Abstract
Health-strengthening (Fu-Zheng) herbs is a representative type of traditional Chinese medicine (TCM) widely used for cancer treatment in China, which is in contrast to pathogen eliminating (Qu-Xie) herbs. However, the commonness in the biological basis of health-strengthening herbs remains to be holistically elucidated. In this study, an innovative high-throughput research strategy integrating computational and experimental methods of network pharmacology was proposed, and 22 health-strengthening herbs were selected for the investigation. Additionally, 25 pathogen-eliminating herbs were included for comparison. First, based on network-based, large-scale target prediction, we analyzed the target profiles of 1446 TCM compounds. Next, the actions of 166 compounds on 420 antitumor or immune-related genes were measured using a unique high-throughput screening strategy by high-throughput sequencing, referred to as HTS2. Furthermore, the structural information and the antitumor activity of the compounds in health-strengthening and pathogen-eliminating herbs were compared. Using network pharmacology analysis, we discovered that: (1) Functionally, the predicted targets of compounds from health strengthening herbs were enriched in both immune-related and antitumor pathways, similar to those of pathogen eliminating herbs. As a case study, galloylpaeoniflorin, a compound in a health strengthening herb Radix Paeoniae Alba (Bai Shao), was found to exert antitumor effects both in vivo and in vitro. Yet the inhibitory effects of the compounds from pathogen eliminating herbs on tumor cells proliferation as a whole were significantly stronger than those in health-strengthening herbs (p < 0.001). Moreover, the percentage of assay compounds in health-strengthening herbs with the predicted targets enriched in the immune-related pathways (e.g., natural killer cell mediated cytotoxicity and antigen processing and presentation) were significantly higher than that in pathogen-eliminating herbs (p < 0.05). This finding was supported by the immune-enhancing effects of a group of compounds from health-strengthening herbs indicated by differentially expressed genes in the HTS2 results. (2) Compounds in the same herb may exhibit the same or distinguished mechanisms in cancer treatment, which was demonstrated as the compounds influence pathway gene expressions in the same or opposite directions. For example, acetyl ursolic acid and specnuezhenide in a health-strengthening herb Fructus Ligustri lucidi (Nv Zhen Zi) both upregulated gene expressions in T cell receptor signaling pathway. Together, this study suggested greater potentials in tumor immune microenvironment regulation and tumor prevention than in direct killing tumor cells of health-strengthening herbs generally, and provided a systematic strategy for unveiling the commonness in the biological basis of health-strengthening herbs in cancer treatment.
Highlights
China has a long history of using traditional Chinese medicine (TCM) for treating cancer [1]
By combining target prediction and high-throughput assay, this study proposed a systematic overview on the biological basis underlying the pharmacological effects of health strengthening herbs in cancer treatment
Since the numbers of the related reports of the different TCM compounds varied greatly, which would influence the following analysis results, we only selected the compounds with adequate related reports for the verification of target prediction results
Summary
China has a long history of using traditional Chinese medicine (TCM) for treating cancer [1]. A large amount of medication experience and clinical cases have been accumulated by TCM practitioners, which makes TCM contribute greatly to the development of China’s national health status. According to an urban basic medical insurance survey of inpatient use of health services in China from 2008 to 2010, 42.4% of oncology patients have used antineoplastic TCMs in the Chinese national medical insurance catalogue [2]. With increasing scientific evidence in biological, chemical, and medical research, as well as clinical trials, the use of traditional Chinese medicine in cancer treatment is gradually being recognized as a complementary and alternative therapy all over the world [3,4,5,6]. The clinical treatment strategy by strengthening health reflects the characteristics of focusing on regulatory effects instead of the antagonistic effects of TCM, and embodies the classical therapeutic theory that “pathogenic-qi cannot invade the body if health-qi remains strong” in the Canon of Internal
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