductal breast carcinoma cells to external-beam radiotherapy

Webb, Thomas E.; Davies, Marc; Maher, John; Sarker, Debashis

doi:10.1016/j.ctro.2020.07.002

Cited by 5 publications

(4 citation statements)

References 25 publications

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“…This is contrary to the results of Chambers et al (2016). Inhibition of eIF4A by silvestrol ( 14) was recently also shown to sensitize T-47D breast cancer cells to radiotherapy with minimal effects on unirradiated cells (Webb et al 2020). In a screen of [ 200 flavaglines (= rocaglates) a series of potent synthetic amidino-flavaglines was identified (e.g.…”

Section: Inhibition Of the Translation Initiation Factor (Eif) 4amentioning

confidence: 91%

Comparative phytochemistry of flavaglines (= rocaglamides), a group of highly bioactive flavolignans from Aglaia species (Meliaceae)

Greger

2021

Phytochem Rev

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Flavaglines are formed by cycloaddition of a flavonoid nucleus with a cinnamic acid moiety representing a typical chemical character of the genus Aglaia of the family Meliaceae. Based on biosynthetic considerations 148 derivatives are grouped together into three skeletal types representing 77 cyclopenta[b]benzofurans, 61 cyclopenta[bc]benzopyrans, and 10 benzo[b]oxepines. Apart from different hydroxy, methoxy, and methylenedioxy groups of the aromatic rings, important structural variation is created by different substitutions and stereochemistries of the central cyclopentane ring. Putrescine-derived bisamides constitute important building blocks occurring as cyclic 2-aminopyrrolidines or in an open-chained form, and are involved in the formation of pyrimidinone flavaglines. Regarding the central role of cinnamic acid in the formation of the basic skeleton, rocagloic acid represents a biosynthetic precursor from which aglafoline- and rocaglamide-type cyclopentabenzofurans can be derived, while those of the rocaglaol-type are the result of decarboxylation. Broad-based comparison revealed characteristic substitution trends which contribute as chemical markers to natural delimitation and grouping of taxonomically problematic Aglaia species. A wide variety of biological activities ranges from insecticidal, antifungal, antiprotozoal, and anti-inflammatory properties, especially to pronounced anticancer and antiviral activities. The high insecticidal activity of flavaglines is comparable with that of the well-known natural insecticide azadirachtin. Comparative feeding experiments informed about structure–activity relationships and exhibited different substitutions of the cyclopentane ring essential for insecticidal activity. Parallel studies on the antiproliferative activity of flavaglines in various tumor cell lines revealed similar structural prerequisites that let expect corresponding molecular mechanisms. An important structural modification with very high cytotoxic potency was found in the benzofuran silvestrol characterized by an unusual dioxanyloxy subunit. It possessed comparable cytotoxicity to that of the natural anticancer compounds paclitaxel (Taxol®) and camptothecin without effecting normal cells. The primary effect was the inhibition of protein synthesis by binding to the translation initiation factor eIF4A, an ATP-dependent DEAD-box RNA helicase. Flavaglines were also shown to bind to prohibitins (PHB) responsible for regulation of important signaling pathways, and to inhibit the transcriptional factor HSF1 deeply involved in metabolic programming, survival, and proliferation of cancer cells. Flavaglines were shown to be not only promising anticancer agents but gained now also high expectations as agents against emerging RNA viruses like SARS-CoV-2. Targeting the helicase eIF4A with flavaglines was recently described as pan-viral strategy for minimizing the impact of future RNA virus pandemics.

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Section: Inhibition Of the Translation Initiation Factor (Eif) 4amentioning

confidence: 91%

Comparative phytochemistry of flavaglines (= rocaglamides), a group of highly bioactive flavolignans from Aglaia species (Meliaceae)

Greger

2021

Phytochem Rev

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“…Silvestrol has been shown to sensitize mouse models of lymphoma to doxorubicin, which suggests that eIF4A plays a role in the response to DNA-damaging agents [ 42 ]. Initial studies with silvestrol [ 45 ] and eIF4A knockdown [ 46 ] provided the first evidence that eIF4A inhibition can radiosensitize tumor cells. Treatment of T-47D ductal breast carcinoma cells with 1 nM silvestrol significantly reduced clonogenic survival of irradiated cells.…”

Section: Translation Initiation: Eif4fmentioning

confidence: 99%

Translation Initiation Machinery as a Tumor Selective Target for Radiosensitization

Lehman

Wilson

Camphausen

et al. 2021

IJMS

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Towards improving the efficacy of radiotherapy, one approach is to target the molecules and processes mediating cellular radioresponse. Along these lines, translational control of gene expression has been established as a fundamental component of cellular radioresponse, which suggests that the molecules participating in this process (i.e., the translational machinery) can serve as determinants of radiosensitivity. Moreover, the proteins comprising the translational machinery are often overexpressed in tumor cells suggesting the potential for tumor specific radiosensitization. Studies to date have shown that inhibiting proteins involved in translation initiation, the rate-limiting step in translation, specifically the three members of the eIF4F cap binding complex eIF4E, eIF4G, and eIF4A as well as the cap binding regulatory kinases mTOR and Mnk1/2, results in the radiosensitization of tumor cells. Because ribosomes are required for translation initiation, inhibiting ribosome biogenesis also appears to be a strategy for radiosensitization. In general, the radiosensitization induced by targeting the translation initiation machinery involves inhibition of DNA repair, which appears to be the consequence of a reduced expression of proteins critical to radioresponse. The availability of clinically relevant inhibitors of this component of the translational machinery suggests opportunities to extend this approach to radiosensitization to patient care.

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“…Notably, oncogenes such as mutant KRAS genes possess long and highly structured 5′UTRs [16]. Inhibitors of eIF4A have displayed significant antitumor activity both in vivo and in vitro in various tumors, including pancreatic ductal adenocarcinoma [17], leukemia [18], hepatocellular carcinoma [19], and have been shown to enhance tumor cell radiosensitivity [20,21]. However, the efficacy of silvestrol against glioblastoma remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

Silvestrol alleviates glioblastoma progression through ERK pathway modulation and MANBA and NRG-1 expression

ZHOU,

ZHANG,

TIAN

et al. 2024

BIOCELL

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Background: Glioblastoma, a notably malignant tumor within the central nervous system, is distinguished by its aggressive behavior. Silvestrol, a robust inhibitor of the RNA helicase eukaryotic initiation factor 4A (eIF4A), has shown significant potential as an anticancer compound. Yet, the impact of silvestrol on glioblastoma, especially its molecular mechanisms, has not been fully elucidated. Methods: This investigation employed a variety of in vitro assays, such as cell counting kit-8 (CCK-8), clonogenic, 5-ethynyl-2′-deoxyuridine (EDU), wound healing, and flow cytometry, to evaluate cell cycle progression, apoptosis, cell viability, and migration. Western blot analysis was also performed to study the apoptosis and extracellular regulated kinase (ERK) pathways. After the ERK pathway was inhibited, differentially expressed genes (DEGs) in U87 cells were identified, followed by an analysis of target genes using the gene expression profiling interactive analysis (GEPIA) database. Results: Silvestrol significantly suppressed the proliferation, migration, and colony formation of glioma cells. It caused cell cycle arrest and enhanced apoptosis in these cells. Additionally, silvestrol stimulated the ERK pathway, with these effects being reversible by an ERK phosphorylation inhibitor. Transcriptome combined with GEPIA, GSCA, UALCAN, TIMER database screened 4 potential drug targets of silvestrol: chromosome 1 open reading frame 226 (C1ORF226), mannosidase beta A (MANBA), IQ motif and Sec7 domain 2 (IQSEC2), neuregulin 1 (NRG-1). Among them, C1ORF226 was lower risk gene while MANBA, IQSEC2, and NRG-1 were high-risk genes. Furthermore, silvestrol notably reduced MANBA mRNA levels, which could be reversed by inhibiting ERK phosphorylation. Furthermore, silvestrol markedly decreased NRG-1 protein levels, with an additional reduction observed when the ERK pathway was blocked. Conclusion:Silvestrol's anti-glioma effects are primarily due to the suppression of MANBA expression via the ERK pathway and possibly by hindering the translation of NRG-1 protein, thus reducing its expression. The downregulation of MANBA and NRG-1 proteins may be crucial in hindering glioma development and progression.These results highlight the intricate relationship between the ERK pathway and gene expression regulation in silvestrol's therapeutic effectiveness against glioma. Abbreviations eIF4AEukaryotic initiation factor 4A EIF4F Eukaryotic translation initiation factor 4F CCK-8 Cell counting kit-8 EDU 5-ethynyl-2′-deoxyuridine ERK Extracellular regulated kinase C1ORF226 Chromosome 1 open reading frame 226 MANBA Mannosidase beta A IQSEC2 IQ motif and Sec7 domain 2 NRG-1 Neuregulin 1 TRNP1 TMF1 regulated nuclear protein 1 TUBA4A Tubulin alpha 4A GEPIA Gene expression profiling interactive analysis MEK Mitogen-activated protein kinase kinase MAPK Mitogen-activated protein kinases

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The eIF4A inhibitor silvestrol sensitizes T-47D ductal breast carcinoma cells to external-beam radiotherapy

Cited by 5 publications

References 25 publications

Comparative phytochemistry of flavaglines (= rocaglamides), a group of highly bioactive flavolignans from Aglaia species (Meliaceae)

Comparative phytochemistry of flavaglines (= rocaglamides), a group of highly bioactive flavolignans from Aglaia species (Meliaceae)

Translation Initiation Machinery as a Tumor Selective Target for Radiosensitization

Silvestrol alleviates glioblastoma progression through ERK pathway modulation and MANBA and NRG-1 expression

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