title: Copper Ion Attenuated the Antiproliferative Activity of Di-2-pyridylhydrazone Dithiocarbamate Derivative; However, There Was a Lack of Correlation between ROS Generation and Antiproliferative Activity.
abstract: The use of chelators for cancer treatment has been an alternative option. Dithiocarbamates have recently attracted considerable attention owning to their diverse biological activities; thus, the preparation of new dithiocarbamate derivatives with improved antitumor activity and selectivity as well as probing the underlying molecular mechanism are required. In this study, di-2-pyridylhydrazone dithiocarbamate S-propionic acid (DpdtpA) and its copper complex were prepared and characterized, and its antiproliferative activity was evaluated. The proliferation inhibition assay showed that DpdtpA exhibited excellent antiproliferative effect in hepatocellular carcinoma (IC50 = 1.3 ± 0.3 μM for HepG2, and 2.5 ± 0.6 μM for Bel-7402). However, in the presence of copper ion, the antiproliferative activity of DpdtpA was dramatically attenuated (20-30 fold) owing to the formation of copper chelate. A preliminarily mechanistic study revealed that reactive oxygen species (ROS) generation mediated the antiproliferative activity of DpdtpA, and accordingly induced apoptosis, DNA cleavage, and autophagy. Surprisingly, the cytotoxicity of DpdtpA copper complex (DpdtpA-Cu) was also involved in ROS generation; however, a paradoxical relation between cellular ROS level and cytotoxicity was observed. Further investigation indicated that DpdtpA could induce cell cycle arrest at the S phase; however, DpdtpA-Cu lacked this effect, which explained the difference in their antiproliferative activity.
authors.affiliation: Department of Molecular Biology & Biochemistry, Xinxiang Medical University, Xinxiang 453003, Henan, China. wangting2855@sina.com.|Henan Collaborative Innovation Center of Molecular Diagnostics and Laboratory Medicine, Xinxiang Medical University, Xinxiang 453003, Henan, China. wangting2855@sina.com.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology & Biochemistry, Xinxiang Medical University, Xinxiang 453003, Henan, China. fuyun9801@163.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Molecular Biology & Biochemistry, Xinxiang Medical University, Xinxiang 453003, Henan, China. htengfei@yahoo.com.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Molecular Biology & Biochemistry, Xinxiang Medical University, Xinxiang 453003, Henan, China. liuyouxun@126.com.
authors.forename: Youxun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular Biology & Biochemistry, Xinxiang Medical University, Xinxiang 453003, Henan, China. meihaowu1995@163.com.
authors.forename: Meihao
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Surgery, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan, China. yuanyanbingo@yahoo.com.
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Surgery, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan, China. shaoshanlioo1@sina.com.
authors.forename: Shaoshan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Molecular Biology & Biochemistry, Xinxiang Medical University, Xinxiang 453003, Henan, China. changzhengli@xxmu.edu.cn.|Henan Collaborative Innovation Center of Molecular Diagnostics and Laboratory Medicine, Xinxiang Medical University, Xinxiang 453003, Henan, China. changzhengli@xxmu.edu.cn.
authors.forename: Changzheng
authors.initials: C
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry; D003300:Copper / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D006835:Hydrazones; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; D003300:Copper
keywords: ROS-uncorrelated cytotoxicity; antagonistic effect; antiproliferative activity; antitumor mechanism; apoptosis; autophagy; cell cycle arrest; copper complex; di-2-pyridylhydrazone dithiocarbamate S-propionic acid; tumor microenvironment