title: The antitumor mechanism of di-2-pyridylketone 2-pyridine carboxylic acid hydrazone and its copper complex in ROS generation and topoisomerase inhibition, and hydrazone involvement in oxygen-catalytic iron mobilization.
abstract: Iron depletion and stimulation of iron-dependent free radical damage is a rapidly developing field for chelation therapy, but the iron mobilization from ferritin by chelators has received less attention. In this study, the di-2-pyridylketone 2-pyridine carboxylic acid hydrazone (DPPCAH) and its copper complex was prepared and characterized by NMR and MS spectra. The proliferation inhibition assay showed that both DPPCAH and its copper complex exhibited selectively proliferation inhibition for HepG2 (IC50, 4.6 ± 0.2 µM for DPPACH and 1.3 ± 0.2 µM for its copper complex), but less inhibition for HCT-116 cell line (IC50, >100 µM for DPPACH and 7.8 ± 0.4 µM for its copper complex). The mechanistic studies revealed that DPPACH could remove iron from ferritin in a oxygen-catalytic manner, and contributed to redox activity of labile iron pool (LIP), that is less reported for the chelators that possess significant biological activity. The reactive oxygen species (ROS) generation and DNA cleavage assay in vitro and in vivo showed that both DPPACH-Fe(II) and DPPACH-Cu were redox-active species, indicating that ROS may mediate their antitumor activity. Further study revealed that both DPPACH and its copper complex displayed certain degree of inhibition of type II topoisomerase (Top) which contributed to their antitumor activity. Thus, the mechanism that iron mobilization by DPPACH from ferritin contributed to LIP was proposed, and both DPPACH and its copper complex were involved in ROS generation and Top II inhibition for their antitumor activities.
authors.affiliation: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Huang
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: Xingzhi
authors.initials: X
authors.lastname: Sun
authors.affiliation: Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.
authors.forename: Zhenfu
authors.initials: Z
authors.lastname: Zhu
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 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: 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: D002384:Catalysis; D049109:Cell Proliferation / Q000187:drug effects*; D003300:Copper / Q000737:chemistry; D026942:DNA Topoisomerases / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage* / Q000737:chemistry; D007501:Iron / Q000737:chemistry; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism*; D059003:Topoisomerase Inhibitors / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D006835:Hydrazones; D017382:Reactive Oxygen Species; D059003:Topoisomerase Inhibitors; D003300:Copper; D007501:Iron; D026942:DNA Topoisomerases; D010100:Oxygen