title: Evaluation of resveratrol sensitivities and metabolic patterns in human and rat glioblastoma cells.
abstract: OBJECTIVE
  To further elucidate the correlation of resveratrol sensitivities with biotransformation activities of human and rat glioblastoma cells for personalized anti-glioblastoma therapy.
  
  
  METHODS
  Resveratrol sensitivity of human U251 and rat RG2 and C6 glioblastoma cells was evaluated by 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide/MTT, flow cytometry, and TUNEL assays. The metabolic patterns of those cell lines were analyzed by high-performance liquid chromatography/HPLC coupled with tandem mass spectrum/MS/MS, and high-resolution mass spectrometry/HRMS. Immunocytochemical staining and Western blotting were employed to check resveratrol metabolic enzyme expression.
  
  
  RESULTS
  Both rat RG2 and C6 and human U251 glioblastoma cells are sensitive to 100 μM resveratrol in terms of growth arrest and increased apoptotic fraction. The main resveratrol metabolite in U251 cells is monosulfate biotransformed by sulfotransferases/SULTs and in RG2 and C6 cells is monoglucuronide generated by UDP-glucuronosyltransferase/UGT. Both metabolites show lesser therapeutic efficacy. Although brain-associated UGTs (UGT1A6, 2B7, and 8) and SULTs (SULT1A1, 1C2, and 4A1) are expressed in rat and human glioma cells, the overall level of UGTs is predominant in the rat and SULTs in human glioblastoma cells. In similar to SULT expression pattern, UGT1A6, 2B7, and 8 are frequently downregulated (84.6 %, 82/97; 90.7 %, 88/97; 80.4 %, 78/97) in human glioblastoma tissues.
  
  
  CONCLUSIONS
  Our results suggest (1) the decreased resveratrol biotransforming activity in rat and human resveratrol-sensitive glioblastoma cells; (2) the discrepant resveratrol metabolic patterns between human and rat glioblastoma cells; (3) the more powerful anti-glioblastoma efficacy of trans-resveratrol rather than resveratrol monoglucuronide or monosulfate; and (4) the value of RG2 and C6 cells in establishing resveratrol-based rat in vivo therapeutic model.
authors.affiliation: Liaoning Laboratory of Cancer Genomics, Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Sun
authors.forename: Shun
authors.initials: S
authors.lastname: Shi
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Shu
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Chen
authors.forename: Qing-You
authors.initials: QY
authors.lastname: Kong
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D008297:Male; D050217:Metabolic Detoxication, Phase II; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D000077185:Resveratrol; D013045:Species Specificity; D013267:Stilbenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015238:Sulfotransferases / Q000096:biosynthesis / Q000378:metabolism; D013463:Sulfuric Acid Esters / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D013267:Stilbenes; D013463:Sulfuric Acid Esters; D014453:Glucuronosyltransferase; D015238:Sulfotransferases; D000077185:Resveratrol