Exploring Spatholobus suberectus Dunn as a novel drug in the prevention and treatment of breast cancer

Abstract

Breast cancer (BC) ranks first in incidence among women worldwide. With advances in current surgical and chemo- or targeted therapies, BC survival rates have gradually improved; however, metastasis remains the ultimate fatal factor. About 70% of metastatic BC patients would develop bone metastases, resulting in bone-related events and enormous cancerous pain.

Spatholobus suberectus Dunn (SS) is a unique herbal medicine that revitalizes blood circulation functions. Studies have shown that SS extract effectively inhibits BC cells’ growth and lung metastasis. Based on the earlier investigation, the percolation extract of SS was prepared with 60% ethanol (SSP) and employed for further experiments. Several fractions containing proanthocyanidins (PACs) with varying degrees of polymerization were obtained after the systematic separation of SSP. Among them, Part I had a potential anti-tumor cell growth effect, which was detected using UPLC-MS/MSn. Fourteen PACs were identified or tentatively characterized, which may be responsible for the significant anti-cancer activity.

One of the clinical applications of SS is to treat rheumatic arthralgia, numbness, and paralysis. The inhibitory effect of SSP on BC bone metastases was discovered in the subsequent investigation. The findings showed that SSP exhibited therapeutic effects on suppressing osteoclast differentiation and attenuating bone resorption using in vitro osteoclast differentiation assays and an in vivo osteolytic bone metastasis model, which increased the pharmaceutical potential of SS. Furthermore, the "Target Fishing" strategy was utilized to investigate the molecular target of SSP components on various organs, which was primed according to the Traditional Chinese Medicine (TCM) beliefs of "meridian tropism" and "kidney governing bone." It was found that SSP was more likely to enter the liver and kidney meridians, and thereby we selected a remarkable molecular target, sorting nexin 9 (SNX9). SNX9 was a noteworthy regulatory protein found in the kidney; thus, the role of SNX9 in BC was further explored.

SNX9 was first found as a regulator in the clathrin-mediated endocytosis process, and the impact of SNX9 is highly connected to various cancers. According to the online database, upregulation of SNX9 was highly associated with poorer overall survival in BC patients. In this study, SNX9 was found to enhance BC cell proliferation, colony formation, and cell cycle speed, as well as stimulate BC cell migration and invasion in both lung and bone metastases in vitro and in vivo. SNX9 knockdown in MDA-MB-231 cells resulted in an elongated symmetrical spindle-shaped cell morphology. SNX9 also regulated the production of pseudopodia, such as lamellipodia, filopodia, and invadopodia, in the modulation of actin cytoskeleton dynamics. Furthermore, SNX9 activated the EGFR-ERK1/2 signaling in vivo and in vitro studies. Two pathway inhibitors were also applied in this study, which partially inhibited SNX9-promoted cell growth, colony formation, migration, and invasion. Therefore, SNX9 can be a potential target for BC treatment.

In conclusion, the present study explored diverse chemical constituents, pharmacological anti-BC bone metastases activity, and TCM theory interpretation of SS. However, further comprehensive studies are required, such as optimizing the "Target Fishing" strategy, which may promote the TCM modernization process.