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The activation of p38 and JNK by ROS, contribute to OLO-2-mediated intrinsic apoptosis in human hepatocellular carcinoma cells.
Food Chem Toxicol. 2014 Jan; 63:38-47.FC

Abstract

In this study, we describe that a novel synthesized compound, olean-28,13β-olide 2 (OLO-2), exhibits selective cytotoxic activity via inducing apoptosis in human hepatocellular carcinoma (HCC) cell lines but not normal human hepatic cells in vitro. Exposure of human HCC HepG2 cells to OLO-2 results in significant loss of mitochondrial transmembrane potential (ΔΨm), the release of cytochrome c, the recruitment of B-cell lymphoma 2 (Bcl-2) assaciated X protein (Bax) and the downregulation of Bcl-2. The apoptosis induced by OLO-2 is associated with the activation of caspase-3/9 and the nuclear translocation of apoptosis inducing factor (AIF). Moreover, the increase of phosphorylated p38 and c-Jun N-terminal kinase (JNK) is observed. OLO-2-induced the externalization of phosphatidyl-serine (PS) and the loss of ΔΨm are blocked by p38 inhibitor SB203580 or JNK inhibitor SP600125. In addition, OLO-2 provokes the generation of reactive oxygen species (ROS) in HepG2 cells, while the antioxidant N-acetyl cysteine (NAC) almost completely blocks OLO-2-induced apoptosis and the activation of p38 and JNK. Taken together, the present study demonstrates that OLO-2 exhibits its cytotoxic activity through intrinsic apoptosis via ROS generation and the activation of p38 and JNK. Its potential to be a candidate of anti-cancer agent is worth being further investigated.

Authors+Show Affiliations

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: huijicpu@163.com.Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: zyhtgd@sohu.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24211866

Citation

Zhang, Zhenzhen, et al. "The Activation of P38 and JNK By ROS, Contribute to OLO-2-mediated Intrinsic Apoptosis in Human Hepatocellular Carcinoma Cells." Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association, vol. 63, 2014, pp. 38-47.
Zhang Z, Zhang C, Ding Y, et al. The activation of p38 and JNK by ROS, contribute to OLO-2-mediated intrinsic apoptosis in human hepatocellular carcinoma cells. Food Chem Toxicol. 2014;63:38-47.
Zhang, Z., Zhang, C., Ding, Y., Zhao, Q., Yang, L., Ling, J., Liu, L., Ji, H., & Zhang, Y. (2014). The activation of p38 and JNK by ROS, contribute to OLO-2-mediated intrinsic apoptosis in human hepatocellular carcinoma cells. Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association, 63, 38-47. https://doi.org/10.1016/j.fct.2013.10.043
Zhang Z, et al. The Activation of P38 and JNK By ROS, Contribute to OLO-2-mediated Intrinsic Apoptosis in Human Hepatocellular Carcinoma Cells. Food Chem Toxicol. 2014;63:38-47. PubMed PMID: 24211866.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The activation of p38 and JNK by ROS, contribute to OLO-2-mediated intrinsic apoptosis in human hepatocellular carcinoma cells. AU - Zhang,Zhenzhen, AU - Zhang,Chao, AU - Ding,Ye, AU - Zhao,Qian, AU - Yang,Lifang, AU - Ling,Jingjing, AU - Liu,Ling, AU - Ji,Hui, AU - Zhang,Yihua, Y1 - 2013/11/05/ PY - 2013/07/23/received PY - 2013/09/30/revised PY - 2013/10/27/accepted PY - 2013/11/12/entrez PY - 2013/11/12/pubmed PY - 2014/9/23/medline KW - Apoptosis KW - Cytotoxic KW - Human HCC cells KW - Mitochondria KW - OLO-2 SP - 38 EP - 47 JF - Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association JO - Food Chem Toxicol VL - 63 N2 - In this study, we describe that a novel synthesized compound, olean-28,13β-olide 2 (OLO-2), exhibits selective cytotoxic activity via inducing apoptosis in human hepatocellular carcinoma (HCC) cell lines but not normal human hepatic cells in vitro. Exposure of human HCC HepG2 cells to OLO-2 results in significant loss of mitochondrial transmembrane potential (ΔΨm), the release of cytochrome c, the recruitment of B-cell lymphoma 2 (Bcl-2) assaciated X protein (Bax) and the downregulation of Bcl-2. The apoptosis induced by OLO-2 is associated with the activation of caspase-3/9 and the nuclear translocation of apoptosis inducing factor (AIF). Moreover, the increase of phosphorylated p38 and c-Jun N-terminal kinase (JNK) is observed. OLO-2-induced the externalization of phosphatidyl-serine (PS) and the loss of ΔΨm are blocked by p38 inhibitor SB203580 or JNK inhibitor SP600125. In addition, OLO-2 provokes the generation of reactive oxygen species (ROS) in HepG2 cells, while the antioxidant N-acetyl cysteine (NAC) almost completely blocks OLO-2-induced apoptosis and the activation of p38 and JNK. Taken together, the present study demonstrates that OLO-2 exhibits its cytotoxic activity through intrinsic apoptosis via ROS generation and the activation of p38 and JNK. Its potential to be a candidate of anti-cancer agent is worth being further investigated. SN - 1873-6351 UR - https://www.unboundmedicine.com/medline/citation/24211866/The_activation_of_p38_and_JNK_by_ROS_contribute_to_OLO_2_mediated_intrinsic_apoptosis_in_human_hepatocellular_carcinoma_cells_ DB - PRIME DP - Unbound Medicine ER -