Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status
Daiane Teixeira DE Oliveira1, Andre Luiz Ventura Savio, Joao Paulo DE Castro Marcondes
1Escola de Farmacia, Departamento de Analises Clinicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil.
Abstract:
Silibinin is a natural phenol found in the seeds of the milk thistle plant. Recent data have shown its effectiveness for preventing/treating bladder tumours. Therefore, in this study we investigated the cytotoxic and toxicogenetic activity of silibinin in bladder cancer cells with different TP53 statuses. Two bladder urothelial carcinoma cell lines were used: RT4 (wild-type TP53 gene) and T24 (mutated TP53 gene). Cell proliferation, clonogenic survival, apoptosis rates, genotoxicity and relative expression profile of FRAP/mTOR, FGFR3, AKT2 and DNMT1 genes and of miR100 and miR203 were evaluated. Silibinin promoted decreased proliferation and increased late apoptosis in TP53 mutated cells. Increased early apoptosis rates, primary DNA damage, and decrease of cell colonies in the clonogenic survival assay were detected in both RT4 and T24 cell lines. Down-regulation of FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 expression occurred in RT4 cells. Modulation of miR203 was observed in both cell lines. In conclusion, despite the reduction of clone formation in both cell lines, the toxicogenomic effect of silibinin on FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 was dependent on the TP53 status. Taken together, the data confirmed the role of silibinin as an antiproliferative compound, whose mechanism of action was related to the TP53 status.
Insights
Silibinin, a milk thistle compound, shows antiproliferative effects on bladder cancer cells. Its toxicogenomic impact varies with TP53 gene status, influencing cell death and gene expression.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Silibinin, a milk thistle extract, demonstrates potential in preventing and treating bladder tumors.
- The TP53 gene status is crucial in cancer development and response to therapy.
- Understanding silibinin's effects based on TP53 status is key for targeted bladder cancer treatment.
Purpose of the Study:
- To investigate the cytotoxic and toxicogenetic effects of silibinin on bladder cancer cells with different TP53 gene statuses.
- To evaluate silibinin's impact on cell proliferation, apoptosis, genotoxicity, and specific gene/microRNA expression profiles.
- To determine if silibinin's mechanism of action is influenced by the TP53 status in bladder cancer.
Main Methods:
- Utilized two bladder urothelial carcinoma cell lines: RT4 (wild-type TP53) and T24 (mutated TP53).
- Assessed cell proliferation, clonogenic survival, apoptosis rates, and genotoxicity.
- Analyzed the relative expression of FRAP/mTOR, FGFR3, AKT2, DNMT1 genes, and miR100, miR203.
Main Results:
- Silibinin decreased proliferation and increased late apoptosis in TP53-mutated cells (T24).
- Both cell lines showed increased early apoptosis, DNA damage, and reduced colony formation.
- Differential gene expression (FRAP/mTOR, AKT2, FGFR3, DNMT1, miR100) was observed, particularly in wild-type TP53 cells (RT4), with miR203 modulation in both.
Conclusions:
- Silibinin exhibits antiproliferative activity in bladder cancer cells, with effects modulated by TP53 status.
- The toxicogenomic effects of silibinin on key genes and microRNAs are dependent on the TP53 gene.
- These findings highlight silibinin's potential as a therapeutic agent, with its mechanism linked to TP53 status in bladder cancer.
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