State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research-NCI Strategic Workshop Highlights of Discussion Report.

In May 2016, the Office of Cancer Complementary and Alternative Medicine, Division of Cancer Diagnosis and Treatment, of the National Cancer Institute convened a special workshop focused on the State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research. The current state of the science, gaps, and future opportunities were reviewed and discussed by a distinguished panel of experts in this field of research, and the highlights of this meeting are reported herein.

A Methodology for Cancer Therapeutics by Systems Pharmacology-Based Analysis: A Case Study on Breast Cancer-Related Traditional Chinese Medicines.

Breast cancer is the most common carcinoma in women. Comprehensive therapy on breast cancer including surgical operation, chemotherapy, radiotherapy, endocrinotherapy, etc. could help, but still has serious side effect and resistance against anticancer drugs. Complementary and alternative medicine (CAM) may avoid these problems, in which traditional Chinese medicine (TCM) has been highlighted. In this section, to analyze the mechanism through which TCM act on breast cancer, we have built a virtual model consisting of the construction of database, oral bioavailability prediction, drug-likeness evaluation, target prediction, network construction. The 20 commonly employed herbs for the treatment of breast cancer were used as a database to carry out research. As a result, 150 ingredient compounds were screened out as active molecules for the herbs, with 33 target proteins predicted. Our analysis indicates that these herbs 1) takes a 'Jun-Chen-Zuo-Shi" as rule of prescription, 2) which function mainly through perturbing three pathways involving the epidermal growth factor receptor, estrogen receptor, and inflammatory pathways, to 3) display the breast cancer-related anti-estrogen, anti-inflammatory, regulation of cell metabolism and proliferation activities. To sum it up, by providing a novel in silico strategy for investigation of the botanical drugs, this work may be of some help for understanding the action mechanisms of herbal medicines and for discovery of new drugs from plants.

A systems pharmacology approach to investigate the mechanisms of action of Semen Strychni and Tripterygium wilfordii Hook F for treatment of rheumatoid arthritis.

ETHNOPHARMACOLOGY RELEVANCE: The angiogenesis control at the initiation of rheumatoid arthritis (RA) that mainly blocks the inflammatory cascades expects to attenuate the action of angiogenic mediators, synovial angiogenesis, and to partially reverse the erosive bone damage. Two typical Chinese herbs, Semen Strychni and Tripterygium wilfordii Hook F (TwHF) have been used as a remedy to treat RA since ancient time. However, their functioning mechanisms are still unknown. Thus it is necessary to exploit their underlying mechanism for the treatment of RA. METHODS: This study was undertaken to analyze their underlying mechanism based on a systems biology platform. Firstly, active components of the two herbs were screened out from TcmSP database based on their OB and DL values. Then their potential targets were predicted by using Random Forest, Support Vector Machine, and validated via docking process. Finally, a network of compound-target was constructed. RESULTS: In this work, 27 and 33 active compounds were screened out from Semen Strychni and TwHF, targeting 28 and 32 potential proteins, respectively. The results show that the two herbs modulate the angiogenesis mediators through both direct and indirect pathways, and 21 common targets shared by Semen Strychni and TwHF bear major responsibility for treating RA. CONCLUSIONS: The underlying mechanism of Semen Strychni and TwHF in treatment of RA is through multiple targets interaction by their blocking of the angiogenesis mediator cascades. This may provide us a better understanding of the function of the two herbs for the treatment of RA, as well as a clue to unveil their possible treatment effects of other systemic diseases, and in this way, hopefully the screening models may facilitate the discovery of novel combined drugs.

Systems pharmacology to decipher the combinational anti-migraine effects of Tianshu formula.

Migraine is the most common neurovascular disorder that imparts a considerable burden to health care system around the world. However, currently there are still no effective and widely applicable pharmacotherapies for migraine patients. Herbal formulae, characterized as multiple herbs, constituents and targets, have been acknowledged with clinical effects in treating migraine, which attract more and more researchers' attention although their exact molecular mechanisms are still unclear. In this work, a novel systems pharmacology-based method which integrates pharmacokinetic filtering, target fishing and network analysis was developed and exemplified by a probe, i.e. Tianshu formula, a widely clinically used anti-migraine herbal formula in China which comprises of Rhizoma chuanxiong and Gastrodia elata. The results exhibit that 20 active ingredients of Tianshu formula possess favorable pharmacokinetic profiles, which have interactions with 48 migraine-related targets to provide potential synergistic therapeutic effects. Additionally, from systematic analysis, we speculate that R. chuanxiong as the monarch herb mediates the major targets like PTGS2, ESR1, NOS2, HTR1B and NOS3 to regulate the vascular and nervous systems, as well as the inflammation and pain-related pathways to benefit migraine patients. Meanwhile, as an adjuvant herb, G. elata may not only assist the monarch herb to improve the outcome of migraine patients, but also regulate multiple targets like ABAT, HTR1D, ALOX15 and KCND3 to modify migraine accompanying symptoms like vomiting, vertigo and gastrointestinal disorders.

Systems pharmacology dissection of the anti-inflammatory mechanism for the medicinal herb Folium eriobotryae.

Inflammation is a hallmark of many diseases like diabetes, cancers, atherosclerosis and arthritis. Thus, lots of concerns have been raised toward developing novel anti-inflammatory agents. Many alternative herbal medicines possess excellent anti-inflammatory properties, yet their precise mechanisms of action are yet to be elucidated. Here, a novel systems pharmacology approach based on a large number of chemical, biological and pharmacological data was developed and exemplified by a probe herb Folium Eriobotryae, a widely used clinical anti-inflammatory botanic drug. The results show that 11 ingredients of this herb with favorable pharmacokinetic properties are predicted as active compounds for anti-inflammatory treatment. In addition, via systematic network analyses, their targets are identified to be 43 inflammation-associated proteins including especially COX2, ALOX5, PPARG, TNF and RELA that are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway, the rheumatoid arthritis pathway and NF-κB signaling pathway. All these demonstrate that the integrated systems pharmacology method provides not only an effective tool to illustrate the anti-inflammatory mechanisms of herbs, but also a new systems-based approach for drug discovery from, but not limited to, herbs, especially when combined with further experimental validations.