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| 標題: | Novel histone deacetylase inhibitor AR-42 exhibits antitumor activity in pancreatic cancer cells by affecting multiple biochemical pathways |
| 作者: | Chen, Yi-Jin
Wan, Wen-Hung
Wu, Wan-Yu
Hsu, Chia-Chi
Wei, Ling-Rung
Wang, Sheng-Fan
Hsu, Ya-Wen
Liaw, Chih-Chuang
Tsai, Wan-Chi |
| 貢獻者: | Kaohsiung Med Univ, Dept Med Lab Sci & Biotechnol
Cathay Gen Hosp, Dept Otolaryngol
SijhihCathay Gen Hosp, Dept Otolaryngol
FuJen Catholic Univ, Sch Med
Kaohsiung Med Univ, Ctr Infect Dis & Canc Res
Chia Nan Univ Pharm Sci, Dept Hosp & Hlth Care Adm
Natl Sun Yat Sen Univ, Doctoral Degree Program Marine Biotechnol
Natl Sun Yat Sen Univ, Dept Marine Biotechnol & Resources
Kaohsiung Med Univ Hosp, Dept Lab Med |
| 關鍵字: | Acetyl-L-Cysteine
Hydroxamic Acid Saha
Human Leukemia-Cells
Tumor-Growth
Dna-Damage
Kappa-B
Apoptosis
Death
Thioredoxin
Suppression |
| 日期: | 2017-08-22 |
| 上傳時間: | 2018-11-30 15:55:57 (UTC+8) |
| 出版者: | Public Library Science |
| 摘要: | Objective Pancreatic cancer is one of the most lethal types of cancer with a 5-year survival rate of similar to 5%. Histone deacetylases (HDACs) participate in many cellular processes, including carcinogenesis, and pharmacological inhibition of HDACs has emerged as a potential therapeutic strategy. In this study, we explored antitumor activity of the novel HDAC inhibitor AR-42 in pancreatic cancer. Methods Human pancreatic cancer cell lines BxPC-3 and PANC-1 were used in this study. Real-time PCR, RT-PCR, and western blotting were employed to investigate expression of specific genes and proteins, respectively. Translocation of apoptosis-inducing factor was investigated by immunofluorescence and subcellular fractionation. The number of apoptotic cells, cell cycle stages, and reactive oxygen species (ROS) generation levels were determined by flow cytometry. Cell invasiveness was examined by the Matrigel invasion assay. Efficacy of AR-42 in vivo was evaluated by utilizing BxPC-3 xenograft mouse model. Results AR-42 inhibited pancreatic cancer cell proliferation by causing G2/M cell cycle arrest via regulating expression levels of genes and proteins involved in cell cycle. AR-42 also induced ROS generation and DNA damage, triggering apoptosis of pancreatic cancer cells via both caspase-3-dependent and caspase-3-independent pathways. In addition, AR-42 increased expression levels of negative regulators of p53 (miR-125b, miR-30d, and miR33), which could contribute to lower expression level of mutant p53 in pancreatic cancer cells. Cell invasion assay showed that AR-42 reduced cancer cell aggressiveness and significantly diminished BxPC-3 xenograft tumor growth in vivo. Conclusion AR-42, a novel HDAC inhibitor, inhibited pancreatic cancer cells by regulating p53 expression, inducing cell cycle arrest, particularly at the G2/M stage, and activating multiple apoptosis pathways. Additionally, AR-42 inhibited cell invasiveness and potently suppressed pancreatic cancer tumors in vivo. We conclude that by virtue of its multiple mechanisms of action, AR-42 possesses a considerable potential as an antitumor agent in pancreatic cancer. |
| 關聯: | Plos One, v.12, n.8, e0183368 |
| 顯示於類別: | [醫務管理系(所)] 期刊論文
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