title: Inhibitory effects of lapachol on rat C6 glioma in vitro and in vivo by targeting DNA topoisomerase I and topoisomerase II.
abstract: Lapachol is a natural naphthoquinone compound that possesses extensive biological activities. The aim of this study is to investigate the inhibitory effects of lapachol on rat C6 glioma both in vitro and in vivo, as well as the potential mechanisms.
  
  
  
  The antitumor effect of lapachol was firstly evaluated in the C6 glioma model in Wistar rats. The effects of lapachol on C6 cell proliferation, apoptosis and DNA damage were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS)/ phenazinemethosulfate (PMS) assay, hoechst 33358 staining, annexin V-FITC/PI staining, and comet assay. Effects of lapachol on topoisomerase I (TOP I) and topoisomerase II (TOP II) activities were detected by TOP I and TOP II mediated supercoiled pBR322 DNA relaxation assays and molecular docking. TOP I and TOP II expression levels in C6 cells were also determined.
  
  
  
  High dose lapachol showed significant inhibitory effect on the C6 glioma in Wistar rats (P < 0.05). It was showed that lapachol could inhibit proliferation, induce apoptosis and DNA damage of C6 cells in dose dependent manners. Lapachol could inhibit the activities of both TOP I and II. Lapachol-TOP I showed relatively stronger interaction than that of lapachol-TOP II in molecular docking study. Also, lapachol could inhibit TOP II expression levels, but not TOP I expression levels.
  
  
  
  These results showed that lapachol could significantly inhibit C6 glioma both in vivo and in vitro, which might be related with inhibiting TOP I and TOP II activities, as well as TOP II expression.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, No.10 Youanmenwaixitoutiao, Fengtai District, Beijing, 100069, China.
authors.forename: Huanli
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, No.10 Youanmenwaixitoutiao, Fengtai District, Beijing, 100069, China.
authors.forename: Qunying
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, No.10 Youanmenwaixitoutiao, Fengtai District, Beijing, 100069, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, No.10 Youanmenwaixitoutiao, Fengtai District, Beijing, 100069, China.
authors.forename: Pingxiang
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, No.10 Youanmenwaixitoutiao, Fengtai District, Beijing, 100069, China.
authors.forename: Ru
authors.initials: R
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, No.10 Youanmenwaixitoutiao, Fengtai District, Beijing, 100069, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, No.10 Youanmenwaixitoutiao, Fengtai District, Beijing, 100069, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, No.10 Youanmenwaixitoutiao, Fengtai District, Beijing, 100069, China. xuem@ccmu.edu.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Xue
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D059003:Topoisomerase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009285:Naphthoquinones; D059003:Topoisomerase Inhibitors; C008252:lapachol; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II
keywords: C6 glioma; Lapachol; Topoisomerase I; Topoisomerase II