Introduction
Colorectal cancer (CRC) has been implicated as one of the most commonly diagnosed cancers worldwide, with an estimated 1.85 million new cases in 2018, accounting for 9.2% of all cancer-related deaths [1,2]. Meanwhile, the rate of CRC is growing fast with insufficient therapeutic options. The screening of CRC remains the most important and cost-effective strategy in reducing the incidence and mortality of the disease, but it still lacks the screening programs in the developing countries [3-4]. In addition, the primary strategies for CRC treatment such as surgery, radiotherapy and adjuvant chemotherapy, have greatly improved the survival rate, but there are some obstacles in the application of chemotherapy, such as lack of selectivity, insufficient drug concentrations in tumor tissues, emergence of drug-resistant cancer cells, and inevitable systemic toxicity [5]. Therefore, novel agents with fewer or no side effects are urgent need to improve the outcome of CRC patients.
Autophagy has recently received considerable attention due to its important roles in human diseases and earned a Nobel Prize for physiology or medicine in 2016 [6]. Autophagy commonly includes three types that is macro-autophagy, micro-autophagy and chaperone-mediated autophagy (CMA) [7-9]. Macro-autophagy (hereafter referred to as autophagy) is an evolutionarily conserved biological process by which damaged organelles and macromolecules are degraded and recycled for cell survival and proliferation under physiologic conditions, such as accumulation of reactive oxygen species (ROS) and energy limiting [6,10]. Meanwhile, it also occurs frequently during tumorigenesis and cancer chemotherapy [11-12], even related to cancer drug resistance [13-14]. Due to its “self-digest” function, the role of autophagy in cancer is complex and context-dependent [15]. A growing number of reports indicate that targeting the autophagy process has been regarded as a novel therapeutic approach [16-17]. Therefore, development of novel autophagy regulators has rewired a way of cancer treatment in recent years.
Drug repurposing has recently emerged as an alternative approach to accelerate drug development for cancer treatment. Repurposing the large arsenal of non-anticancer drugs holds promise to achieve a rapid clinical practice at a lower cost than de novo drug development [18]. In the past decades, traditional Chinese medicine (TCM) has drawn growing attention as special drug pool for drug repurposing in the cancer management. Ziyuglycoside II (3β-3-α-L-arabinopyranosyloxy-19-hydroxyurs-12-en-28-oic acid) (Fig. 1A) is one of the major active compounds of Sanguisorba officinalis L , which is widely distributed in the north temperate zone of Asia and Europe, especially in China. And it has a wide range of clinical applications including antibiosis, anti-inflammation, anti-oxidation and anti-cancer. Previous study has identified Ziyu II as a potent anti-tumor agent that inhibits cancer cell proliferation by triggering apoptosis and inducing cell cycle arrest in various cancers, including breast cancer and gastric cancer [19-21]. However, the detailed mechanism underlying the anticancer effect of Ziyu II remains to be further defined.
In this study, we demonstrated that Ziyu II induces growth inhibition and obvious cell death of CRC cells by triggering autophagy and apoptosis both in vitro and in vivo . Notably, Ziyu II promotes complete autophagic flux which results from the inhibition of the Akt/mTOR signaling pathway, leading to growth inhibition of CRC cells. Moreover, Ziyu II synergistically suppresses CRC cell growth with the first-line chemotherapeutic drugs 5-fluorouracil. Together, our findings elucidated the mechanisms of Ziyu II-induced growth inhibition of CRC cell by orchestrating both apoptosis and autophagy, which may pave the way for the use of Ziyu II in clinic treatment of CRC.