Emodin inhibits growth and induces apoptosis in an orthotopic hepatocellular carcinoma model by blocking activation of <scp>STAT3</scp>

Subramaniam, Aruljothi; Shanmugam, Muthu K.; Ong, Tina H.; Li, Feng; Perumal, Ekambaram; Chen, Luxi; Vali, Shireen; Abbasi, Taher; Kapoor, Shweta; Ahn, Kwang Seok; Kumar, Alan Prem; Hui, Kam M.; Sethi, Gautam

doi:10.1111/bph.12302

Cited by 134 publications

(99 citation statements)

References 43 publications

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“…The given doses of emodin were similar with others demonstrating the significant effects in the inhibition of other cancer types [30, 59]. More experiments are required to further determine the critical role of IGFBP1 in this process using cells stable transfected with shRNA and exogenously expression vector of IGFBP1 in nude mice model.…”

Section: Discussionsupporting

confidence: 81%

“…Luciferase-expressing A549 cells were injected subcutaneously in nude mice. Mice bearing xenografted lung tumors were treated with control or emodin [30] via intraperitoneal injection for up to 30 days, followed by intraperitoneal injection of D-luciferin. We showed that, compared to the control group, the high dose (50 mg/kg) emodin-treated mice demonstrated a significant growth-inhibitory effect as assessed by the Xenogen IVIS200 System (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Xenografts were allowed to grow for over one week when the initial measurement was made with calipers. Mice were randomly divided into control, low (25 g/kg) and high doses (50 g/kg) of emodin group [30], which given via intraperitoneal injection (once another day) for up to 30 days (n=8-10/group).…”

Section: Methodsmentioning

confidence: 99%

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Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Tang¹,

Wu²,

Zheng³

et al. 2017

Cell Physiol Biochem

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Background: Emodin has anti-neoplastic activities on multiple tumors. However, the molecular mechanisms underlying this effect still remain to be fully understood. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays and flow cytometry, respectively. Cell invasion and migration were examined by transwell invasion and wound healing assays. Western blot analysis was performed to examine the phosphorylation and protein expression of AMP-activated protein kinase alpha (AMPKα), extracellular signaling-regulated kinase 1/2 (ERK1/2), peroxisome proliferators-activated receptor gamma (PPARγ), insulin-like growth factor (IGF) binding protein 1 (IGFBP1) and the transcription factor Sp1. QRT-PCR was used to examine the mRNA levels of the IGFBP1 gene. Small interfering RNAs (siRNAs) were used to knockdown PPARγ and IGFBP1 genes. Exogenously expression of IGFBP1 and Sp1 was determined by transient transfection assays. IGFBP1 promoter activity was measured by Secrete-Pair Dual Luminescence Assay Kit. In vivo nude mice xenograft model and bioluminescent imaging system were used to confirm the findings. Results: We showed that emodin induced cell cycle arrest of NSCLC cells. Emodin increased PPARγ protein and luciferase reporter activity, which were abolished by inhibitors of MAPK extracellular signaling-regulated kinase (ERK) kinase (MEK)/ERK and AMPK. Silencing of PPARγ abrogated emodin-inhibited cell growth and cell cycle arrest. Furthermore, emodin elevated IGFBP1 mRNA, protein, and promoter activity through activation of PPARγ. Intriguingly, overexpressed Sp1 attenuated emodin-induced IGFBP1 expression, which was not observed in cells with silenced PPARγ gene. Moreover, silencing of IGFBP1 gene blunted emodin-induced inhibition of cell growth and cell cycle arrest. On the contrary, overexpressed IGFBP1 enhanced emodin-induced phosphorylation of AMPKα and ERK1/2, and restored emodin-inhibited growth in cells with silenced endogenous IGFBP1 gene. Emodin also inhibited growth of lung xenograft tumors and Sp1, and increased IGFBP1 and PPARγ protein expressions In vivo. Conclusion: Collectively, our results show that emodin inhibits growth of non-small-cell lung cancer (NSCLC) cells through ERK and AMPKα-mediated induction of PPARγ, followed by reduction of Sp1. This in turn induces IGFBP1 gene expression. Thus, the signaling cascades, positive feedback loop and cooperative interplay between transcription factors-induced the expression of IGFBP1 gene contribute to the overall responses of emodin. This study provides a novel mechanism by which emodin inhibits growth of human lung cancer cells.

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Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

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Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Tang¹,

Wu²,

Zheng³

et al. 2017

Cell Physiol Biochem

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“…Emodin, an anthraquinone derivative from the root and rhizome of Rheum palmatum L., was found to have antitumor effects in several types of cancer by regulating multi-molecular targets involved in tumor growth, apoptosis and angiogenesis (16). Recent research demonstrated that emodin may inhibit growth and induce apoptosis in an orthotopic hepatocellular carcinoma model by blocking activation of signal transducer and activator of transcription 3 (17). It was also reported that emodin may suppresses migration and invasion through the modulation of C-X-C chemokine receptor type 4 expression in an orthotopic model of HCC (18).…”

Section: Discussionmentioning

confidence: 99%

Emodin inhibits migration and invasion of MHCC-97H human hepatocellular carcinoma cells

Lin

Zhong

Liang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Emodin, an anthraquinone derivative from the root and rhizome of Rheum palmatum L., was found to have antitumor effects in different types of cancer by regulating multi-molecular targets. The aim of the present study was to explore the effect of emodin on the migration and invasion of MHCC-97H human hepatocellular carcinoma cells and the underlying molecular mechanisms. Firstly, it was demonstrated that emodin can inhibit cell proliferation and induce apoptosis of cells in a time-and dose-dependent manner, using a MTT assay and flow cytometry, respectively. However, when emodin concentration was <50 µmol/l, it had little effect on the inhibition of proliferation or the induction of apoptosis. Then, it was observed that emodin can significantly suppress cell migration and invasion with a treatment dose <50 µmol/l compared with the control (P<0.05), which was not attributed to a decrease in cell number. Further study demonstrated that emodin significantly suppressed the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 compared with the control, which may be mediated by the activation of the p38 mitogen-activated protein kinases (MAPK) signaling pathway and suppression of extracellular signal regulated kinase (ERK)/MAPK and phosphatidylinositol 3-kinase/Akt signaling pathways. Therefore, the present study, for the first time, used MHCC-97H cells, which have the high potential of malignant invasion, to demonstrate that emodin may inhibit cell migration and invasion. IntroductionHepatocellular carcinoma (HCC) is one of the most frequent malignancies worldwide, representing the fifth most common cause of cancer in men and the seventh in women, and the third most frequent cause of cancer-related mortality (1-3). Globally, there are ~750,000 new cases of liver cancer reported per year (4). Although surgical resection provides better results in patients with HCC in early stages, the long-term prognosis remains unsatisfactory because many patients are diagnosed at the advanced stage, and tumors have an inherent capacity for invasiveness and metastasis (5,6). At present, chemotherapy is commonly used in the treatment of metastatic HCC. However, this treatment remains ineffective due to its toxicity to normal cells and the rapid development of resistance. Therefore, to further explore the biology of metastasis and develop novel therapeutics that specifically target metastasis and metastatic progression are required (7,8).Increasing attention has been paid to drugs among traditional Chinese medicines, since these materials typically share high safety profiles and can effectively prevent and control metastasis (9,10). Rheum palmatum L. is a plant that has been widely used in Chinese medicine as a laxative for thousands of years. Emodin is an anthraquinone derivative from its root and rhizome (11). It has been reported that emodin possesses a number of biological properties such as anti-inflammatory, antiviral and anti-proliferative effects (12). In the context of cancer, several studies have indicated...

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“…Around one million new cases of HCC are estimated to arise every year [3] . Conventional treatments including chemotherapeutic synthetic drugs or interferons cause serious side effects [4] . Consequently, searching for new treatments and protections especially from medicinal plants provides an unlimited source for alternative strategies to alleviate and limit the HCC severity and expansion.…”

Section: Research Papermentioning

confidence: 99%

Hepatoprotective Activities of the Methanol Extract of Angelica shikokiana and Isoepoxypteryxin against Hepatocellular Carcinoma

Mira¹,

Elsherbiny²,

Alkhiary³

et al. 2017

pharmaceutical-sciences

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JapanMira, et al.: Hepatoprotective Activity of Angelica shikokiana Angelica shikokiana (Apiaceae) is a Japanese traditional herb and widely marketed as a dietary food supplement as a health tea preparation consumed as a daily beverage for its health benefits. Our previous research showed that the methanol extract of the aerial parts of A. shikokiana and its major coumarin, isoepoxypteryxin had a significant cytotoxicity against HepG2 cell line. In this study, we investigated the hepatoprotective activity more deeply by the in vitro inhibition of HepG2 cells invasion assay and in vivo using thioacetamide-induced hepatocellular carcinoma model in rats. The ex vivo levels of nitric oxide production, inducible nitric oxide synthase, vascular endothelial cell growth factor-C and caspase-3 were also estimated to investigate the possible mechanisms of hepatoprotection. The methanol extract of A. shikokiana and isoepoxypteryxin concentration-dependently depressed the invasion of HepG2 cells induced by 12-O-tetradecanoylphorbol 13-acetate. In vivo, they significantly reduced the levels of alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase, total bilirubin and nitric oxide production when compared with hepatocellular carcinoma group. Besides, the thioacetamide-injected groups treated with methanol extract of A. shikokiana and isoepoxypteryxin exhibited a significant increase in the level of caspase-3 protein and a significant decrease of inducible nitric oxide synthase and vascular endothelial cell growth factor C levels when compared with hepatocellular carcinoma group. To the best of our knowledge, this is the first report of the hepatoprotective effect of A. shikokiana and isoepoxypteryxin against hepatocellular carcinoma.

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Emodin inhibits growth and induces apoptosis in an orthotopic hepatocellular carcinoma model by blocking activation of STAT3

Cited by 134 publications

References 43 publications

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

Emodin inhibits migration and invasion of MHCC-97H human hepatocellular carcinoma cells

Hepatoprotective Activities of the Methanol Extract of Angelica shikokiana and Isoepoxypteryxin against Hepatocellular Carcinoma

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