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

Abstract

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.

Keywords: 2-(3,4-difluorobenzylidene)hydrazinecarbothioamide; Anticancer; Apoptosis; Mitochondria-dependent pathway; ROS; Thiosemicarbazone.