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Inhibition of urinary bladder cancer cell proliferation by silibinin
Tatiane M B Barros1, Ana P B Lima1, Tamires C Almeida1
1Programa de Pós-graduação em Ciências Farmacêuticas (CIPHARMA), Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
Abstract:
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. © 2020 Wiley Periodicals, Inc.
Insights
Silibinin, a milk thistle compound, inhibits urinary bladder cancer cell growth regardless of TP53 gene status. However, TP53 influences silibinin
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Silibinin from milk thistle shows antitumor potential in urinary bladder cancer.
- The role of the TP53 gene in silibinin's effects remains unclear.
- Understanding these mechanisms is crucial for targeted cancer therapies.
Purpose of the Study:
- To investigate the antiproliferative and molecular mechanisms of silibinin in urinary bladder cancer cells.
- To determine the influence of TP53 gene status on silibinin's efficacy.
- To evaluate silibinin's effects on cytotoxicity, cell cycle, migration, and gene expression.
Main Methods:
- Treatment of urinary bladder cancer cell lines (RT4, 5637, T24) with varying silibinin concentrations.
- Assessment of cytotoxicity, prooxidant effects, cell morphology, migration, and cell cycle progression.
- Analysis of global DNA methylation and expression of key genes (HOXB3, c-MYC, PLK1, SMAD4, SRC, HAT, HDAC, RASSF1A).
Main Results:
- Silibinin exhibited cytotoxic and prooxidant effects across all tested cell lines.
- Mutated TP53 cells showed significant interference in migration and G2/M cell cycle arrest.
- Wild-type TP53 cells displayed a sub-G1 apoptotic population; hypomethylation occurred in high-grade tumors.
- Differential gene expression modulation was observed, impacting cell growth, migration, cell cycle, angiogenesis, and epigenetic events.
Conclusions:
- Silibinin inhibits urinary bladder tumor cell proliferation independently of TP53 gene status.
- Cell cycle effects, gene expression changes, and migration alterations are dependent on TP53 status.
- Silibinin represents a potential therapeutic agent for bladder cancer, with TP53 status influencing specific cellular responses.
