title: Redox cycling of a copper complex with benzaldehyde nitrogen mustard-2-pyridine carboxylic acid hydrazone contributes to its enhanced antitumor activity, but no change in the mechanism of action occurs after chelation.
abstract: Many anticancer drugs used in the clinical have potent metal chelating ability. The formed metal complex(es) may exhibit improved (or antagonistic) antitumor activity. However, the underlying mechanism has received limited attention. Therefore, investigation of the mechanism involved in the change upon chelation is required to extend our understanding of the effects of various drugs. In the present study, the proliferation inhibition effect of benzaldehyde nitrogen mustard-2-pyridine carboxylic acid hydrazone (BNMPH) and its copper complex on tumor cell lines was investigated. The copper chelate exhibited almost a 10-fold increase in antitumor activity (with IC50 <5 µM). The results showed that both BNMPH and its copper complex induced reactive oxygen species (ROS) generation, and caused upregulation of caspase 8 and Bax as well as the downregulation of Bcl-2, indicating that apoptosis was involved in the cytotoxic effects. DNA fragmentation noted in the comet assay further supported ROS involvement. The present study indicated that BNMPH and its copper complex effectively induced S phase arrest and the cell cycle arrest was associated with the downregulation of cyclin D1. The formation of acidic vesicular organelles (AVOs) and an increase in cleaved LC3-II demonstrated that autophagy occurred in the HepG2 cells treated with the agents. Taken together, BNMPH and its copper complex exhibited proliferation inhibition via apoptosis, cell cycle arrest and autophagy, which was dependent on ROS. The enhanced antitumor activity of the copper complex was due to its redox-cycling ability, but the mechanism was not altered compared to BNMPH. Our findings may significantly contribute to the understanding of the anti-proliferative effect of BNMPH and its copper complex.
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Yinli
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Cuiping
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Youxun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Pingxin
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Department of Surgery, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Henan Collaborative Innovation Center of Molecular Diagnostics and Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Sufeng
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Surgery, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Shaoshan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Changzheng
authors.initials: C
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001343:Autophagy / Q000187:drug effects*; D053181:Caspase 8 / Q000096:biosynthesis; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D056831:Coordination Complexes / Q000008:administration & dosage; D003300:Copper / Q000008:administration & dosage; D053938:DNA Fragmentation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D006835:Hydrazones; D009588:Nitrogen Mustard Compounds; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C000595456:benzaldehyde nitrogen mustard-2-pyridine carboxyl acid hydrazone; D003300:Copper; C505530:CASP8 protein, human; D053181:Caspase 8