Predicting and understanding synergistic pairwise compound combinations of Shexian Baoxin Pill (SBP) using network biology

Abstract The Traditional Chinese Medicine (TCM) formulation Shexiang Baoxin Pill (SBP) is commonly used in the treatment of coronary heart disease (CHD) in East Asia and regarded to promote the regulation of angiogenesis and to improve endothelial function. SBP comprises of seven TCM materials; however, the interactions of their effects in a biological system are unknown. In this work we developed an algorithm to predict the synergy of pairwise combinations of 22 compounds present in SBP. The algorithm is based on the targets of the compounds network properties in an angiogenesis- and CHD-specific network. We evaluated our synergy score prospectively by testing the 20 highest-ranked and the 20 lowest-ranked compound combinations for their synergistic potential to promote cell proliferation of Human Umbilical Vascular Endothelial Cells. Results showed that 70% of the 20 highest-ranked combinations increased cell proliferation synergistically, while only 30% of the 20 lowest-ranked combinations had a synergistic effect. Based on the target and pathway predictions for the combinations, we hypothesized that two complementary pathways are responsible for the synergistic effect, apoptosis through caspase-3 and caspase-8 and cell growth through the proto-oncogene c-Fos and fibroblast growth factor 1. Hence, in this work we introduce an algorithm which was able to increase the probability of identifying compound pairs from SBP exhibiting synergy, which was experimentally validated in a disease-relevant model. Furthermore, we were able, based on this model, to provide a hypothesis for interactions causing synergy to promote endothelial cell growth.