Therapeutic effect of Teng Qi formula on triple-negative breast cancer : efficacy, active principles, and mechanisms

Abstract

Breast cancer (BC) has had the highest incidence of newly diagnosed cases worldwide since 2020. Triple-negative breast cancer (TNBC) is one of the most fatal subtypes with a high propensity for recurrence and aggressiveness. Spatholobus suberectus Dunn (SSD), named “Jixueteng” in Chinese, belongs to the Leguminosae. According to a scoping review, the anti-cancer property of SSD is the trendiest issue of SSD-related research. However, the anti-TNBC efficacy of SSD has not been tested yet, that is where my project came from. Both in-vitro and in-vivo evidence indicates that SSP (Percolation extract of Spatholobus suberectus Dunn) plays a positive role in anti-TNBC. Through morphological analysis and LDH release assay, the pyroptotic features of tumor cells treated with SSP were observed. Then, the activated pyroptosis of tumor cells was verified by the detection of pyroptotic executioners. Moreover, the GSH rescue experiment indicated that the efficacy and mechanism of SSP in anti-TNBC are dependent on Reactive Oxygen Species (ROS) accumulation-caused pyroptosis. Distant metastasis is the major cause of mortality in BC patients, and bone is the most common BC metastatic site. Unfortunately, there are few medications but palliative treatments for breast cancer bone metastasis (BCBM) prevention. In this project, based on Traditional Chinese Medicine theory and the clinical practice experience of Dr. Jianping Chen, the efficacy and mechanism of the Teng Qi Formula (SSD-supplemented formulations) and SSP in the management of bone metastasis of BC were investigated. It has been shown that the Teng Qi formula treatment had remarkable correlations with the inhibition of tumor cell motility, a longer overall survival time, and bone protection in mice with BCBM. Network pharmacological analysis indicated that "Teng Qi" formula regulates about 24 distinct signaling pathways. Based on the Western blotting assay, the Teng Qi formula was shown to prevent EMT, independent of GSK3β pathways. Potential drug toxicities and drug interactions of redundant compounds of plant complexes such as herbal medicines aforementioned may cause unexpected clinical responses or even severe adverse events. On the other hand, super-additivity of drug interactions between natural products and synthetic drugs may be utilized to eliminate the side effects of drugs. Based on the SwissSimilarity and PubChem platforms, for the first time, a feasible workflow of prediction of both toxicity and drug interaction of plant complexes was built in this project. From the PubChem database, 31 different sections of toxicity information such as “Acute Effects”, “Interactions”, “Hepatotoxicity”, “Carcinogenicity”, “Symptoms”, and “Human Toxicity Values” sections have been retrieved. Remarkably, in SSD, there are 9 out of 24 active compounds predicted to play synergistic effects on cancer management with various drugs or factors. Additionally, the synergistic effects of Spatholobus suberectus Dunn and docetaxel in the management of triple-negative breast cancer were proved by the combination index assay, synergy score detection assay, and xenograft model. Collectively, based on the in-vitro and in-vivo evidence, chemical and biological informatics, Spatholobus suberectus Dunn and SSD-supplemented “Teng Qi” formula may be a potential herbal medicine for Triple-negative breast cancer therapy and BCBM prevention.