title: The efficacy of mitochondrial targeting antiresistant epirubicin liposomes in treating resistant leukemia in animals.
abstract: BACKGROUND
  Multidrug resistance (MDR) of cancers can be circumvented by inducing programmed cell death, which is known as apoptosis. Mitochondria play a crucial role in apoptosis. Mitochondria-specific therapy would provide an efficient strategy for treating resistant cancers.
  
  
  METHODS
  A strategy was proposed here to overcome MDR by designing cancer mitochondria-specific drug-loaded liposomes, namely, antiresistant epirubicin mitosomes, aimed at treating resistant leukemia by targeting mitochondria. Evaluations were performed on human chronic leukemia K562, MDR K562/ADR cells, and female BALB/c nude mice xenografted with MDR K562/ADR cells. The liposomes were characterized through assays of cytotoxicity, mitochondrial targeting, caspase-9 and caspase-3, antitumor activities, and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) analysis.
  
  
  RESULTS
  The average size of antiresistant epirubicin mitosomes was in the range of 105-115 nm. Antiresistant epirubicin mitosomes were effective in inhibiting proliferation of MDR K562/ADR cells in vitro and selectively accumulated into the mitochondria. Caspase-9 and caspase-3 activity was increased after applying antiresistant epirubicin mitosomes. In xenografted resistant MDR K562/ADR tumor in nude mice, antiresistant tumor effect of antiresistant epirubicin mitosomes was evidently observed. Apoptotic inducing effects by antiresistant epirubicin mitosomes were noticeably evidenced via mitochondrial pathway.
  
  
  CONCLUSIONS
  Antiresistant epirubicin mitosomes had significant inhibitory effect against resistant leukemia in vitro and in vivo, hence providing a promising strategy for improving therapeutic efficacy in resistant human leukemia.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Men
authors.forename: Xiao-Xing
authors.initials: XX
authors.lastname: Wang
authors.forename: Ruo-Jing
authors.initials: RJ
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Tian
authors.forename: Hong-Juan
authors.initials: HJ
authors.lastname: Yao
authors.forename: Rui-Jun
authors.initials: RJ
authors.lastname: Ju
authors.forename: Xue
authors.initials: X
authors.lastname: Ying
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Wan-Liang
authors.initials: WL
authors.lastname: Lu
mesh_terms: D017311:Amlodipine; D000704:Analysis of Variance; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000378:metabolism*; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D017311:Amlodipine; D015251:Epirubicin; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9