Deoxyshikonin isolated from Arnebia euchroma inhibits colorectal cancer by down-regulating the PI3K/Akt/mTOR pathway

Abstract

Context: Shikonins, a series of natural occurring naphthoquinones extracted from Arnebia euchroma (Royle) Jonst. (Boraginaceae), have antitumor activities and low toxicity. Objective: To illuminate potential activity and mechanism of shikonins against colorectal cancer (CRC). Materials and methods: Five shikonins were isolated from A. euchroma , and elucidated by extensive spectroscopic analysis. Anti-proliferative activities of shikonins (0–100 μg/mL) on human colorectal cells were evaluated by MTT and CCK-8 for 24 or 48 h. Cell apoptosis and cycle distribution were examined by FCM analysis. The expression of PI3K/Akt/mTOR pathway mRNAs and proteins was analysed by RT-PCR and Western blot, respectively. Cell viability, cell apoptosis, cell cycle and protein expression were measured, when co-treated with PI3K/Akt/mTOR pathway inhibitors. The in vivo activity of deoxyshikonin was evaluated using xenograft tumour model. Results: Deoxyshikonin and another four shikonins were isolated and identified. Deoxyshikonin exhibited anti-proliferative activity with IC 50 of 10.97 μM against HT29 cells. Moreover, the percentage of early apoptotic cells and G0/G1 cells increased from 1 to 29% and 44 to 67% with 0–50 μg/mL deoxyshikonin, respectively. Deoxyshikonin also down-regulated the expression of PI3K, p-PI3K, Akt, p-Akt308 and mTOR proteins in HT29 and DLD-1 cells. Moreover, LY294002, NVP-BEZ235 and MK-2206 can make deoxyshikonin more cell proliferation inhibited, cell cycle arrested at G0/G1 and apoptosis promoted. In vivo study, the weight of tumour tissues at deoxyshikonin groups was significantly reduced compared with the control group, and PI3K, p-PI3K, Akt, p-Akt308 and mTOR expression was decreased. Discussion and conclusions: We can conclude that deoxyshikonin isolated from Arnebia euchroma inhibited CRC through the PI3K/Akt/mTOR pathway.

Discovery of natural products capable of inducing porcine host defense peptide gene expression using cell-based high throughput screening

“…Deoxyshikonin is found in Lithospermum erythrorhizon and a promising drug candidate for the treatment of wounds and cancers [ 41 , 42 ]. Deoxyshikonin is a derivative of shikonin, which is a well-known traditional Chinese medicine that has long been used for the treatment of burns, external wounds, infected crusts, and hemorrhoids owing to its numerous pharmacological properties [ 43 , 44 ].…”

Deoxyshikonin Inhibits Viability and Glycolysis by Suppressing the Akt/mTOR Pathway in Acute Myeloid Leukemia Cells

“…Acetylshikonin, another shikonin derivative, significantly inhibited the anchorage-independent growth of pancreatic cancer cells by suppressing the nuclear factor-kappa B signaling pathway ( 27 ). More importantly, it was previously demonstrated that deoxyshikonin exhibited anti-proliferative and pro-apoptotic activities in colorectal cancer cells through the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway ( 10 ). Nevertheless, whether deoxyshikonin showed an anti-tumor activity in AML remained far from being addressed.…”

“…An increasing number of researches reveal that shikonin derivatives have garnered much research interest due to its limited toxicity and stronger anti-tumor activities in miscellaneous cancers ( 9 ). Interestingly, a previous investigation proved that deoxyshikonin (its chemical structure is shown in Figure 1 ), a derivative of shikonin, exhibited an anti-tumor effect in colorectal cancer ( 10 ). However, no studies are available to illustrate the effect of deoxyshikonin on AML.…”

Shikonin Derivatives from Onsoma visianii Decrease Expression of Phosphorylated STAT3 in Leukemia Cells and Exert Antitumor Activity

“…We have shown that both derivatives increased the percentage of JVM-13 cells in the G0/G1 phase ( Figure 4 b), while the percentage of BCL1 cells in the G0/G1 phase was increased after MBS treatment ( Figure 4 a). Cyclin D3 binds to CDK4 and CDK6 and plays a role as the initial activator of the G1 phase [ 28 , 29 , 30 , 31 ]. In line with this, MBS treatment induced a decrease in the mRNA level of cyclin D3 in BCL1 cells ( Figure 4 c) and the percentage of cyclin D3 expressing JVM-13 ( Figure 4 d) but significantly enhanced the expression of the protein level of the inhibitor of cyclin D–CDK4/CDK6 complex, p16 [ 28 ], the universal cyclin-CDK inhibitor, p21 [ 29 ], and the inhibitor of cyclin E-CDK2, cyclin A-CDK2, and cyclin D-CDK4 complexes, p27 [ 30 ], in BCL1 cells ( Figure 4 e).…”