Discussion and Conclusions
Ziyu II is one of the major active components of S. officinalis L . Previous studies have demonstrated the anticancer effect of Ziyu II in a variety of cancer types. In the present study, we demonstrated its anticancer effect against CRC cells both in vitro and in vivo . We showed that ROS-induced apoptosis and the autophagy induced by the inhibition of Akt/mTOR signaling both contribute to the growth inhibition of Ziyu II against CRC cells. In addition, Ziyu II acts synergistically with the first-line chemotherapeutic drugs 5-fluorouracil in the suppression of CRC cell growth, suggesting Ziyu II as a potential anticancer drug or chemosensitizer for CRC treatment.
One of the key points in the development of anti-cancer drugs is to find active ingredients from natural substances. At present, a large number of studies have shown that TCM is a kind of multi-target anti-cancer drug by inhibiting cell proliferation, causing cell cycle arrest, promoting cell apoptosis, inhibiting neovascularization, and blocking invasion and metastasis of tumors [31-33]. S. officinalis L. is a popular traditional Chinese medicinal plant used in the treatment of inflammation, metabolic diseases and various cancers. Ziyu II is one of the major active components of S. officinalis L . Until now, anticancer effects of Ziyu II have been reported in human breast and gastric cancer and the detailed underlying mechanisms are different. Ziyu II can effectively induce G2/M phase arrest and apoptosis in MCF-7 and MDA-MB-231 human breast cells [20,21]. In addition to several breast cancer cells, Ziyu II exerts anticancer activity by inducing apoptosis or antiangiogenic, but not cell cycle arrest, in BGC-823 human gastric carcinoma cells [22]. Thus, the action of Ziyu II on cancer cells might appear differently dependent on cell types. To provide clarity, we investigated the anticancer effects of Ziyu II on colorectal cancer cells. In this study, the molecular mechanism of anti-cancer effect of Ziyu II in CRC cells is inducing both apoptosis and autophagy.
Drug repurposing has been recognized as an attractive strategy to offer more-effective options to patients with cancer, and has the substantial advantages of cheaper, faster and safer than de novo drug development [34]. Previous studies have demonstrated that many types of TCM have been identified as potential anticancer drugs via drug repurposing screen. For example, Shikonin is a medicinal compound extracted from Lithospermum erythrorhizon , an herb which has been used for centuries in Chinese medicine for the treatment of burns, cuts, and lesions caused by disease [35]. Growing evidence has demonstrated Shikonin as potential anticancer drug or chemosensitizer via inducing apoptosis and necroptosis [36, 37]. Our previous works have also identified several natural compounds which exhibit potential anticancer activities [38 -40]. Among these candidates, Ziyu II, a major active component of S. officinalis L used for anti-inflammation and anti-oxidation, has been found to suppress CRC growth by apoptosis and autophagy in the present study, further highlighting the important role of drug repurposing in cancer drug development.
Apoptosis and autophagy are involved in the physiological process of cells such as growth, differentiation, death and also closely related to the development of tumor [41,42]. The machinery of apoptosis and autophagy are quite complex, with many signaling pathways involved. Apoptosis can be triggered by multiple factors including ROS [43]. Meanwhile, CRC is characterized by partially inhibited apoptosis, which in turn provides a selective advantage for the survival of tumors and becomes a major obstacle to treatment [44]. In the same way, numerous evidences have suggested that many signaling pathways are involved in the regulation of autophagy, and Akt-mTOR is one of the most classical signaling pathways that negatively regulate autophagy. In the present study, we investigated the anti-cancer effect of Ziyu II in CRC cells both in vitro and in vivo . Interestingly, we found that Ziyu II induced apoptosis and autophagy through the different pathway in CRC cells. Ziyu II-induced apoptosis is caused by excessive accumulation of ROS. While Ziyu II induced autophagy through inhibition of Akt/mTOR signaling pathway as evidenced by decreased phosphorylation of Akt, mTOR and downstream substrates. Overall, our findings suggest that targeting the Akt/mTOR signaling pathway may deserve exploration as a potential therapeutic strategy for CRC treatment.
In summary, our current findings demonstrate that the Chinese herbal medicine extract-Ziyu II inhibits colorectal cancer growth by orchestrating Akt/mTOR-mediated autophagic cell death and ROS-induced apoptosis. These findings provide new insights into the mechanisms of Ziyu II induced colorectal cancer suppression and support the rational utility of Ziyu II for therapeutic treatment of colorectal cancer.