Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status

Oliveira, Daiane Teixeira de; Sávio, André Luiz Ventura; Marcondes, João Paulo de Castro; Barros, Tatiane Martins Barcelos; Barbosa, Ludmila Correia; Salvadori, Daisy Maria Fávero; Silva, Glenda Nicioli da

doi:10.1007/s12038-016-9654-5

Cited by 23 publications

(14 citation statements)

References 68 publications

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“…Molecular mechanisms of silibinin in TP53 wild‐type cells. Silibinin treatment downregulated PI3K (Imai‐Sumida et al ., 2017) and the fibroblast growth factor receptor 3 ( FGFR3 ) genes, which promoted downregulation of the AKT/mTOR genes (De Oliveira et al ., 2017). Silibinin downregulated HDAC , which downregulated the expression of the c‐MYC , SRC , PLK1 , and HOXB3 genes.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the results of gene expression in RT4 cells, a network involving the TP53 gene was created. Previous studies by our group have shown that silibinin downregulated the fibroblast growth factor receptor 3 (FGFR3)–AKT–mTOR pathway in RT4 cells (De Oliveira et al ., 2017). We demonstrated that the FGFR3–AKT–mTOR pathway appears to downregulate, indirectly, the HDAC , PLK1 , SRC , HOXB3 , and C‐MYC gene expression.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of urinary bladder cancer cell proliferation by silibinin

Barros

Lima

Almeida

et al. 2020

Environ and Mol Mutagen

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Silibinin, a natural compound extracted from milk thistle, has demonstrated antitumor properties in urinary bladder cancer cells; however, the role of TP53 gene in these effects is unclear. In order to better understand the molecular and antiproliferative mechanisms of this compound, urinary bladder cancer cells with different TP53 gene status, RT4 (low-grade tumor, wild TP53 gene), 5637 (high-grade tumor, Grade 2, mutated TP53 gene), and T24 (high-grade tumor, Grade 3, mutated TP53 gene) were treated with several concentrations of silibinin (1, 5, 10, 50, 100, and 150 μM). Cytotoxicity, prooxidant effect, morphological changes, cell migration, cell cycle progression, global methylation profile, and relative expression of HOXB3, c-MYC, PLK1, SMAD4, SRC, HAT, HDAC, and RASSF1A genes were evaluated. The silibinin presented cytotoxic and prooxidant effects in the three cell lines. In mutated TP53 cells, significant interference in cell migration and cell cycle arrest at the G2/M phase was observed. Additionally, silibinin induced global DNA hypomethylation in the highest grade tumor cells. For wild-type TP53 cells, a sub-G1 apoptotic population was present. Furthermore, there was modulation of gene expression responsible for cell growth (SMAD and c-MYC), migration (SRC), cell cycle kinetics (PLK1), angiogenesis (HOXB3), and of genes associated with epigenetic events such as DNA acetylation (HAT) and deacetylation (HDAC).In conclusion, the silibinin inhibited the urinary bladder tumor cell proliferation independently of TP53 status; however, cell cycle effects, gene expression changes, and alteration of cell migration are dependent on TP53 status.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of urinary bladder cancer cell proliferation by silibinin

Barros

Lima

Almeida

et al. 2020

Environ and Mol Mutagen

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“…The analysis of genetic expression was conducted as described previously by De Oliveira et al (2017) with minor modifications. Cells were seeded into plates at a density of 1 × 10 6 cells/25 cm 3 culture flask.…”

Section: Quantification Of Dna Methylationmentioning

confidence: 99%

“…Clonogenic assay was used to evaluate the long-term effects of resveratrol and was performed as previously described by De Oliveira et al (2017). Cells were plated at a density of 1 × 10 6 cells/25 cm 3 culture flask.…”

Section: Clonogenic Survivalmentioning

confidence: 99%

Antiproliferative and toxicogenomic effects of resveratrol in bladder cancer cells with different TP53 status

Almeida

Guerra

Assis

et al. 2019

Environ and Mol Mutagen

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The antitumor activity of resveratrol, a polyphenolic compound found mainly in grapes, has been studied in several types of cancer. In bladder cancer, its antiproliferative effects have already been demonstrated; however, its mechanism of action is not completely understood. The aim of this study was to evaluate resveratrol antitumor activity (12.5, 25, 50, 100, 150, 200, and 250 μM) and its possible mechanisms of action in bladder tumor cells with different TP53 gene status (RT4, grade 1, TP53 wild type; 5637‐grade 2 and T24‐grade 3, TP53 mutated). Cell proliferation, clonogenic survival, morphological changes, cell cycle progression, apoptosis rates, genotoxicity, global methylation, immunocytochemistry for p53 and PCNA and relative expression profiles of the AKT, mTOR, RASSF1A, HOXB3, SRC, PLK1, and DNMT1 were evaluated. Resveratrol decreased cell proliferation and induced DNA damage in all cell lines. Regarding the long‐term effects, resveratrol reduced the number of colonies in all cell lines; however, TP53 wild type cells were more resistant. Increased rates of apoptosis were found in the TP53 wild type cells and this was accompanied by AKT, mTOR, and SRC downregulation. In addition, the resveratrol antiproliferative effects in wild type TP53 cells were accompanied by modulation of the DNMT1 gene. In the TP53 mutated cells, cell cycle arrest at S phase with PLK1 downregulation was observed. Additionally, there was modulation of the HOXB3/RASSF1A pathway and nuclear PCNA reduction in the highest‐grade cells. In conclusion, resveratrol has antiproliferative activity in bladder tumor cells; however, the mechanisms of action are dependent on TP53 status. Environ. Mol. Mutagen., 60:740–751, 2019. © 2019 Wiley Periodicals, Inc.

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“…Silibinin compounds are members of the flavonoids family, and have received attention for their antitumor activities (16)(17)(18). Evidence indicates that silibinin may inhibit the proliferation, invasion and migration of tumor cells.…”

Section: Silibinin Inhibits the Migration And Invasion Of Human Gastrmentioning

confidence: 99%

Silibinin inhibits the migration and invasion of human gastric cancer SGC7901 cells by downregulating MMP‑2 and MMP‑9 expression via the p38MAPK signaling pathway

Zhang

Chen

et al. 2017

Oncol Lett

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Abstract. The objective of the present study was to observe the effects of silibinin and the p38 mitogen-activated protein kinase (MAPK) signaling pathway inhibitor SB203580 on the migration and invasion capabilities of SGC7901 cells, and to explore the underlying associated mechanisms. Scratch, Transwell and Matrigel invasion assays were performed to study the effects of silibinin on cell migration and invasion. Western blot analysis was used to determine the expression levels of p38MAPK, phosphorylated (p-)p38MAPK, matrix metalloproteinase (MMP)-2 and MMP-9. At the genomic level, quantitative polymerase chain reaction was performed to evaluate the expression levels of MMP-2 and MMP-9. The results of scratch assay indicated that silibinin inhibited the migration capabilities of human gastric cancer SGC7901 cells in a dose-dependent manner. Additionally, Matrigel invasion and Transwell migration assays revealed that silibinin and SB203580 combined treatment significantly reduced the number of invasive cells. Western blot analysis indicated a reduced phosphorylation of p38MAPK without marked changes in p38MAPK expression. In addition, the expression of MMP-2 and MMP-9 significantly decreased in the presence of silibinin, SB203580, and the combination of silibinin and SB203580. In summary, silibinin decreased the invasion and migration abilities of SGC7901 cells by downregulating the expression of MMP-2 and MMP-9 through inhibiting p38MAPK signaling cascades.

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Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status

Cited by 23 publications

References 68 publications

Inhibition of urinary bladder cancer cell proliferation by silibinin

Inhibition of urinary bladder cancer cell proliferation by silibinin

Antiproliferative and toxicogenomic effects of resveratrol in bladder cancer cells with different TP53 status

Silibinin inhibits the migration and invasion of human gastric cancer SGC7901 cells by downregulating MMP‑2 and MMP‑9 expression via the p38MAPK signaling pathway

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