Luo Yi, Song Lei, Wang Xinyu, Huang Yujie, Liu Yongqiang, Wang Qi, Hong Ming, Yuan Zhongyu
Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China.
Front Pharmacol. 2020 Aug 13;11:1264. doi: 10.3389/fphar.2020.01264. eCollection 2020.
Hepatocellular carcinoma (HCC) is a fatal and dominant form of liver cancer that currently has no effective treatment or positive prognosis. In this study, we explored the antitumor effects of cryptotanshinone (CPT) against HCC and the molecular mechanisms underlying these effects using a systems pharmacology and experimental validation approach. First, we identified a total of 296 CPT targets, 239 of which were also HCC-related targets. We elucidated the mechanisms by which CPT affects HCC through multiple network analysis, including CPT-target network analysis, protein-protein interaction network analysis, target-function network analysis, and pathway enrichment analysis. In addition, we found that CPT induced apoptosis in Huh7 and MHCC97-H ells due to increased levels of cleaved PARP, Bax, and cleaved caspase-3 and decreased Bcl-2 expression. CPT also induced autophagy in HCC cells by increasing LC3-II conversion and the expression of Beclin1 and ATG5, while decreasing the expression of p62/SQSTM1. Autophagy inhibitors (3-methyladenine and chloroquine) enhanced CPT-induced proliferation and apoptosis, suggesting that CPT-induced autophagy may protect HCC cells against cell death. Furthermore, CPT was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Interestingly, activation of PI3K by insulin-like growth factor-I inhibited CPT-induced apoptosis and autophagy, suggesting that the PI3K/AKT/mTOR signaling pathway is involved in both CPT-induced apoptosis and autophagy. Finally, CPT was found to inhibit the growth of Huh7 xenograft tumors. In conclusion, we first demonstrated the antitumor effects of CPT in Huh7 and MHCC97-H cells, both and . We elucidated the potential antitumor mechanism of CPT, which involved inducing apoptosis and autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway. Our findings may provide valuable insights into the clinical application of CPT, serving as a potential candidate therapeutic agent for HCC treatment.
肝细胞癌（HCC）是一种致命且占主导地位的肝癌形式，目前尚无有效的治疗方法或良好的预后。在本研究中，我们采用系统药理学和实验验证方法，探究了隐丹参酮（CPT）对HCC的抗肿瘤作用及其潜在分子机制。首先，我们共鉴定出296个CPT靶点，其中239个也是与HCC相关的靶点。我们通过多种网络分析阐明了CPT影响HCC的机制，包括CPT-靶点网络分析、蛋白质-蛋白质相互作用网络分析、靶点-功能网络分析和通路富集分析。此外，我们发现CPT通过增加裂解的PARP、Bax和裂解的caspase-3水平以及降低Bcl-2表达，诱导Huh7和MHCC97-H细胞凋亡。CPT还通过增加LC3-II转化以及Beclin1和ATG5的表达，同时降低p62/SQSTM1的表达，诱导HCC细胞自噬。自噬抑制剂（3-甲基腺嘌呤和氯喹）增强了CPT诱导的增殖和凋亡，表明CPT诱导的自噬可能保护HCC细胞免于细胞死亡。此外，发现CPT抑制磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（Akt）/雷帕霉素哺乳动物靶点（mTOR）信号通路。有趣的是，胰岛素样生长因子-I对PI3K的激活抑制了CPT诱导的凋亡和自噬，表明PI3K/AKT/mTOR信号通路参与了CPT诱导的凋亡和自噬。最后，发现CPT抑制Huh7异种移植瘤的生长。总之，我们首次证明了CPT在Huh7和MHCC97-H细胞中的抗肿瘤作用。我们阐明了CPT潜在的抗肿瘤机制，即通过抑制PI3K/Akt/mTOR信号通路诱导凋亡和自噬。我们的研究结果可能为CPT的临床应用提供有价值的见解，作为HCC治疗的潜在候选治疗药物。
