Reactive oxygen species-mediated activation of the Akt/ASK1/p38 signaling cascade and p21Cip1 downregulation are required for shikonin-induced apoptosis

Ahn, Junho; Won, Misun; Choi, Jeong-Hae; Kim, Yong‐Sung; Jung, Cho-Rock; Im, Dong-Su; Kyun, Mi-Lang; Lee, Kyeong; Song, Kyung‐Bin; Chung, Kyung‐Sook

doi:10.1007/s10495-013-0835-5

Cited by 60 publications

(45 citation statements)

References 48 publications

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“…In the human gastric cancer cell line AGS, shikonin induces apoptosis through the inhibition of PI3K/Akt and ERK activities and the augmentation of p38 activity [45]. In the cervical cancer cell line HeLa, the colon cancer cell line Hct116, the lung cancer cell line A549, and the hepatocellular carcinoma cell lines Hep3B, BEL7402, and Huh7, shikonin increases ROS production, inactivates PI3K/Akt, and subsequently promotes apoptosis [46,47]. Shikonin promotes glucose transporter 4 translocation into the plasma membrane via the PI3K/Akt pathway [48].…”

Section: Discussionmentioning

confidence: 99%

Shikonin inhibits oxidized LDL-induced monocyte adhesion by suppressing NFκB activation via up-regulation of PI3K/Akt/Nrf2-dependent antioxidation in EA.hy926 endothelial cells

Huang

Lin

Yang

et al. 2015

Biochemical Pharmacology

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Section: Discussionmentioning

confidence: 99%

Shikonin inhibits oxidized LDL-induced monocyte adhesion by suppressing NFκB activation via up-regulation of PI3K/Akt/Nrf2-dependent antioxidation in EA.hy926 endothelial cells

Huang

Lin

Yang

et al. 2015

Biochemical Pharmacology

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“…Inhibition of angiogenesis and migration by fenofibrate was related to the decreased Akt [43,44]. Akt activation might either inhibit apoptosis by phosphorylation of Bad [45], or lead to cell cycle arrest by down-regulation of p27/Kip1 [46] and p21 [47]. Inhibition of PI3K activity, leading to inhibition of Akt, induced G0/G1 phase cell cycle arrest accompanied by the decreased expressions of Cyclin D1 and Cdk4 [48].…”

Section: Discussionmentioning

confidence: 99%

Fenofibrate induces apoptosis of triple-negative breast cancer cells via activation of NF-κB pathway

Zhang

et al. 2014

BMC Cancer

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BackgroundThere are a lot of unmet needs in patients with triple-negative breast cancer (TNBC). Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, has been used for decades to treat hypertriglyceridaemia and mixed dyslipidaemia. Recent studies show that it might have anti-tumor effects, however, the mechanism remains unclear. Here, we assessed the ability of fenofibrate to induce apoptosis of TNBC in vitro and in vivo and explored involved mechanisms.MethodsMTT method was used to evaluate the anti-proliferation effect of fenofibrate, and invert microscope to observe the apoptotic morphological changes. The percentage of apoptotic cells and distribution ratios of cell cycle were determined by flow cytometric analysis. The related protein levels were measured by Western blot method. The changes of genes and pathways were detected by gene expression profiling. The tumor growth in vivo was assessed by MDA-MB-231 xenograft mouse model. Terminal deoxytransferase-catalyzed DNA nick-end labeling (TUNEL) assay was employed to estimate the percentage of apoptotic cells in vivo. In order to evaluate the safety of fenofibrate, blood sampled from rat eyes was detected.ResultsWe found that fenofibrate had anti-proliferation effects on breast cancer cell lines, of which the first five most sensitive ones were all TNBC cell lines. Its induction of apoptosis was independent on PPAR-α status with the highest apoptosis percentage of 41.8 ± 8.8%, and it occurred in a time- and dose-dependent manner accompanied by up-regulation of Bad, down-regulation of Bcl-xl, Survivin and activation of caspase-3. Interestingly, activation of NF-κB pathway played an important role in the induction of apoptosis by fenofibtate and the effect could be almost totally blocked by a NF-κB specific inhibitor, pyrrolidine dithiocarbamate (PDTC). In addition, fenofibrate led to cell cycle arrest at G0/G1 phase accompanied by down-regulation of Cyclin D1, Cdk4 and up-regulation of p21, p27/Kip1. In vivo, fenofibrate slowed down tumor growth and induced apoptosis with a good safety profile in the MDA-MB-231 xengograft mouse model.ConclusionsIt is concluded that fenofibrate induces apoptosis of TNBC via activation of NF-κB pathway in a PPAR-α independent way, and may serve as a novel therapeutic drug for TNBC therapy.

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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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Reactive oxygen species-mediated activation of the Akt/ASK1/p38 signaling cascade and p21Cip1 downregulation are required for shikonin-induced apoptosis

Cited by 60 publications

References 48 publications

Shikonin inhibits oxidized LDL-induced monocyte adhesion by suppressing NFκB activation via up-regulation of PI3K/Akt/Nrf2-dependent antioxidation in EA.hy926 endothelial cells

Shikonin inhibits oxidized LDL-induced monocyte adhesion by suppressing NFκB activation via up-regulation of PI3K/Akt/Nrf2-dependent antioxidation in EA.hy926 endothelial cells

Fenofibrate induces apoptosis of triple-negative breast cancer cells via activation of NF-κB pathway

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

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