Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
Anticancer Res. 2021 May;41(5):2431-2440. doi: 10.21873/anticanres.15018.
BACKGROUND/AIM: Oncolytic reovirus, which is a non-enveloped virus possessing a 10-segmented double-stranded RNA genome, has been anticipated as a novel class of antitumor agent. Hepatocellular carcinoma (HCC) is considered to be a target suitable for reovirus-mediated virotherapy. Transforming growth factor (TGF)-β plays an important role in the pathogenesis of HCC. TGF-β-signaling inhibitors have proceeded to clinical trials as potential antitumor agents for HCC. On the other hand, TGF-β is involved in induction of expression of cathepsins B and L, which are important for reovirus infection. It remains to be examined whether TGF-β signaling inhibitors affect reovirus-mediated lysis of HCC cells. The aim of this study was to evaluate the effects of TGF-β-signaling inhibitors on tumor cell lysis efficiency of reovirus in human HCC cells.
Reovirus was added to four types of human HCC cell lines pretreated with one of three TGF-β type I receptor inhibitors: SB431542, A-83-01, or galunisertib (LY2157299). Cell viability, virus genome copy numbers, and virus protein expression were evaluated following reovirus infection.
SB431542 significantly inhibited reovirus-mediated killing of human HCC cell lines, while A-83-01 and galunisertib did not inhibit.
These data indicate that SB431542 inhibited reovirus-mediated lysis of human HCC cells in a TGF-β signaling-independent manner.
背景/目的：溶瘤呼肠孤病毒是一种无包膜病毒，具有 10 个节段的双链 RNA 基因组，被认为是一类新型抗肿瘤药物。肝细胞癌（HCC）被认为是适合溶瘤病毒治疗的靶点。转化生长因子-β（TGF-β）在 HCC 的发病机制中起着重要作用。TGF-β 信号抑制剂已作为 HCC 的潜在抗肿瘤药物进入临床试验。另一方面，TGF-β 参与了组织蛋白酶 B 和 L 的表达诱导，这对呼肠孤病毒感染很重要。TGF-β 信号抑制剂是否影响呼肠孤病毒介导的 HCC 细胞裂解仍有待研究。本研究旨在评估 TGF-β 信号抑制剂对人 HCC 细胞中呼肠孤病毒肿瘤细胞裂解效率的影响。
用三种 TGF-β 型 I 受体抑制剂之一预处理四种人 HCC 细胞系后加入呼肠孤病毒：SB431542、A-83-01 或 galunisertib（LY2157299）。感染呼肠孤病毒后评估细胞活力、病毒基因组拷贝数和病毒蛋白表达。
SB431542 显著抑制了呼肠孤病毒介导的人 HCC 细胞系的杀伤，而 A-83-01 和 galunisertib 则没有抑制。
这些数据表明，SB431542 以 TGF-β 信号非依赖的方式抑制了呼肠孤病毒介导的人 HCC 细胞裂解。
