Danthron, an Anthraquinone Derivative, Induces DNA Damage and Caspase Cascades-Mediated Apoptosis in SNU-1 Human Gastric Cancer Cells through Mitochondrial Permeability Transition Pores and Bax-Triggered Pathways

被引:197
作者
Chiang, Jo-Hua [2 ]
Yang, Jai-Sing [3 ]
Ma, Chia-Yu [4 ]
Yang, Mei-Due [5 ]
Huang, Hui-Ying [6 ]
Hsia, Te-Chun [7 ,8 ]
Kuo, Hsiu-Maan [9 ]
Wu, Ping-Ping [10 ]
Lee, Tsung-Han [2 ]
Chung, Jing-Gung [1 ,11 ]
机构
[1] China Med Univ, Dept Biol Sci & Technol, Taichung 404, Taiwan
[2] Natl Chung Hsing Univ, Dept Life Sci, Taichung 402, Taiwan
[3] China Med Univ, Dept Pharmacol, Taichung 404, Taiwan
[4] Technol & Sci Inst No Taiwan, Dept Food & Beverage Management, Taipei 112, Taiwan
[5] China Med Univ Hosp, Dept Surg, Taichung 404, Taiwan
[6] China Med Univ, Dept Nutr, Taichung 404, Taiwan
[7] China Med Univ, Sch Chinese Med, Taichung 404, Taiwan
[8] China Med Univ Hosp, Dept Internal Med, Taichung 404, Taiwan
[9] China Med Univ, Dept Parasitol, Taichung 404, Taiwan
[10] China Med Univ, Sch Pharm, Taichung 404, Taiwan
[11] Asia Univ, Dept Biotechnol, Taichung 413, Taiwan
关键词
ENDOPLASMIC-RETICULUM STRESS; FACTOR-KAPPA-B; SIGNAL-TRANSDUCTION; DEPENDENT PATHWAYS; IN-VITRO; EMODIN; INHIBITION; INDUCTION; GROWTH; MECHANISMS;
D O I
10.1021/tx100248s
中图分类号
R914 [药物化学];
学科分类号
100705 [微生物与生化药学];
摘要
Anthraquinones have been shown to induce apoptosis in different types of tumor cells, but the mechanisms of danthron-induced cytotoxicity and apoptosis in human gastric cancer cells have not been adequately explored. This study investigated the roles of caspase cascades, ROS, DNA damage, mitochondrial disruption, and Bax and Bcl-2 proteins in danthron-induced apoptosis of SNU-1 human gastric cancer cells, a commonly used cell culture system for in vitro studies. Cells were incubated with different concentrations of danthron in a time- and/or dose-dependent manner. Cell morphological changes (shrinkage and rounding) were examined by a phase-contrast microscope, whereas cell viability and apoptotic populations were determined by flow cytometric analysis using propidium iodide (PI) and annexin V FITC staining. The fluorescent DAPI nucleic acid stain and Comet assay were applied to detect danthron-induced chromatin condensation (an apoptotic characteristic) and DNA damage. Increasing the levels of caspase-3, -8, and -9 activities was involved in danthron-induced apoptosis, and they could be attenuated by inhibitors of specific caspases, indicating that danthron triggered the caspase-dependent apoptotic pathway. Further studies with flow cytometric analyses indicated that cellular levels of ROS, cytosolic Ca2+, and mitochondrial permeability transition (MPT) pore opening were increased, but the level of mitochondrial membrane potential (Delta Psi(m)) was decreased. Also, the ratio of Bax/Bcl-2 levels and other proapoptotic proteins associated with modulating the Delta Psi(m) were up-regulated. Apoptotic signaling was also stimulated after exposure to danthron and determined by Western blotting and real-time PCR analyses. In summary, it is suggested that danthron-induced apoptotic cell death was involved in mitochondrial depolarization, which led to release of cytochrome c, apoptosis-inducing factor (AIF), and endonuclease G (Endo G) and caused the activation of caspase-9 and -3 in SNU-1 human gastric cancer cells.
引用
收藏
页码:20 / 29
页数:10
相关论文
共 51 条
[1]
Resveratrol regulates cellular PKC α and δ to inhibit growth and induce apoptosis in gastric cancer cells [J].
Atten, MJ ;
Godoy-Romero, E ;
Attar, BM ;
Milson, T ;
Zopel, M ;
Holian, O .
INVESTIGATIONAL NEW DRUGS, 2005, 23 (02) :111-119
[2]
The mitochondrial permeability transition from in vitro artifact to disease target [J].
Bernardi, P ;
Krauskopf, A ;
Basso, E ;
Petronilli, V ;
Blalchy-Dyson, E ;
Di Lisa, F ;
Forte, MA .
FEBS JOURNAL, 2006, 273 (10) :2077-2099
[3]
Apoptotic and Necrotic Action Mechanisms of Trimethyltin in Human Hepatoma G2 (HepG2) Cells [J].
Cai, Jiali ;
Wang, Mengmeng ;
Li, Bowen ;
Wang, Chonggang ;
Chen, Yixin ;
Zuo, Zhenghong .
CHEMICAL RESEARCH IN TOXICOLOGY, 2009, 22 (09) :1582-1587
[4]
Gypenosides induced G0/G1 arrest via CHk2 and apoptosis through endoplasmic reticulum stress and mitochondria-dependent pathways in human tongue cancer SCC-4 cells [J].
Chen, Jung-Chou ;
Lu, Kung-Wen ;
Tsai, Ming-Li ;
Hsu, Shu-Chun ;
Kuo, Chao-Lin ;
Yang, Jai-Sing ;
Hsia, Te-Chun ;
Yu, Chun-Shu ;
Chou, Su-Tze ;
Kao, Ming-Ching ;
Chung, Jing-Gung ;
Wood, W. Gibson .
ORAL ONCOLOGY, 2009, 45 (03) :273-283
[5]
The synthesized 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-1) promoted G2/M arrest through inhibition of CDK1 and induced apoptosis through the mitochondrial-dependent pathway in CT-26 murine colorectal adenocarcinoma cells [J].
Chou, Li-Chen ;
Yang, Jai-Sing ;
Huang, Li-Jiau ;
Wu, Hsi-Chin ;
Lu, Chi-Cheng ;
Chiang, Jo-Hua ;
Chen, Kuan-Tin ;
Kuo, Sheng-Chu ;
Chung, Jing-Gung .
JOURNAL OF GASTROENTEROLOGY, 2009, 44 (10) :1055-1063
[6]
Proteomic approach to studying the cytotoxicity of YCA on U937 leukemia cells and antileukernia activity in orthotopic model of leukemia mice [J].
Chung, Jing-Gung ;
Yang, Jai-Sing ;
Huang, Li-Jiau ;
Lee, Fang-Yu ;
Teng, Che-Ming ;
Tsai, Sheng-Chung ;
Lin, Kuei-Li ;
Wang, Shu-Fang ;
Kuo, Sheng-Chu .
PROTEOMICS, 2007, 7 (18) :3305-3317
[7]
Clark GB, 2001, CURR SCI INDIA, V80, P170
[8]
Enniatin exerts p53-dependent cytostatic and p53-independent cytotoxic activities against human cancer cells [J].
Dornetshuber, Rita ;
Heffeter, Petra ;
Kamyar, Majid-Reza ;
Peterbauer, Thomas ;
Berger, Walter ;
Lemmens-Gruber, Rosa .
CHEMICAL RESEARCH IN TOXICOLOGY, 2007, 20 (03) :465-473
[9]
Human immunodeficiency virus type 1 cDNA integration: New aromatic hydroxylated inhibitors and studies of the inhibition mechanism [J].
Farnet, CM ;
Wang, B ;
Hansen, M ;
Lipford, JR ;
Zalkow, L ;
Robinson, WE ;
Siegel, J ;
Bushman, F .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1998, 42 (09) :2245-2253
[10]
BAX activation is initiated at a novel interaction site [J].
Gavathiotis, Evripidis ;
Suzuki, Motoshi ;
Davis, Marguerite L. ;
Pitter, Kenneth ;
Bird, Gregory H. ;
Katz, Samuel G. ;
Tu, Ho-Chou ;
Kim, Hyungjin ;
Cheng, Emily H. -Y. ;
Tjandra, Nico ;
Walensky, Loren D. .
NATURE, 2008, 455 (7216) :1076-U6