Oncotarget

Research Papers:

3'-hydroxy-4'-methoxy-β-methyl-β-nitrostyrene inhibits tumorigenesis in colorectal cancer cells through ROS-mediated DNA damage and mitochondrial dysfunction

Chun-Hao Tsai, Amos C. Hung, Yuan-Yin Chen, Ya-Wen Chiu, Pei-Wen Hsieh, Yi-Chen Lee, Yu-Han Su, Po-Chih Chang, Stephen Chu-Sung Hu and Shyng-Shiou F. Yuan _

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Oncotarget. 2017; 8:18106-18117. https://doi.org/10.18632/oncotarget.14996

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Abstract

Chun-Hao Tsai1,2,*, Amos C. Hung1,*, Yuan-Yin Chen1, Ya-Wen Chiu1, Pei-Wen Hsieh3, Yi-Chen Lee1,4, Yu-Han Su1, Po-Chih Chang5, Stephen Chu-Sung Hu6,7, Shyng-Shiou F. Yuan1,2,8

1Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

2Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

3Graduate Institute of Natural Products, School of Traditional Chinese Medicine, and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

5Division of General Surgery, Department of Surgery, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan

6Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

7Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

8Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Shyng-Shiou F. Yuan, email: yuanssf@ms33.hinet.net

Keywords: β-nitrostyrene, cell cycle, ROS, colorectal cancer, DNA damage

Received: August 02, 2016    Accepted: January 03, 2017    Published: February 02, 2017

ABSTRACT

The β-nitrostyrene family has been shown to suppress cell proliferation and induce apoptosis in types of various cancers. However, the mechanisms underlying the anticancer effects of β-nitrostyrenes in colorectal cancer remain poorly understood. In this study, we synthesized a β-nitrostyrene derivative, CYT-Rx20 (3’-hydroxy-4’-methoxy-β-methyl-β-nitrostyrene), and investigated its anticancer activities in human colorectal cancer cells both in vitro and in vivo. Our findings showed that treatment with CYT-Rx20 reduced cell viability and induced DNA damage in colorectal cancer cells. In addition, CYT-Rx20 induced cell cycle arrest of colorectal cancer cells at the G2/M phase and upregulated the protein expression of phospho-ERK, cyclin B1, phospho-cdc2 (Tyr15), aurora A, and aurora B, while it downregulated the expression of cdc25A and cdc25C. Furthermore, we found that CYT-Rx20 caused accumulation of intracellular reactive oxygen species (ROS) and reduction of mitochondrial membrane potential. The effects of CYT-Rx20 on cell viability, DNA damage, and mitochondrial membrane potential were reversed by pretreatment with the thiol antioxidant N-acetyl-L-cysteine (NAC), suggesting that ROS-mediated DNA damage and mitochondrial dysregulation play a critical role in these events. Finally, the nude mice xenograft study showed that CYT-Rx20 significantly reduced tumor growth of implanted colorectal cancer cells accompanied by elevated protein expression of aurora A, aurora B, γH2AX, phosphor-ERK, and MDA in the tumor tissues. Taken together, these results suggest that CYT-Rx20 may potentially be developed as a novel β-nitrostyrene-based anticancer agent for colorectal cancer.


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