Tumors are heterogeneous, and there are differences in the proliferation rate, metabolic level, and immune response of tumor cell populations. Single drug therapy often cannot achieve ideal curative effects. Quiescent cancer cells, also known as dormant tumor cells, refer to cancer cells that temporarily withdraw from the cell cycle process and enter the G0 phase, which can remain latent in the human body for decades. Quiescent cancer cells are a non-negligible component of tumor heterogeneity. They are insensitive to radiotherapy and most chemotherapeutic drugs, and have immune escape ability, which is one of the main reasons for tumor drug resistance. Quiescent cancer cells can reactivate and proliferate under certain conditions, leading to cancer recurrence and metastasis. Therefore, the development of drugs that target the elimination of quiescent cancer cells or inhibit their reactivation is of great significance for improving the efficacy of cancer treatment and preventing cancer recurrence and metastasis.
In the past ten years, the research team led by Professor Hongxi Xu and Associate Professor Zhichao Xi has focused on the biological characteristics of quiescent cancer cells and the discovery of active lead compounds. The research team established and improved a series of in vivo and in vitro models and detection methods for molecular mechanism research and drug development of quiescent cancer cells and proposed a drug development strategy targeting quiescent cancer cells.
In order to find active ingredients that target the elimination of quiescent cancer cells and inhibit their reactivation, the research team screened Chinese medicine extracts, small molecule libraries, and marketed drug libraries, and discovered several active small molecules targeting quiescent cancer cells compounds, and conducted in-depth studies on their mechanism of action, including Guttiferone K and Garoliganthone C in Garcinia plants, crocetal and saikosaponin A, etc., and the results were published in journals such as Cell Death & Disease.
Saikosaponin A is derived from the traditional Chinese medicine Bupleuri (Chaihu), which has anti-inflammatory, anti-oxidation and anti-fibrosis effects, and has been approved as a marketed drug by PMDA in Japan. In this study, it was proved that quiescent prostate cancer cells have strong tolerance to a variety of common chemotherapeutic drugs, saikosaponin A can selectively eliminate these drug-resistant quiescent cancer cells, but the same dose could not kill cancer cells of the proliferating phase. Combining saikosaponin A during the intermittent period of Docetaxel treatment can significantly improve the therapeutic effect of the tumor and reduce the volume of the tumor. Mechanistic studies have found that the autophagy level of quiescent prostate cancer cells is significantly higher than that of proliferating cells, indicating that autophagy may play an important role in the survival of quiescent cancer cells. Saikosaponin A can further induce the autophagy level of quiescent cancer cells, break the balance of autophagy that maintains its survival, and induce autophagic death and apoptosis of cells. Studies have shown that the Akt/mTOR/rpS6 signaling pathway is the main molecular mechanism for saikosaponin A to selectively induce excessive autophagy in quiescent cancer cells.
Traditional Chinese medicine has a unique role and rich clinical experience in tumor treatment. Patients often take Chinese medicine after surgery, radiotherapy and chemotherapy to improve the therapeutic effect, prevent recurrence and metastasis, and prolong the time of "survival with tumor". Taking quiescent cancer cells as an entry point, discovering the active ingredients of traditional Chinese medicine and elucidating their mechanism of action will help reveal the material basis and scientific connotation of the unique anti-tumor effect of traditional Chinese medicine.
Saikosaponin a enhances Docetaxel efficacy by selectively inducing death of dormant prostate cancer cells through excessive autophagy. Cancer Lett. 2022 Nov 25;216011. doi: 10.1016/j.canlet.2022.216011. Online ahead of print.