Shikonin Induces Apoptosis through Reactive Oxygen Species/Extracellular Signal-Regulated Kinase Pathway in Osteosarcoma Cells

Chang, I-Chang; Huang, Yen-Hsiang; Chiang, Tsay-I; Yeh, Chi-Wei; Hsu, Li‐Sung

doi:10.1248/bpb.33.816

Cited by 89 publications

(74 citation statements)

References 34 publications

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“…Shikonin is also reported to influence apoptosis to some extent (Chang et al 2010;Liu et al 2014) and can regulate the AKT/ASK1/p38 pathway or reactive oxygen species levels to induce apoptosis (Ahn et al 2013;Duan et al 2014;Lee et al 2014). Our study revealed that a low concentration of shikonin has no apparent effect on apoptosis, but in the presence of TNF-␣, shikonin induces apoptosis in a concentrationdependent manner, promotes the activation of caspase-3 and (G, H) The expression levels of cyclin D1 and cyclin E were measured by Western blot after treatment with different concentrations of shikonin and TNF-␣.…”

Section: Discussionmentioning

confidence: 99%

Shikonin inhibits TNF-α-induced growth and invasion of rat aortic vascular smooth muscle cells

Zhang

et al. 2015

Can. J. Physiol. Pharmacol.

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Shikonin is a naphthoquinone compound extracted from the Chinese herb purple gromwell. Shikonin has broad antibacterial, anti-inflammatory, and antitumor activities. The tumor necrosis factor-α (TNF-α)-induced proliferation and invasion of vascular smooth muscle cells (VSMCs) is an important factor that contributes to atherosclerosis. The effects of shikonin on the proliferation and apoptosis of VSMCs have been reported; however, the function of shikonin on TNF-α-mediated growth and invasion of VSMCs during atherosclerosis remains unclear. In this study, we used Western blot, flow cytometry, real-time quantitative PCR, and enzyme-linked immunosorbent assay to investigate the effect of shikonin on the TNF-α-induced growth and invasion of VSMCs and to determine the underlying mechanism. Our results showed that shikonin inhibits the TNF-α-mediated growth and invasion. Further study revealed that shikonin regulates the activation of nuclear factor kappa B and phosphatidyl inositol 3-kinase signaling pathways; modulates the expression of cyclin D1, cyclin E, B-cell lymphoma 2, and Bax; activates caspase-3 and caspase-9; induces cell cycle arrest; and promotes the apoptosis of VSMCs. Together, our results indicate that shikonin may become a promising agent for the treatment of atherosclerosis and they also establish foundation for the development of anti-atherosclerosis drugs.

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Section: Discussionmentioning

confidence: 99%

Shikonin inhibits TNF-α-induced growth and invasion of rat aortic vascular smooth muscle cells

Zhang

et al. 2015

Can. J. Physiol. Pharmacol.

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“…In general, ERK-mediated growth factors enhance cell proliferation, whereas JNK and p38 kinases transduce signals from stress and inflammation to promote apoptosis (26). Flavonoid-triggered cancer cells undergo apoptosis through the modulation of MAPK protein kinases (27)(28)(29). Epigallocatechin-3-gallate (EGCG) inhibits ERK activation and increases p38 kinases and JNK activity, which subsequently enhances apoptosis in pancreatic cancer cells (30).…”

Section: Discussionmentioning

confidence: 99%

Butein inhibits the proliferation of breast cancer cells through generation of reactive oxygen species and modulation of ERK and p38 activities

Yang

Lin

et al. 2012

Molecular Medicine Reports

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Butein (3,4,2',4'-tetrahydroxychalcone) is a polyphenol derived from various natural plants and is capable of inducing several types of death in cancer cells. However, the molecular mechanisms underlying butein-induced breast cancer cell apoptosis remain unknown. The present study aimed to prove that butein inhibits the proliferation of MDA-MB‑231 human breast cancer cells in a dose- and time-dependent manner. Butein markedly induced the generation of reactive oxygen species (ROS), decreased the phosphorylation of extracellular signal-regulated kinase (ERK), increased p38 activity, diminished Bcl-2 expression, induced caspase 3 cleavage and was associated with poly(ADP-ribose) polymerase (PARP) cleavage. Our findings also indicate that ROS may play an important role in butein-induced apoptosis, as pre-treatment with the antioxidant, N-acetyl cysteine (NAC), prevented butein-induced apoptosis. In conclusion, our results demonstrate that butein inhibits the proliferation of breast cancer cells through the generation of ROS and the modulation of ERK and p38 activities. We also demonstrate that these effects may be abrogaged by pre-treatment with NAC. Our results suggest that butein may function as a potential therapeutic agent for the treatment of breast cancer.

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“…The anticancer effects of SHK have been investigated in numerous prior studies (18)(19)(20)(21)(22)(23)(24). SHK is not toxic to normal cells (25), but exerts cytotoxic effects against various neoplastic cells, and has not been demonstrated to promote anticancer drug resistance (26).…”

Section: Introductionmentioning

confidence: 99%

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

Liu¹,

Sun²

2017

Oncology Letters

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Abstract. Shikonin (SHK) is a natural naphthoquinone pigment isolated from Lithospermum erythrorhizon, that has been reported to suppress the growth of a number of cancer cell types. Adriamycin (AD) is typically used as an effective anticancer agent; however, it has the propensity to induce drug resistance. The aim of the present study was to investigate the effects of SHK alone and in combination with AD on lung adenocarcinoma cells and the underlying molecular mechanisms of their effects. Colony formation, MTT and propidium iodide staining assays demonstrated that the co-treatment of A549 cells with SHK and AD significantly decreased cell viability and potently induced apoptosis. The mitochondrial membrane potential was assessed using 5,5', 6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide staining and fluorescence microscopy. Cells co-treated with SHK and AD exhibited marked mitochondrial membrane damage. In addition, co-treatment with SHK and AD significantly reduced ATP levels in A549 cells compared with the control. Western blot analysis revealed that SHK enhanced the antitumor effects of AD by inhibiting the expression of ATP-binding cassette transporters. These results suggest that the inhibition of glycolysis could be an effective approach for lung cancer treatment. Therefore, SHK has the potential to be used as an anticancer agent in the treatment of lung adenocarcinoma, and thus warrants further investigation and development.

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Shikonin Induces Apoptosis through Reactive Oxygen Species/Extracellular Signal-Regulated Kinase Pathway in Osteosarcoma Cells

Cited by 89 publications

References 34 publications

Shikonin inhibits TNF-α-induced growth and invasion of rat aortic vascular smooth muscle cells

Shikonin inhibits TNF-α-induced growth and invasion of rat aortic vascular smooth muscle cells

Butein inhibits the proliferation of breast cancer cells through generation of reactive oxygen species and modulation of ERK and p38 activities

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

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