Kaempferol Induces Cell Death Through ERK and Akt-Dependent Down-Regulation of XIAP and Survivin in Human Glioma Cells

Jeong, Ji Cheon; Kim, Min Soo; Kim, Thae Hyun; Kim, Yong Keun

doi:10.1007/s11064-008-9868-5

Cited by 82 publications

(63 citation statements)

References 59 publications

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“…We previously observed that flavonoids such as silibinin and kaempferol induce cell death through ROS generation (14,15). Similarly, the LCR extract in the present study increased ROS generation and the LCR extract-induced cell death was prevented by antioxidants ( Fig.…”

Section: Discussionsupporting

confidence: 77%

“…Activation of ERK is inhibited by flavonoids in vascular smooth muscle cells (34), human epidermal carcinoma cells (35), and neuronal cells (36), whereas it is increased following flavonoid treatment in lung cancer cells (37). Previously, we observed that ERK is activated by silibinin (15) and inhibited by kaempferol (14) in human glioma cells. These studies suggest that the effect of flavonoids on ERK activation may be dependent on cell types and flavonoid structures.…”

Section: Discussionmentioning

confidence: 93%

“…Previous studies have shown that the LCR extract improves insulin resistance and lipid metabolism in obesediabetic rats (10). Since it has been known that LCR contains a variety of physiologically active compounds such as apigenin, luteolin, kaempferol, quercetin, oleanolic acid, and urosolic acid (11,12) which may have anticancer activities (13)(14)(15), LCR may exert an inhibitory effect on tumor growth. However, little information is available regarding the effect of LCR on cancer cell growth.…”

Section: Introductionmentioning

confidence: 99%

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Lycii cortex radicis extract inhibits glioma tumor growth in vitro and in vivo through downregulation of the Akt/ERK pathway

Jeong

Kim²,

Kim³

et al. 2012

Oncol Rep

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Abstract. Lycii cortex radicis (LCR) is a traditional Korean medicinal herb. The present study was undertaken to examine the effect of an LCR extract on glioma cell growth and to determine its molecular mechanism in U87MG human glioma cells. The LCR extract resulted in apoptotic cell death in a dose-and time-dependent manner. The LCR extract-induced cell death was associated with generation of reactive oxygen species (ROS). Western blot analysis showed that the LCR extract caused downregulation of Akt and ERK. The LCR-induced cell death was prevented by transfection with the constitutively active forms of Akt and MEK. Oral administration of LCR extracts in subcutaneous U87MG xenograft models reduced glioma tumor volume. Taken together, these findings suggest that the LCR extract results in human glioma cell death through mechanisms involving ROS generation, downregulation of Akt and ERK, and caspase activation in vitro and reduces glioma tumor growth in vivo. These data suggest that the LCR extract may serve as a potential therapeutic agent for malignant human glioblastomas.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Lycii cortex radicis extract inhibits glioma tumor growth in vitro and in vivo through downregulation of the Akt/ERK pathway

Jeong

Kim²,

Kim³

et al. 2012

Oncol Rep

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“…On the other hand, ROS can trigger downregulation of the ERK and Akt pathway (Jeong et al, 2009). In the present study, silibinin-induced inhibition of ERK and Akt was blocked by the antioxidant NAC (Fig.…”

Section: Discussionsupporting

confidence: 50%

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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“…Emerging evidence suggests that activation of ERKs contributes to apoptosis. Recent studies showed that kaempferol causes cancer cells to undergo apoptosis through an ERK-dependent pathway (24). Shikonin decreases the levels of phosphorylated EGFR, ERKs and protein tyrosine kinases and increases intracellular levels of apoptosis-related proteins, which leads to apoptosis of epidermoid carcinoma cells (25).…”

Section: Discussionmentioning

confidence: 99%

Chelidonium majus L. extract induces apoptosis through caspase activity via MAPK-independent NF-κB signaling in human epidermoid carcinoma A431 cells

Park

Kim

et al. 2014

Oncology Reports

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Abstract. Chelidonium majus L. (C. majus L.) is known to possess certain biological properties such as anti-inflammatory, antimicrobial, antiviral and antitumor activities. We investigated the effects of C. majus L. extract on human epidermoid carcinoma A431 cells through multiple mechanisms, including induction of cell cycle arrest, activation of the caspase-dependent pathway, blocking of nuclear factor-κB (NF-κB) activation and involvement in the mitogen-activated protein kinase (MAPK) pathway. C. majus L. inhibited the proliferation of A431 cells in a dose-and time-dependent manner, increased the percentage of apoptotic cells, significantly decreased the mRNA levels of cyclin D1, Bcl-2, Mcl-1 and survivin and increased p21 and Bax expression. Exposure of A431 cells to C. majus L. extract enhanced the activities of caspase-3 and caspase-9, while co-treatment with C. majus L., the pancaspase inhibitor Z-VAD-FMK and the caspase-3 inhibitor Z-DEVE-FMK increased the proliferation of A431 cells. C. majus L. extract not only inhibited NF-κB activation, but it also activated p38 MAPK and MEK/ERK signaling. Taken together, these results demonstrate that C. majus L. extract inhibits the proliferation of human epidermoid carcinoma A431 cells by inducing apoptosis through caspase activation and NF-κB inhibition via MAPK-independent pathway. IntroductionChelidonium majus is commonly known as greater celandine. It belongs to the family Papaveraceae and is widely distributed in Europe and western Asia. Extracts of Chelidonium majus L.(C. majus L.) have been shown to exhibit a variety of biological effects including anti-inflammatory, antimicrobial, antiviral and antitumor activities (1,2). The antitumor, antigenotoxic and hepatoprotective effects of C. majus L. extract suggest that it may be potentially useful as an anticancer therapeutic agent (3).Apoptosis is mediated through at least 3 major pathways, which are regulated by death receptors, mitochondria and the endoplasmic reticulum. Activation of the apoptosis pathway is a key mechanism by which cytotoxic drugs kill tumor cells. Defects in apoptosis signaling contribute to the drug resistance of tumor cells (4,5). The Bcl-2 family consists of important apoptotic regulators of programmed cell death. This family of proteins includes both anti-apoptotic molecules such as Bcl-2 and pro-apoptotic molecules such as Bax (6). Bcl-2 and Bcl-X L are members of the Bcl-2 family and are regulated by nuclear factor-(NF)-κB. These proteins can prevent release of cytochrome c and activation of caspases (7).Mitogen-activated protein kinase (MAPK) cascades are involved in the signaling pathways that regulate various cellular responses such as inflammation, proliferation and cell death (8). Three major mammalian MAPK subfamilies have been described: extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases and p38 kinases. Each MAPK is activated through a specific phosphorylation cascade (9,10). The ERK cascade is activated through receptor-mediated signaling stimuli and is...

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Kaempferol Induces Cell Death Through ERK and Akt-Dependent Down-Regulation of XIAP and Survivin in Human Glioma Cells

Cited by 82 publications

References 59 publications

Lycii cortex radicis extract inhibits glioma tumor growth in vitro and in vivo through downregulation of the Akt/ERK pathway

Lycii cortex radicis extract inhibits glioma tumor growth in vitro and in vivo through downregulation of the Akt/ERK pathway

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

Chelidonium majus L. extract induces apoptosis through caspase activity via MAPK-independent NF-κB signaling in human epidermoid carcinoma A431 cells

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