Author(s): Kuo, TC (Kuo, Tzu-Ching); Yang, JS (Yang, Ja-Sing); Lin, MW (Lin, Meng-Wei);
Hsu, SC (Hsu, Shu-Chun); Lin, JJ (Lin, Jen-Jyh); Lin, HJ (Lin, Hui-Ju); Hsia, TC (Hsia, Te- Chun); Liao, CL (Liao, Ching-Lung); Yang, MD (Yang, Mei-Due); Fan, MJ (Fan, Ming-Jen);
Wood, WG (Wood, W. G.); Chung, JG (Chung, Jing-Gung)
Title: Emodin Has Cytotoxic and Protective Effects in Rat C6 Glioma Cells: Roles of Mdr1a and Nuclear Factor kappa B in Cell Survival
Source: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 330 (3):
736-744 SEP 2009 Language: English Document Type: Article
KeyWords Plus: TYROSINE KINASE INHIBITOR; INDUCED APOPTOSIS; SIGNALING PATHWAY; ARSENIC TRIOXIDE; CANCER CELLS; ACTIVATION; MECHANISMS;
RESISTANCE; GROWTH; DEATH
Abstract: 1,3,8-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 kappa B (NF-kappa B) expression in 24 h of treatment, but in 48 h, emodin increased NF-kappa B activity. A confocal microscope showed that emodin induced NF-kappa 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.
Addresses: [Chung, Jing-Gung] China Med Univ, Coll Life Sci, Dept Biol Sci & Technol, Taichung 404, Taiwan; [Kuo, Tzu-Ching] China Med Univ, Dept Microbiol, Taichung 404, Taiwan; [Yang, Ja-Sing] China Med Univ, Dept Pharmacol, Taichung 404, Taiwan; [Hsu, Shu- Chun] China Med Univ, Grad Inst Chinese Pharmaceut Sci, Taichung 404, Taiwan; [Lin, Jen- Jyh; Hsia, Te-Chun; Liao, Ching-Lung] China Med Univ, Grad Inst Chinese Med Sci, Taichung
404, Taiwan; [Lin, Jen-Jyh] China Med Univ Hosp, Div Cardiol, Taichung, Taiwan; [Lin, Hui-Ju]
China Med Univ Hosp, Dept Ophthalmol, Taichung, Taiwan; [Hsia, Te-Chun] China Med Univ Hosp, Dept Internal Med, Taichung, Taiwan; [Yang, Mei-Due] China Med Univ Hosp, Dept Surg, Taichung, Taiwan; [Fan, Ming-Jen; Chung, Jing-Gung] Asia Univ, Dept Biotechnol, Taichung, Taiwan; [Wood, W. G.] Univ Minnesota, Sch Med, Dept Pharmacol, Minneapolis, MN 55455 USA; [Wood, W. G.] Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Minneapolis, MN 55417 USA
Reprint Address: Chung, JG, China Med Univ, Coll Life Sci, Dept Biol Sci & Technol, 91 Hsueh Shih Rd, Taichung 404, Taiwan.
E-mail Address: [email protected] Funding Acknowledgement:
Funding Agency Grant Number
China Medical University, Taichung, Taiwan CMU95-056
This work was supported by the China Medical University, Taichung, Taiwan [Grant CMU95- 056].
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Publisher: AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS Publisher Address: 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA ISSN: 0022-3565
DOI: 10.1124/jpet.109.153007
29-char Source Abbrev.: J PHARMACOL EXP THER ISO Source Abbrev.: J. Pharmacol. Exp. Ther.
Source Item Page Count: 9
Subject Category: Pharmacology & Pharmacy ISI Document Delivery No.: 485SO
