Uncovering the Mechanisms of Cryptotanshinone as a Therapeutic Agent Against Hepatocellular Carcinoma

Yi Luo,Yujie Huang,Xinyu Wang,Ming Hong,Qi Wang,Lei Song,Zhongyu Yuan,Yongqiang Liu

doi:10.3389/fphar.2020.01264

Abstract

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 in vitro and in vivo. 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.

Highlights

Hepatocellular carcinoma (HCC) is a type of primary liver malignancy that typically occurs in the context of chronic liver inflammation and is the most common cause of cancer-related deaths worldwide (Forner et al, 2012)
Detailed information regarding the common targets of CPT and HCC is shown in Supplementary Table S3
The combined treatment of CPT and Insulin-like growth factor-I (IGF-I) decreased the LC3-II conversion and Beclin1 expression. These results indicate that phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is a crucial pathway for CPT-induced apoptosis and autophagy in HCC

Summary

Introduction

Hepatocellular carcinoma (HCC) is a type of primary liver malignancy that typically occurs in the context of chronic liver inflammation and is the most common cause of cancer-related deaths worldwide (Forner et al, 2012). HCC treatment includes surgical resection and comprehensive treatment (immunotherapy, radiotherapy, chemotherapy, interventional therapy, or a combination); the overall survival rate of patients with HCC remains low. Partial ablation, and liver resection remain the mainstream curative options for very early and early-stage HCC HCC (Montironi et al, 2019; Sarcognato et al, 2019). Most patients are typically diagnosed at an advanced stage with severe comorbidities, making them unsuitable for surgery. The overall survival rate can be improved by sorafenib treatment, but this is associated with significant side effects and potential toxicity (Ayoub et al, 2019; Inchingolo et al, 2019; Lu et al, 2019). There is an urgent need to develop novel HCC therapeutic strategies

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