Sulforaphane induces apoptosis in rhabdomyosarcoma and restores TRAIL-sensitivity in the aggressive alveolar subtype leading to tumor elimination in mice

Bergantin, Elisa; Quarta, Carmelo; Nanni, Cristina; Fanti, Stefano; Pession, Andrea; Cantelli‐Forti, Giorgio; Tonelli, Roberto; Hrelia, Patrizia

doi:10.4161/cbt.29684

Cited by 22 publications

(18 citation statements)

References 24 publications

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“…ANOVA: analysis of variance; DAPI: 4′,6-diamidino-2-phenylindole; TGF-β1: transforming growth factor β1 4 | DISCUSSION Sulforaphane is a plant-derived isothiocyanate particularly abundant in cruciferous vegetables. It has been shown to be protective against a variety of pathological conditions including carcinogenesis (Gamet-Payrastre et al, 2000), chronic inflammation (Yehuda et al, 2012), tumorigenesis (Bergantin et al, 2014), and fibrosis (Artaud-Macari et al, 2013;Kawarazaki et al, 2017). Intake of cruciferous vegetables high in sulforaphane has been correlated to decreased risk of cardiovascular disease in epidemiological studies (Mukherjee et al, 2010).…”

Section: Matrix Metalloproteinase Expressionmentioning

confidence: 99%

Effects of the isothiocyanate sulforaphane on TGF‐β1‐induced rat cardiac fibroblast activation and extracellular matrix interactions

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Carver‐Molina

Chakrabarti

et al. 2019

Journal Cellular Physiology

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An important step in many pathological conditions, particularly tissue and organ fibrosis, is the conversion of relatively quiescent cells into active myofibroblasts. These are highly specialized cells that participate in normal wound healing but also contribute to pathogenesis. These cells possess characteristics of smooth muscle cells and fibroblasts, have enhanced synthetic activity secreting abundant extracellular matrix components, cytokines, and growth factors, and are capable of generating contractile force. As such, these cells have become potential therapeutic targets in a number of disease settings. Transforming growth factor β (TGF‐β) is a potent stimulus of fibrosis and myofibroblast formation and likewise is an important therapeutic target in several disease conditions. The plant‐derived isothiocyanate sulforaphane has been shown to have protective effects in several pathological models including diabetic cardiomyopathy, carcinogenesis, and fibrosis. These studies suggest that sulforaphane may be an attractive preventive agent against disease progression, particularly in conditions involving alterations of the extracellular matrix and activation of myofibroblasts. However, few studies have evaluated the effects of sulforaphane on cardiac fibroblast activation and their interactions with the extracellular matrix. The present studies were carried out to determine the potential effects of sulforaphane on the conversion of quiescent cardiac fibroblasts to an activated myofibroblast phenotype and associated alterations in signaling, expression of extracellular matrix receptors, and cellular physiology following stimulation with TGF‐β1. These studies demonstrate that sulforaphane attenuates TGF‐β1‐induced myofibroblast formation and contractile activity. Sulforaphane also reduces expression of collagen‐binding integrins and inhibits canonical and noncanonical TGF‐β signaling pathways.

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Section: Matrix Metalloproteinase Expressionmentioning

confidence: 99%

Effects of the isothiocyanate sulforaphane on TGF‐β1‐induced rat cardiac fibroblast activation and extracellular matrix interactions

Fix

Carver‐Molina

Chakrabarti

et al. 2019

Journal Cellular Physiology

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“…Although xenograft models have previously been reported in RMS and MRT, many of the studies were related to the establishment of xenograft models in human-adapted mice from cell lines and patient-derived xenografts for individualized care in advanced sarcoma [19][20][21][22][23][24][25][26][27][28]. The advantage of xenograft models over in vitro cell lines is that the tumor tissue better resembles the original tumors, and once established, xenograft tumors may be grown indefinitely [17,18,29,30].…”

Section: Discussionmentioning

confidence: 99%

The Role of Immunohistochemistry in Rhabdomyosarcoma Diagnosis Using Tissue Microarray Technology and a Xenograft Model

Machado

Mayordomo‐Aranda

Giner

et al. 2015

Fetal and Pediatric Pathology

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Rhabdomyosarcomas (RMS) may resemble other non-myogenic sarcomas and malignant rhabdoid tumor (MRT). Alveolar rhabdomyosarcoma (ARMS) often harbors a typical translocation, but embryonal rhabdomyosarcoma (ERMS) lacks any specific rearrangement. Histopathology is not always sufficient for an unequivocal diagnosis, necessitating ancillary studies, including immunohistochemistry (IHC). Sixteen genetically tested RMS and two MRT were xenografted and followed in successive passages. Tissue microarrays were constructed including samples from original and xenograft tumors. Desmin, myogenin, CK, EMA, INI1, LSD1, AP2β, fibrillin-2, HMGA2, nestin, and SIRT1 were tested using immunohistochemical staining. Desmin and myogenin were positive in all RMS, and the epithelial markers were negative in almost all RMS. New markers (LSD1, AP2β, HMGA2, Nestin, and SIRT1) were positive in all RMS and MRT. There were no differences in IHC expression between the three RMS subtypes tested except fibrillin-2, which was negative in ARMS. Applying new IHC markers can contribute to RMS diagnosis. Nevertheless, most markers are also expressed in MRT, and further studies are needed to confirm their value against this and other small round cell tumors.

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“…In this context, the following agents should act to address the biology of ARMS by acting at genomic and proteomic levels: 1) Entinostat by virtue of its ability to: a) inhibit class I HDAC [32] and thereby, to interrupt the YY1-EZH2-HDAC1 inhibition of miR-29b2 and mir-29c allowing arrest of ARMS cell proliferation and promoting differentiation [11–17, 28]; and b) its ability to effect direct transcriptional supression of PAX3:FOXO1 [33] and to inhibit the phosphorylative activation of PAX3—FOXO1 by polo-like kinase (PLK)1 [29, 34, 35]; 2) celecoxib inhibits the NF-kappaB pathway at multiple points [36] and should reduce the overproduction of YY1; 3) sulforaphane, a nutraceutical suppresses polycomb group protein level including EZH2 [37] and this should promote alveolar rhabdomyosarcoma's differentiation to a more benign form, induce apoptosis in the tumor cells [38] and reduce the survival of alveolar rhabdomyosarcoma leading to elimination of the tumor (in the latter study, sulforaphane was also shown to decrease the mRNA and protein levels of PAX3-FKHR, MYCN and MET in ARMS cells); 4) retinoic acid upregulates miR-214 which downregulates EZH2 protein in embryonic stem cells and miR-214-mediated EZH2 protein reduction accelerates skeletal muscle cell differentiation [39] (Both all-trans retinoic acid, ATRA and 9-cis retinoic acid suppressed the cell growth of alveolar rhabdomyosarcoma with evidence of a differentiating effect [40]. ATRA increased the expression of some genes associated with muscle differentiation and slowed the proliferation and promoted a more differentiated myogenic phenotype in ARMS cell lines [41].…”

Section: Discussionmentioning

confidence: 99%

Alveolar rhabdomyosarcoma: morphoproteomics and personalized tumor graft testing further define the biology of PAX3-FKHR(FOXO1) subtype and provide targeted therapeutic options

et al. 2016

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Alveolar rhabdomyosarcoma (ARMS) represents a block in differentiation of malignant myoblasts. Genomic events implicated in the pathogenesis of ARMS involve PAX3-FKHR (FOXO1) or PAX7-FKHR (FOXO1) translocation with corresponding fusion transcripts and fusion proteins. Commonalities in ARMS include uncontrollable proliferation and failure to differentiate. The genomic-molecular correlates contributing to the etiopathogenesis of ARMS incorporate PAX3-FKHR (FOXO1) fusion protein stimulation of the IGF-1R, c-Met and GSK3-β pathways. With sequential morphoproteomic profiling on such a case in conjunction with personalized tumor graft testing, we provide an expanded definition of the biology of PAX3-FKHR (FOXO1) ARMS that integrates genomics, proteomics and pharmacogenomics. Moreover, therapies that target the genomic and molecular biology and lead to tumoral regression and/or tumoral growth inhibition in a xenograft model of ARMS are identified.SignificanceThis case study could serve as a model for clinical trials using relatively low toxicity agents in both initial and maintenance therapies to induce remission and reduce the risk of recurrent disease in PAX3-FKHR (FOXO1) subtype of ARMS.

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Sulforaphane induces apoptosis in rhabdomyosarcoma and restores TRAIL-sensitivity in the aggressive alveolar subtype leading to tumor elimination in mice

Cited by 22 publications

References 24 publications

Effects of the isothiocyanate sulforaphane on TGF‐β1‐induced rat cardiac fibroblast activation and extracellular matrix interactions

Effects of the isothiocyanate sulforaphane on TGF‐β1‐induced rat cardiac fibroblast activation and extracellular matrix interactions

The Role of Immunohistochemistry in Rhabdomyosarcoma Diagnosis Using Tissue Microarray Technology and a Xenograft Model

Alveolar rhabdomyosarcoma: morphoproteomics and personalized tumor graft testing further define the biology of PAX3-FKHR(FOXO1) subtype and provide targeted therapeutic options

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