title: Biological evaluation of a cytotoxic 2-substituted benzimidazole copper(II) complex: DNA damage, antiproliferation and apoptotic induction activity in human cervical cancer cells.
abstract: Exploring novel chemotherapeutic agents is a great challenge in cancer medicine. To that end, 2-substituted benzimidazole copper(II) complex, [Cu(BMA)Cl2]·(CH3OH) (1) [BMA = N,N'-bis(benzimidazol-2-yl-methyl)amine], was synthesized and its cytotoxicity was characterized. The interaction between complex 1 and calf thymus DNA was detected by spectroscopy methods. The binding constant (K b = 1.24 × 10(4 )M(-1)) and the apparent binding constant (K app = 6.67 × 10(6 )M(-1)) of 1 indicated its moderate DNA affinity. Complex 1 induced single strand breaks of pUC19 plasmid DNA in the presence of H2O2 through an oxidative pathway. Cytotoxicity studies proved that complex 1 could inhibit the proliferation of human cervical carcinoma cell line HeLa in both time- and dose-dependent manners. The results of nuclei staining by Hoechst 33342 and alkaline single-cell gel electrophoresis proved that complex 1 caused cellular DNA damage in HeLa cells. Furthermore, treatment of HeLa cells with 1 resulted in S-phase arrest, loss of mitochondrial potential, and up-regulation of caspase-3 and -9 in HeLa cells, suggesting that complex 1 was capable of inducing apoptosis in cancer cells through the intrinsic mitochondrial pathway.
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Qiao
authors.forename: Zhong-Ying
authors.initials: ZY
authors.lastname: Ma
authors.forename: Jia
authors.initials: J
authors.lastname: Shao
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Bao
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Xu
authors.forename: Zhao-Yan
authors.initials: ZY
authors.lastname: Qiang
authors.forename: Jian-Shi
authors.initials: JS
authors.lastname: Lou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000737:chemistry*; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006367:HeLa Cells; D006801:Humans; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D009942:Organometallic Compounds; D003300:Copper; D004247:DNA; C427203:calf thymus DNA; C031000:benzimidazole