title: The cytotoxicity of benzaldehyde nitrogen mustard-2-pyridine carboxylic acid hydrazone being involved in topoisomerase IIα inhibition.
abstract: The antitumor property of iron chelators and aromatic nitrogen mustard derivatives has been well documented. Combination of the two pharmacophores in one molecule in drug designation is worth to be explored. We reported previously the syntheses and preliminary cytotoxicity evaluation of benzaldehyde nitrogen mustard pyridine carboxyl acid hydrazones (BNMPH) as extended study, more tumor cell lines (IC50 for HepG2: 26.1 ± 3.5 μM, HCT-116: 57.5 ± 5.3 μM, K562: 48.2 ± 4.0 μM, and PC-12: 19.4 ± 2.2 μM) were used to investigate its cytotoxicity and potential mechanism. In vitro experimental data showed that the BNMPH chelating Fe(2+) caused a large number of ROS formations which led to DNA cleavage, and this was further supported by comet assay, implying that ROS might be involved in the cytotoxicity of BNMPH. The ROS induced changes of apoptosis related genes, but the TFR1 and NDRG1 metastatic genes were not obviously regulated, prompting that BNMPH might not be able to deprive Fe(2+) of ribonucleotide reductase. The BNMPH induced S phase arrest was different from that of iron chelators (G1) and alkylating agents (G2). BNMPH also exhibited its inhibition of human topoisomerase IIα. Those revealed that the cytotoxic mechanism of the BNMPH could stem from both the topoisomerase II inhibition, ROS generation and DNA alkylation.
authors.affiliation: Department of Molecular Biology & Biochemistry, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, Henan 453003, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Clinical Skill Training Center, Xinxiang Medical University, Xinxiang, Henan 453003, China.
authors.forename: Sufeng
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Molecular Biology & Biochemistry, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, Henan 453003, China.
authors.forename: Youxun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular Biology & Biochemistry, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, Henan 453003, China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular Biology & Biochemistry, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, Henan 453003, China.
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Molecular Biology & Biochemistry, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, Henan 453003, China.
authors.forename: Changzheng
authors.initials: C
authors.lastname: Li
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D001547:Benzaldehydes / Q000008:administration & dosage* / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009369:Neoplasms / Q000188:drug therapy; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage*; D059005:Topoisomerase II Inhibitors / Q000008:administration & dosage*
chemical_list: D000951:Antigens, Neoplasm; D001547:Benzaldehydes; D004268:DNA-Binding Proteins; D006835:Hydrazones; D009363:Neoplasm Proteins; D009588:Nitrogen Mustard Compounds; D059005:Topoisomerase II Inhibitors; C000595456:benzaldehyde nitrogen mustard-2-pyridine carboxyl acid hydrazone; D004250:DNA Topoisomerases, Type II; C032175:benzaldehyde