期刊
INTERNATIONAL JOURNAL OF ONCOLOGY
卷 47, 期 5, 页码 1854-1862出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2015.3158
关键词
topoisomerase inhibition; iron mobilization; di-2-pyridylketone 2-pyridine carboxylic acid hydrazone; reactive oxygen species; ferritin
类别
资金
- Henan Science and Technology Agency [210073]
- Xinxiang Medical University [505026]
- Plan of Health Scientific and Technological Innovation Talents of Henan Province [2109901]
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 mu M for DPPACH and 1.3+/-0.2 mu M for its copper complex), but less inhibition for HCT-116 cell line (IC50 >100 mu M for DPPACH and 7.8+/-0.4 mu M 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.
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