Molecular targets of Chinese herbs: a clinical study of hepatoma based on network pharmacology

Scientific Reports, May 2016

Traditional Chinese medicine (TCM) has been used to treat tumors for years and has been demonstrated to be effective. However, the underlying molecular mechanisms of herbs remain unclear. This study aims to ascertain molecular targets of herbs prolonging survival time of patients with advanced hepatocellular carcinoma (HCC) based on network pharmacology, and to establish a research method for accurate treatment of TCM. The survival benefit of TCM treatment with Chinese herbal medicine (CHM) was proved by Kaplan–Meier method and Cox regression analysis among 288 patients. The correlation between herbs and survival time was performed by bivariate correlation analysis. Network pharmacology method was utilized to construct the active ingredient-target networks of herbs that were responsible for the beneficial effects against HCC. Cox regression analysis showed CHM was an independent favorable prognostic factor. The median survival time was 13 months and the 5-year overall survival rates were 2.61% in the TCM group, while there were 6 months, 0 in the non-TCM group. Correlation analysis demonstrated that 8 herbs closely associated with prognosis. Network pharmacology analysis revealed that the 8 herbs regulated multiple HCC relative genes, among which the genes affected proliferation (KRAS, AKT2, MAPK), metastasis (SRC, MMP), angiogenesis (PTGS2) and apoptosis (CASP3) etc.

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Molecular targets of Chinese herbs: a clinical study of hepatoma based on network pharmacology

Abstract Traditional Chinese medicine (TCM) has been used to treat tumors for years and has been demonstrated to be effective. However, the underlying molecular mechanisms of herbs remain unclear. This study aims to ascertain molecular targets of herbs prolonging survival time of patients with advanced hepatocellular carcinoma (HCC) based on network pharmacology, and to establish a research method for accurate treatment of TCM. The survival benefit of TCM treatment with Chinese herbal medicine (CHM) was proved by Kaplan–Meier method and Cox regression analysis among 288 patients. The correlation between herbs and survival time was performed by bivariate correlation analysis. Network pharmacology method was utilized to construct the active ingredient-target networks of herbs that were responsible for the beneficial effects against HCC. Cox regression analysis showed CHM was an independent favorable prognostic factor. The median survival time was 13 months and the 5-year overall survival rates were 2.61% in the TCM group, while there were 6 months, 0 in the non-TCM group. Correlation analysis demonstrated that 8 herbs closely associated with prognosis. Network pharmacology analysis revealed that the 8 herbs regulated multiple HCC relative genes, among which the genes affected proliferation (KRAS, AKT2, MAPK), metastasis (SRC, MMP), angiogenesis (PTGS2) and apoptosis (CASP3) etc. Introduction Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide1,2,3. More than 70% of new cases are diagnosed in Asia each year, and 50% are diagnosed in China alone4. The incidence of HCC is increasing and it is the second most common cause of cancer-related mortality2,3,5. The incidence and mortality rates are similar because most cases of HCC are diagnosed at an advanced stage6. Five-year survival rates had been improved but still less than 30%7. Previous studies reported that the median survival of patients with advanced HCC was less than 5 months8,9. But unfortunately, few therapies could be performed in advanced HCC (stage III–IV), only trans-arterial chemoembolization (TACE) and the drug Sorafenib have been shown to provide a survival benefit10,11. Traditional Chinese medicine (TCM) has been widely used in China for thousands of years. Chinese herbal medicine (CHM) has become a treatment option in many cancer centers in Asia, Western countries and Africa12,13,14. Many clinical studies have shown that CHM is effective in the treatment of breast, gastric, lung and pancreatic cancers15,16,17. Our previous clinical and experimental studies indicated that CHM was effective on HCC18,19. However, whether patients with advanced HCC (stage III–IV) could obtain a benefit from CHM or not should be confirmed, and the mechanisms of CHM acting on HCC remain largely unsuspected. Two famous Chinese herbal formulae, Carapacis Trionycis Bolus (Synopsis of Golden Chamber) and Cang Niu Fangji Decoction (Synopsis of Golden Chamber; Yao-zhong Fang, 1921–1995), are commonly used for cirrhosis, chronic liver disease and hepatocellular carcinoma. Chinese herbal formulae always contain many kinds of herbs and could have effect on many targets, so the anti-tumor mechanisms of herbal formulae are hard to understand. Encouragingly, the newly emerged network pharmacology approach, first proposed by Andrew L Hopkins20, brings the hope to study the effective constituents and targets of herbs in a traditional Chinese formula. As bioinformatics, systems biology and poly-pharmacology have rapidly progressed, network pharmacology method could clarify the mechanisms of drug action in a holistic way21,22,23,24. So, using the method, combined with the rich experience of TCM treatment, could hopefully shift the “one target, one drug” model to a “network targets, multi-component” strategy25. In recent years, there was an increasing concern about applying the network pharmacology to reveal the scientific basis and systematic features of CHM. In the present work, the herbs are selected based on our clinical therapy; therefore it is much more reliable than those based on literature retrieval. The flowchart of the whole study design is illustrated in Fig. 1, and the following is a brief description: firstly, we proposed a method to screen out herbs that are effective for prolonging overall survival (OS) of patients with advanced HCC, and then predicted molecular mechanisms of these herbs by using the network pharmacology approach. This process would contribute to clarifying the molecular mechanisms of TCM and improving the effectiveness and specificity of TCM clinical treatment. Figure 1: Process overview. Full size image Results Patient characteristics In this study, a total of 288 patients with advanced HCC (stage III–IV) were included, and 227 (78.8%) patients were more than 50 years old when diagnosed. It has been demonstrated that age would not affect the survival time of patients with advanced HCC (P = 0.842) based (...truncated)


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Li Gao, Xiao-dong Wang, Yang-yang Niu, Dan-dan Duan, Xue Yang, Jian Hao, Cui-hong Zhu, Dan Chen, Ke-xin Wang, Xue-mei Qin, Xiong-zhi Wu. Molecular targets of Chinese herbs: a clinical study of hepatoma based on network pharmacology, Scientific Reports, 2016, Issue: 6, DOI: 10.1038/srep24944