Induction of Apoptosis in Hepatocellular Carcinoma Cell Lines by Emodin

Jing, Xubin; Ueki, Noboru; Cheng, Jidong; Imanishi, Hiroyasu; Hada, Toshikazu

doi:10.1111/j.1349-7006.2002.tb01332.x

Cited by 94 publications

(67 citation statements)

References 33 publications

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“…However, several studies indicated that emodin-induced apoptosis was mediated by ROS-generated (Jing et al, 2002;Su et al, 2005) and caspase-and mitochondrial-dependent pathways in human cervical cancer cells (Srinivas et al, 2003). Emodin induced apoptosis in human lung squamous cell carcinoma (Zhang et al, 1999;Lee, 2001), and HepG2/C3A cells were mediated through the activation of p53, p21, Fas/APO-1, and caspase-3 (Shieh et al, 2004).…”

mentioning

confidence: 99%

Emodin Has Cytotoxic and Protective Effects in Rat C6 Glioma Cells: Roles of Mdr1a and Nuclear Factor κB in Cell Survival

Kuo¹,

Yang²,

Meng³

et al. 2009

J Pharmacol Exp Ther

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ABSTRACT1,3,8-Trihydroxy-6-methylanthaquinone (emodin) is recognized as an antiproliferative compound. In the present study, however, we show that emodin has both toxic and survival effects in glioma cells and that the survival effects involve Mdr1a. Emodin inhibited the proliferation and induced apoptosis of C6 cells in a 12-h treatment, but C6 cells survived a 72-h drug treatment, indicating resistance to emodin. Emodin-induced apoptosis was reduced by inhibition of the expression and activation of apoptosis-associated proteins including p53, Bax, Bcl-2, Fas, and caspase-3. C6 cells could express antioxidant proteins (superoxide dismutase and catalase) to decrease reactive oxygen species-induced cytotoxicity of emodin and overexpress multidrug resistance genes (Mdr1a, MRP2, MRP3, and MRP6) to decrease the intracellular accumulation of emodin. Electrophoretic mobility shift analysis showed that emodin decreased nuclear factor B (NF-B) expression in 24 h of treatment, but in 48 h, emodin increased NF-B activity. A confocal microscope showed that emodin induced NF-B translocation from cytoplasm to nuclei. C6 cells would activate the mitogen-activated protein kinase survival pathway and express the DNA repair gene (MGMT) and associated proteins (PARP and XRCC1) to recover the cell activity. C6 cells also expressed GRP78 to decrease emodin-induced endoplasmic reticulum (ER) stress that would cause apoptosis in C6 cells, and GRP78 inhibited the expression of GADD153 to enhance the expression of Bcl-2 that could balance the ER-and mitochondria-induced apoptosis of C6 cells.

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mentioning

confidence: 99%

Emodin Has Cytotoxic and Protective Effects in Rat C6 Glioma Cells: Roles of Mdr1a and Nuclear Factor κB in Cell Survival

Kuo¹,

Yang²,

Meng³

et al. 2009

J Pharmacol Exp Ther

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“…Indeed, in HCC, Fas is downregulated while its ligand is highly expressed, thereby allowing cancer cells to protect themselves and to kill immune cells alike. Several studies have shown that reduced Fas expression in HCC negatively correlates with patient survival (93,94). It has also been found that the anti-apoptotic protein Bcl-XL is overexpressed in HCC, which confers resistance to mitochondria-mediated apoptosis.…”

Section: -Apoptosis In Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

“…First, Jing et al (94) found that emodin induces apoptotic responses in the HCC lines Mahlavu, PLC/PRF/5 and HepG2 (hepatoma cell line), thus effecting a time-and dose-dependent growth inhibition. Specifically, ROS generated in response to emodin treatment caused a reduction in the mitochondrial transmembrane potential (ΔΨM) that was followed by the activation of caspases 9 and 3 and led to DNA fragmentation and apoptosis.…”

Section: -Apoptosis In Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

Apoptosis in selected liver diseases

Kiliçarslan

Kahraman²,

Akkız³

et al. 2009

Turk J Gastroenterol

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“…Moreover, emodin inhibits cell growth in several types of tumor cells, (Zhang et al, 1998;Chen et al, 2002;Jing et al, 2002;Srinivas et al, 2003), and it regulates genes related to the control of cell proliferation, cell apoptosis, oncogenesis, and cancer cell invasion and metastasis (Cha et al, 2005;Kim et al, 2005;Huang et al, 2006;Kwak et al, 2006). Our previous studies indicated that emodin decreases the protein and mRNA expression levels of excision repair cross-complementing 1 gene and Rad51 by increasing the protein and mRNA instability in human lung cancer cells (Ko et al, 2009).…”

Section: Rad51 and Erk1/2 In Emodin And Mmc-induced Cytotoxicity 639mentioning

confidence: 99%

Role of Rad51 Down-Regulation and Extracellular Signal-Regulated Kinases 1 and 2 Inactivation in Emodin and Mitomycin C-Induced Synergistic Cytotoxicity in Human Non–Small-Cell Lung Cancer Cells

Su¹,

Tsai²,

Kuo³

et al. 2009

Mol Pharmacol

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Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. It is a tyrosine kinase inhibitor and has anticancer effects on lung cancer. Rad51 plays a central role in homologous recombination, and high levels of Rad51 expression are observed in chemo-or radioresistant carcinomas. Our previous studies have shown that the mitogen-activated protein kinase kinase (MKK) 1/2-extracellular signal-regulated kinase (ERK) 1/2 signal pathway maintains the expression of Rad51. Therefore, in this study, we hypothesized that emodin could enhance the effects of the antitumor antibiotic mitomycin C (MMC)-mediated cytotoxicity by decreasing the expression of Rad51 and the phosphorylation of ERK1/2. Exposure of the human non-small-cell lung cancer H1703 or A549 cell lines to emodin decreased the MMC-elicited phosphorylated ERK1/2 and Rad51 levels. Moreover, emodin significantly decreased the MMC-elicited Rad51 mRNA and protein levels by increasing the instability of Rad51 mRNA and protein. In emodin-and MMC-cotreated cells, ERK1/2 phosphorylation was enhanced by constitutively active MKK1/2 (MKK1/2-CA), thus increasing Rad51 protein levels and protein stability. The synergistic cytotoxic effects induced by emodin combined with MMC were remarkably decreased by MKK1-CA-mediated enhancement of ERK1/2 activation. Depletion of endogenous Rad51 expression by small interfering Rad51 RNA transfection significantly enhanced MMC-induced cell death and cell growth inhibition. In contrast, overexpression of Rad51 protects lung cancer cells from the synergistic cytotoxic effects induced by emodin and MMC. We conclude that suppression of Rad51 expression or a combination of emodin with chemotherapeutic agents may be considered as potential therapeutic modalities for lung cancer.Lung cancer is the leading cause of cancer-related death in the world and can be broadly classified into small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) (Bhattacharjee et al., 2001). NSCLC accounts for approximately 85% of all lung cancers (Landis et al., 1999), and unlike SCLC, NSCLC is less sensitive to chemotherapeutic agents; the average 5-year survival rates are 10 to 15% . Mitomycin C (MMC) is an anticancer drug that forms monoadducts and intrastrand cross-links between the N-2 guanines of the d(CpG) sequence in the minor groove of DNA (Warren and Hamilton, 1996;Dronkert and Kanaar, 2001). MMC is typically used as a first-or second-line regimen to treat NSCLC and is often combined with other chemotherapeutic agents during advanced NSCLC treatment (Babiak et al., 2007). The therapeutic value of MMC depends on the ability of cells to remove DNA damage (McHugh et al., 2001).

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Induction of Apoptosis in Hepatocellular Carcinoma Cell Lines by Emodin

Cited by 94 publications

References 33 publications

Emodin Has Cytotoxic and Protective Effects in Rat C6 Glioma Cells: Roles of Mdr1a and Nuclear Factor κB in Cell Survival

Emodin Has Cytotoxic and Protective Effects in Rat C6 Glioma Cells: Roles of Mdr1a and Nuclear Factor κB in Cell Survival

Apoptosis in selected liver diseases

Role of Rad51 Down-Regulation and Extracellular Signal-Regulated Kinases 1 and 2 Inactivation in Emodin and Mitomycin C-Induced Synergistic Cytotoxicity in Human Non–Small-Cell Lung Cancer Cells

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