title: A promising antitumor activity of evodiamine incorporated in hydroxypropyl-β-cyclodextrin: pro-apoptotic activity in human hepatoma HepG2 cells.
abstract: BACKGROUND
  Evodiamine has gained wide interests recently because of its antitumor activities. However, a superior bioavailability is required to achieve better efficacy due to its poor water solubility. The aim of this study was to enhance the evodiamine's aqueous solubility by preparing evodiamine/hydroxypropyl-β-cyclodextrin (EVO/HP-β-CD) inclusion complex, which is incorporated evodiamine into HP-β-CD, and compare the antitumor activities before and after inclusion with HP-β-CD in human hepatoma HepG2 cells.
  
  
  RESULTS
  The EVO/HP-β-CD inclusion complexes were prepared by the kneading method and structurally characterized. P-glycoprotein ATPase assays firstly demonstrated that evodiamine was a substrate of P-glycoprotein, while HP-β-CD and EVO/HP-β-CD inclusion complexes inhibited P-glycoprotein by blocking P-glycoprotein ATPase activity. The EVO/HP-β-CD inclusion complexes may be a promising anticancer drug candidate without drug resistance. After given evodiamine or EVO/HP-β-CD inclusion complexes intervention, cell viability evaluation indicated that the half inhibition concentration of evodiamine and EVO/HP-β-CD inclusion complexes on HepG2 cells was 8.516 and 0.977 μM, respectively. The caspase-3 enzyme activity analysis and Annexin V/PI double-staining revealed that EVO/HP-β-CD inclusion complexes possessed better antitumor activities than evodiamine. Additionally, Hoechst 33258 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay demonstrated that EVO/HP-β-CD inclusion complexes induced HepG2 cell apoptosis more effectively than evodiamine.
  
  
  CONCLUSIONS
  The improved antitumor activities of evodiamine were attributed to the enhanced solubility and P-glycoprotein inhibition by HP-β-CD. These results are promising for the drug administration of EVO/HP-β-CD inclusion complexes to enhance the bioavailability of evodiamine in vivo.
authors.affiliation: Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, No. 88 YuQuan Road, Nankai District, Tianjin, 300193 China ; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193 China.
authors.forename: Chao
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, No. 88 YuQuan Road, Nankai District, Tianjin, 300193 China ; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193 China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Gao
authors.affiliation: Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, No. 88 YuQuan Road, Nankai District, Tianjin, 300193 China ; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193 China.
authors.forename: Kuo
authors.initials: K
authors.lastname: Yan
authors.affiliation: Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, No. 88 YuQuan Road, Nankai District, Tianjin, 300193 China ; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193 China.
authors.forename: Yuan-Lu
authors.initials: YL
authors.lastname: Cui
authors.affiliation: Department of Pharmaceutical Sciences, Zibo Vocational Institute, Zibo, 255314 Shandong China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
keywords: Antitumor; Apoptosis; Evodiamine; Hydroxypropyl-β-cyclodextrin; P-glycoprotein