Abstract
Background: Acetylshikonin, a major constituent isolated from Arnebia euchroma, is a potential candidate for anti-colorectal cancer drugs. However, the potential activity and underlying mechanism of Acetylshikonin against colorectal cancer remain unclear. Methods: In this study, Acetylshikonin was isolated from the active CHCl3 extract of Arnebia euchroma using activity-guided screening, and elucidated by the extensive spectroscopic analysis and comparison with literature data. Human colorectal cancer cells HT29, DLD-1, HCT116 or Caco-2 were exposed to different concentrations of Acetylshikonin (6.25 - 100 μg/mL) for 24 or 48 h. Cell viability, cell apoptosis and cell cycle distribution were detected. The activity of Acetylshikonin and potential mechanism of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway were evaluated in vitro and vivo. Results: We found that Acetylshikonin exhibited remarkable anti-proliferative activity in a dose-dependent manner against HT29 cells with the IC50 values of 60.82 μg/ml and 30.78 μg/ml at 24, 48 h, respectively. Moreover, Acetylshikonin induced cell cycle arrest at G0/G1 phase and early apoptosis through inhibition of PI3K/Akt/mTOR pathway. Furthermore, the assays of cell inhibition, early apoptosis and G0/G1 phase distribution showed that suppression of the PI3K/Akt pathway using LY294002 enhanced the anti-cancer effect of Acetylshikonin. Similarly, Acetylshikonin also decreased the growth of tumour in colorectal cancer xenografts in mice through PI3K/Akt/mTOR pathway. Conclusions: To sum up, these new findings provided a framework for further exploration of Acetylshikonin which possessed the potential antitumor activity by inhibiting PI3K/Akt/mTOR pathway.
Highlights
Acetylshikonin, a major constituent isolated from Arnebia euchroma, is a potential candidate for anti-colorectal cancer drugs
Human colorectal cancer cells including Caco-2, HCT116, DLD-1 and HT29 were treated with Acetylshikonin for 48 h, and cell proliferation analysis was conducted by Cell Counting Kit-8
These results suggest that Acetylshikonin inhibits the growth of colorectal cancer cells in vitro
Summary
Acetylshikonin, a major constituent isolated from Arnebia euchroma, is a potential candidate for anti-colorectal cancer drugs. The potential activity and underlying mechanism of Acetylshikonin against colorectal cancer remain unclear. The activity of Acetylshikonin and potential mechanism of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway were evaluated in vitro and vivo. Acetylshikonin induced cell cycle arrest at G0/G1 phase and early apoptosis through inhibition of PI3K/Akt/mTOR pathway. Chemotherapy is a common therapeutic strategy after surgery, and the marketed chemotherapy drugs kill tumour cells through competitive inhibition of nucleotide synthesis or cytotoxicity. These drugs often cause vomiting, myelosuppression, drug resistance and other adverse effects [2]. Shikonin derivatives have strong anti-tumour activities with few adverse effects, which make shikonin derivatives as promising anti-tumour agents [8]
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