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.