Silibinin Inhibits Tumor Growth through Downregulation of Extracellular Signal-Regulated Kinase and Akt <i>in Vitro</i> and <i>in Vivo</i> in Human Ovarian Cancer Cells

Cho, Hyun Jin; Suh, Dong Soo; Moon, Soo Hyeon; Song, Yong Jung; Yoon, Man Soo; Park, Do Yoon; Choi, Kyung Un; Kim, Yong Keun; Kim, Ki Hyung

doi:10.1021/jf400192v

Cited by 35 publications

(36 citation statements)

References 39 publications

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“…The Akt signaling pathway also played a pivotal role in cell proliferation and cell apoptosis by transferring the signals to prevent apoptosis [37], [38]. Huang et al reported that the abnormalities of Akt signaling in ovarian cancer may be used to predict patient outcomes [39].…”

Section: Resultsmentioning

confidence: 99%

Synergistic Apoptosis-Inducing Effects on A375 Human Melanoma Cells of Natural Borneol and Curcumin

Chen

et al. 2014

PLoS ONE

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This study was to investigate the synergistic effect of NB/Cur on growth and apoptosis in A375 human melanoma cell line by MTT assay, flow cytometry and Western blotting. Our results demonstrated that NB effectively synergized with Cur to enhance its antiproliferative activity on A375 human melanoma cells by induction of apoptosis, as evidenced by an increase in sub-G1 cell population, DNA fragmentation, PARP cleavage and caspase activation. Further mechanistic studies by Western blotting showed that after treatment of the cells with NB/Cur, up-regulation of the expression level of phosphorylated JNK and down-regulation of the expression level of phosphorylated ERK and Akt contributed to A375 cells apoptosis. Moreover, NB also potentiated Cur to trigger intracellular ROS overproduction and the DNA damage with up-regulation of the expression level of phosphorylated ATM, phosphorylated Brca1 and phosphorylated p53. The results indicate the combinational application potential of NB and Cur in treatments of cancers.

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Section: Resultsmentioning

confidence: 99%

Synergistic Apoptosis-Inducing Effects on A375 Human Melanoma Cells of Natural Borneol and Curcumin

Chen

et al. 2014

PLoS ONE

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“…Our previous studies have shown that downregulation of ERK and Akt is involved in flavonoid-induced apoptosis in various cancer cells (Jeong et al, 2009;Cho et al, 2013). However, the underlying mechanism of such a downregulation of kinases remains unclear.…”

Section: Discussionmentioning

confidence: 98%

Silibinin Induces Cell Death through Reactive Oxygen Species–Dependent Downregulation of Notch-1/ERK/Akt Signaling in Human Breast Cancer Cells

Kim

Woo

Kim

et al. 2014

J Pharmacol Exp Ther

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The present study was undertaken to determine the underlying mechanism of silibinin-induced cell death in human breast cancer cell lines MCF7 and MDA-MB-231. Silibinin-induced cell death was attenuated by antioxidants, N-acetylcysteine (NAC) and 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid, suggesting that the effect of silibinin was dependent on generation of reactive oxygen species (ROS). Western blot analysis showed that silibinin induced downregulation of extracellular signal-regulated kinase (ERK) and Akt. When cells were transiently transfected with constitutively active (ca) mitogen-activated protein kinase (MEK), an upstream kinase of ERK and caAkt, they showed resistance to silibinin-induced cell death. Silibinin decreased the cleavage of Notch-1 mRNA and protein levels. Notch-1-overexpressed cells were resistant to the silibinin-induced cell death. Inhibition of Notch-1 signaling was dependent on ROS generation. Overexpression of Notch-1 prevented silibinin-induced inhibition of ERK and Akt phosphorylation. Silibinin-induced cell death was accompanied by increased cleavage of caspase-3 and was prevented by caspase-3 inhibitor in MDA-MB-231 cells but not in MCF7 cells. Silibinin induced translocation of apoptosisinducing factor (AIF), which was blocked by NAC, and transfection of caMEK and caAkt. Silibinin-induced cell death was prevented by silencing of AIF expression using small interfering AIF RNA in MCF7 cells but not in MDA-MB-231 cells. In conclusion, silibinin induces cell death through an AIF-dependent mechanism in MCF7 cells and a caspase-3-dependent mechanism in MDA-MB-231 cells, and ROS generation and Notch-1 signaling act upstream of the ERK and Akt pathway. These data suggest that silibinin may serve as a potential agent for induction of apoptosis in human breast cancer cells.

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“…Several types of flavonoids have been identified as having antiproliferative efficacy in various cancers, including silymarin, genistein, quercetin, daidzein, luteolin, kaempferol, apigenin, and epigallocatechin 3-gallate [11, 12]. These aforementioned compounds have been reported to have anticancer and preventive effects against prostate [13], colorectal [14], breast [15], thyroid [16], lung [17], and ovarian [18] cancers, among others [19–21]. Their chemopreventive efficacy is mediated by (1) inhibiting the development of new cancer cells; (2) preventing carcinogens from reaching their activation sites; and (3) decreasing the toxicity of certain compounds by inhibiting their metabolism [22–24].…”

Section: Flavonoids In Cancer Chemopreventionmentioning

confidence: 99%

Cancer chemoprevention through dietary flavonoids: what’s limiting?

2017

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Flavonoids are polyphenols that are found in numerous edible plant species. Data obtained from preclinical and clinical studies suggest that specific flavonoids are chemo-preventive and cytotoxic against various cancers via a multitude of mechanisms. However, the clinical use of flavonoids is limited due to challenges associated with their effective use, including (1) the isolation and purification of flavonoids from their natural resources; (2) demonstration of the effects of flavonoids in reducing the risk of certain cancer, in tandem with the cost and time needed for epidemiological studies, and (3) numerous pharmacokinetic challenges (e.g., bioavailability, drug–drug interactions, and metabolic instability). Currently, numerous approaches are being used to surmount some of these challenges, thereby increasing the likelihood of flavonoids being used as chemo-preventive drugs in the clinic. In this review, we summarize the most important challenges and efforts that are being made to surmount these challenges.

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Silibinin Inhibits Tumor Growth through Downregulation of Extracellular Signal-Regulated Kinase and Akt in Vitro and in Vivo in Human Ovarian Cancer Cells

Cited by 35 publications

References 39 publications

Synergistic Apoptosis-Inducing Effects on A375 Human Melanoma Cells of Natural Borneol and Curcumin

Synergistic Apoptosis-Inducing Effects on A375 Human Melanoma Cells of Natural Borneol and Curcumin

Silibinin Induces Cell Death through Reactive Oxygen Species–Dependent Downregulation of Notch-1/ERK/Akt Signaling in Human Breast Cancer Cells

Cancer chemoprevention through dietary flavonoids: what’s limiting?

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