title: Water-soluble oxoglaucine-Y(III), Dy(III) complexes: in vitro and in vivo anticancer activities by triggering DNA damage, leading to S phase arrest and apoptosis.
abstract: Complexes of yttrium(III) and dysprosium(III) with the traditional Chinese medicine active ingredient oxoglaucine (OG), namely [Y(OG)2(NO3)3]·CH3OH (1) and [Dy(OG)2(NO3)3]·H2O (2), were synthesized and characterized by elemental analysis, IR, ESI-MS, (1)H and (13)C NMR as well as single-crystal X-ray diffraction analysis. In vitro the complexes exhibited higher anticancer activity than the free ligand OG against the tested cancer cell lines. Among the tested cell lines, HepG2 is the most sensitive to the complexes. Complex 2 can trigger DNA damage in HepG2 cells, resulting in cell cycle arrest in the S phase and leading to cell apoptosis. The S phase cell-cycle arrest is caused via the ATM (ataxia-telangiectasia mutated)-Chk2-Cdc25A pathway. Chk2 is phosphorylated and activated in an ATM-dependent manner. It, in turn, phosphorylates Cdc25A phosphatise on serine124, causing the inactivation of Cdc25A in ubiquitin-mediated proteolytic degradation. The cyclin-Cdk complexes of the S phase could also be inhibited by limited supply of cyclins A and E. This irreversible cell cycle arrest process ultimately induces mitochondria-involved apoptotic cell death via the activation of Bcl-2 protein. Complex e2 ffectively inhibited tumour growth in the BEL-7402 xenograft mouse model and exhibited higher safety in vivo than cisplatin.
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy, Guangxi Normal University, Guilin 541004, China. chenzf@gxnu.edu.cn hliang@gxnu.edu.cn.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Wei
authors.forename: Zhen-Feng
authors.initials: ZF
authors.lastname: Chen
authors.forename: Jiao-Lan
authors.initials: JL
authors.lastname: Qin
authors.forename: Yan-Cheng
authors.initials: YC
authors.lastname: Liu
authors.forename: Zhu-Quan
authors.initials: ZQ
authors.lastname: Li
authors.forename: Taj-Malook
authors.initials: TM
authors.lastname: Khan
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Jiang
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Shen
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004419:Dysprosium / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008516:Medicine, Chinese Traditional; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D012995:Solubility; D059003:Topoisomerase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction; D015019:Yttrium / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; D059003:Topoisomerase Inhibitors; D014867:Water; D004419:Dysprosium; C111587:oxoglaucine; D015019:Yttrium; D004247:DNA; D001058:Apomorphine