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.