title: Reversal of multidrug resistance by 5,5'-dimethoxylariciresinol-4-O-β-D-glucoside in doxorubicin-resistant human leukemia K562/DOX.
abstract: OBJECTIVE
  The objective of this study was to investigate the reversal effects of 5,5'-dimethoxylariciresinol-4'-O-β-D-glucoside (DMAG) extracted from traditional Chinese medicines Mahonia on multidrug resistance (MDR) of human leukemia cells to chemotherapeutic agents.
  
  
  METHODS
  MTT(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to determine the effect of DMAG on doxorubicin sensitivity to K562/DOX cells. Propidium iodide /Hoechst 33342 double staining assay was used to investigate the effect of DMAG on doxorubicin-induced cellular apoptosis. Intracellular accumulation of doxorubicin and rhodamine 123 assay were performed to evaluate the effect of DMAG on drugs efflux activity of P-glycoprotein.
  
  
  RESULTS
  DMAG significantly enhanced the doxorubicin cytotoxicity to K562/DOX cells. In the presence of 1.0 μM of DMAG, the IC50 of doxorubicin decreased from 34.93 ± 1.37 μM to 12.51 ± 1.28 μM. DMAG of 1.0 μM significantly enhanced doxorubicin-induced cell apoptosis in K562/DOX cells and the enhancement was time-dependent. A significant increase in accumulation of doxorubicin in the presence of DMAG was observed. After treatment of the K562/DOX cells for 1 h with 15.0 μM doxorubicin alone, the fluorescence intensity was 33093.12. With the addition of 1.0 μM of DMAG, the fluorescence intensity of doxorubicin was 2.3-fold higher. A significant increase of accumulation of rhodamine 123 in the presence of DMAG was also observed. With the addition of 1.0 μM of DMAG, the fluorescence intensity was increased by 49.11% compared with rhodamine 123 alone.
  
  
  CONCLUSIONS
  DMAG was shown to effectively enhance chemosensitivity of resistant cells, which makes it might be a suitable candidate for potential MDR-reversing agents.
authors.affiliation: Institute of Traditional Chinese Medicine, College of Pharmacy, Henan University, Kaifeng, Henan Province, China.
authors.forename: Tian-Xiao
authors.initials: TX
authors.lastname: Wang
authors.affiliation: Institute of Traditional Chinese Medicine, College of Pharmacy, Henan University, Kaifeng, Henan Province, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Shi
authors.affiliation: Institute of Traditional Chinese Medicine, College of Pharmacy, Henan University, Kaifeng, Henan Province, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Cong
authors.affiliation: Institute of Traditional Chinese Medicine, College of Pharmacy, Henan University, Kaifeng, Henan Province, China ; College of Huaxin, Zhengzhou, Henan Province, China.
authors.forename: Shi-Guang
authors.initials: SG
authors.lastname: Wang
authors.affiliation: Institute of Traditional Chinese Medicine, College of Pharmacy, Henan University, Kaifeng, Henan Province, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Institute of Traditional Chinese Medicine, College of Pharmacy, Henan University, Kaifeng, Henan Province, China.
authors.forename: Zhong-Qin
authors.initials: ZQ
authors.lastname: Zhang
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D004317:Doxorubicin / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple; D005960:Glucosides / Q000627:therapeutic use*; D006801:Humans; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy*; D017705:Lignans / Q000627:therapeutic use*
chemical_list: C000591012:5,5'-dimethoxylariciresinol-4-O-glucoside; D000903:Antibiotics, Antineoplastic; D005960:Glucosides; D017705:Lignans; D004317:Doxorubicin
keywords: 5,5’-dimethoxylariciresinol-4’-O-β-D-glucoside; doxorubicin; leukemia; multidrug resistance