Inhibition of urinary bladder cancer cell proliferation by silibinin

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.

Anticancer Potential of Silibinin Loaded Polymeric Nanoparticles against Breast Cancer Cells: Insight into the Apoptotic Genes Targets

“…Moreover, SIL treatment decreased the growth and invasiveness of renal cancer 786-O cell while restraining the growth of cell and inducing program cell death in cancer Caki-1 cells through prevention of EGF, ERK1/2 (Raina et al, 2016). In accordance with these findings, several studies have demonstrated the growth inhibitory effects SIL in rat models of urinary bladder cancer, associated with elevated levels of p53 expression, phosphorylation of ERK1/2 and phospho-p65, as well as downregulation of survivin, cyclin D1 (Barros et al, 2020). The use of Sil in breast cancer cells has caused cell apoptosis in MDA-MB-231 and MCF-7 cells, which synergized with inhibition of metastasis through several proteins including insulin growth factor receptor (Si et al, 2020).…”

<p>Ribosome Binding Protein 1 Correlates with Prognosis and Cell Proliferation in Bladder Cancer</p>

“…[27][28][29] TGF-β/Smad signaling plays a key role in the epithelial-mesenchymal transition pathway and carcinogenesis in many cancer types. [30][31][32] Results show TGF-β/Smad signaling was activated by RRBP1 overexpression. Therefore, these data indicated that RRBP1 overexpression promoted cell proliferation, which was connected with the TGF-β/Smad pathway.…”

Silibinin Therapy Improves Cholangiocarcinoma Outcomes by Regulating ERK/Mitochondrial Pathway

“…Silibinin can have an important function across different stages of carcinogenesis, including inhibiting proliferation of cancer cells, regulating cell cycle and inducing apoptosis in order to play a considerable role in anti-tumor activity ( Bosch-Barrera and Menendez, 2015 ). Many studies have demonstrated that silibinin has promising anticancer effects across both androgen dependent and independent prostate, skin, bladder, lung, colon, breast and liver cancers ( Polachi et al, 2016 ; Vue et al, 2016 ; Barros et al, 2020 ; Liu Y et al, 2020 ). However, thus far, there have been no reports on the application of silibinin on cholangiocarcinoma treatment.…”