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.

中文翻译：

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水飞蓟宾抑制膀胱癌细胞增殖。

水飞蓟宾是一种从水飞蓟中提取的天然化合物，已在膀胱癌细胞中显示出抗肿瘤特性。然而，TP53基因在这些作用中的作用尚不清楚。为了更好地了解该化合物的分子和抗增殖机制，具有不同TP53基因状态，RT4（低度肿瘤，野生TP53基因），5637（高度肿瘤，2级突变TP53基因）的膀胱癌细胞和T24（高级别肿瘤，3级，突变的TP53基因）用几种浓度的水飞蓟宾（1、5、10、50、100和150μM）处理。评估了细胞毒性，促氧化作用，形态变化，细胞迁移，细胞周期进程，整体甲基化谱以及HOXB3，c-MYC，PLK1，SMAD4，SRC，HAT，HDAC和RASSF1A基因的相对表达。水飞蓟宾在这三种细胞系中均表现出细胞毒性和促氧化作用。在突变的TP53细胞中，观察到了对细胞迁移和G2 / M期细胞周期停滞的显着干扰。另外，水飞蓟宾在最高等级的肿瘤细胞中诱导总体DNA低甲基化。对于野生型TP53细胞，存在亚G1细胞凋亡。此外，对负责细胞生长的基因表达（SMAD和c-MYC），迁移（SRC），细胞周期动力学（PLK1），血管生成（HOXB3）以及与表观遗传事件相关的基因（如DNA乙酰化）的调节）和脱乙酰化（HDAC）。总之，水飞蓟宾能独立于TP53状态抑制膀胱肿瘤细胞的增殖。但是，细胞周期效应，基因表达发生变化，细胞迁移的改变和改变取决于TP53的状态。©2020 Wiley Periodicals，Inc.