A novel fluorinated thiosemicarbazone derivative- 2-(3,4-difluorobenzylidene) hydrazinecarbothioamide induces apoptosis in human A549 lung cancer cells via ROS-mediated mitochondria-dependent pathway

• Published in: Biochemical and biophysical research communications Vol. 491; no. 1; pp. 65 - 71
• Main Authors: Zhao, Yue, Guo, Chuanlong, Wang, Lijun, Wang, Shuaiyu, Li, Xiangqian, Jiang, Bo, Wu, Ning, Guo, Shuju, Zhang, Renshuai, Liu, Kun, Shi, Dayong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.09.2017
• Subjects: 2-(3,4-difluorobenzylidene)hydrazinecarbothioamide; A549 Cells; Anticancer; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Fluorine Compounds - chemical synthesis; Fluorine Compounds - pharmacology; Humans; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria-dependent pathway; Reactive Oxygen Species - metabolism; ROS; Signal Transduction - drug effects; Thiosemicarbazone; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - pharmacology; Mitochondria-dependent pathway; Thiosemicarbazone; Anticancer; ROS; 2-(3,4-difluorobenzylidene)hydrazinecarbothioamide; Apoptosis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.07.042

Thiosemicarbazone, a class of compounds with excellent biological activity, especially antitumor activity, have attracted wide attention. In this study, a novel fluorinated thiosemicarbazone derivative, 2-(3,4-difluorobenzylidene) hydrazinecarbothioamide (compound 1) was synthesized and its antitumor activities were further investigated on a non-small cell lung cancer cell line (A549) along with its underlying mechanisms. Compound 1 showed significant anti-proliferative activity on A549 cells, which was further proved by colony formation experiment. Compound 1 also inhibits the invasion of A549 cells in a trans-well culture system. Moreover, compound 1 markedly induced apoptosis on A549 cells, and the ratio of Bcl-2/Bax was decreased while the amount of p53, Cleaved-Caspase 3 and Cleaved-PARP expression were increased significantly. Compound 1 decreased the mitochondrial membrane potential, while the content of reactive oxygen was increased obviously. It is revealed that compound 1 mediated cell cycle arrest in G0/G1 phase by reducing G1 phase dependent proteins, CDK4 and Cyclin D1. As a result, it is indicated that compound 1 induced apoptosis on A549 cells was realized by regulating ROS-mediated mitochondria-dependent signaling pathway. •Compound 1 induced apoptosis in lung cancer cells.•Compound 1 induced G0/G1 phase arrest in lung cancer cells.•ROS-mitochondria pathway plays a vital role in compound 1-induced apoptosis.