title: A platinum(II) complex of liriodenine from traditional Chinese medicine (TCM): Cell cycle arrest, cell apoptosis induction and telomerase inhibition activity via G-quadruplex DNA stabilization.
abstract: Liriodenine (L), an antitumor active ingredient from the traditional Chinese medicine (TCM), Zanthoxylum nitidum, afforded a platinum(II) complex (1) of L, cis-[PtCl2(L)(DMSO)], which previously reported for its in vitro antitumor activity and intercalative binding with DNA. In this study, complex 1 was further discussed for its antitumor mechanism and structure-activity relationship, comparing with L and cisplatin. Towards the most sensitive BEL-7404 human hepatoma cells, complex 1 significantly induced cell cycle arrest at both G2/M phase and S phase. It suggests that double helix DNA is not the simplex intracellular target for 1. On the other hand, the BEL-7404 cells incubated with 1 and stained by Hoechst 33258 and AO/EB showed typical cell apoptosis in dose-dependent manner. The BEL-7404 cells incubated with 1 and stained by JC-1 were also characteristic for cell apoptosis on the loss of mitochondrial membrane potential. Furthermore, the G-quadruplex DNA binding property of complex 1 was also investigated by spectroscopic analyses, fluorescent indicator displacement (FID) assay and fluorescence resonance energy transfer (FRET) assay. The results indicated that 1 stabilized the human telomeric G4-HTG21 DNA better than L. The telomerase inhibition ratio of 1 ((62.50±0.03)%), which was examined by telomerase polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA), was much higher than L ((21.77±0.01)%). It can be ascribed to the better G4-HTG21 DNA stabilization of 1 than L. The results suggested that the nuclei, mitochondria and telomerase via G-quadruplex DNA stabilization all should be key targets for the antitumor mechanism of 1, in which the central platinum(II) played a key role.
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy of Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Yu-Lan
authors.initials: YL
authors.lastname: Li
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy of Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Qi-Pin
authors.initials: QP
authors.lastname: Qin
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy of Guangxi Normal University, Guilin 541004, PR China. Electronic address: ycliugxnu@aliyun.com.
authors.forename: Yan-Cheng
authors.initials: YC
authors.lastname: Liu
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy of Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Zhen-Feng
authors.initials: ZF
authors.lastname: Chen
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy of Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001060:Aporphines / Q000008:administration & dosage / Q000737:chemistry*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000008:administration & dosage / Q000737:chemistry*; D054856:G-Quadruplexes / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008516:Medicine, Chinese Traditional; D010984:Platinum / Q000008:administration & dosage / Q000737:chemistry*; D017671:Platinum Compounds / Q000008:administration & dosage / Q000737:chemistry; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001060:Aporphines; D056831:Coordination Complexes; D017671:Platinum Compounds; D010984:Platinum; C026980:liriodenine; D019098:Telomerase
keywords: Cell apoptosis; G-quadruplex DNA; Liriodenine; Platinum complex; Telomerase