title: Aspirin-/TMZ-coloaded microspheres exert synergistic antiglioma efficacy via inhibition of β-catenin transactivation.
abstract: OBJECTIVE
  Currently temozolomide (TMZ) as a potent agent is widely used to treat the glioblastoma multiforme (GBM), whereas recurrence due to intrinsic or acquired therapeutic resistance often occurs. Combination chemotherapy with TMZ may be a promising therapeutic strategy to improve treatment efficacy.
  
  
  METHODS
  Aspirin, TMZ, and aspirin-/TMZ-coloaded poly (L-lactide-co-glycolide) (PLGA) microspheres were prepared by spray drying, and cytotoxicities of glioblastoma cells were measured.
  
  
  RESULTS
  Aspirin microsphere treatment induced slight apoptosis and modestly inhibited proliferation of LN229 and U87 cells in vitro and in vivo through inhibition of β-catenin transactivation. However, aspirin-/TMZ-coloaded microspheres presented synergistic antitumor efficacy compared with single TMZ-loaded microspheres. Aspirin/TMZ microspheres induced more apoptosis and repressed proliferation of LN229 and U87 cells. Corresponding to inhibition of β-catenin signaling, β-catenin/TCF4 transcriptional activity and STAT3 luciferase activity were strongly suppressed, and downstream targets expression was decreased. Furthermore, aspirin/TMZ microsphere intratumoral injection downregulated the expression of β-catenin, TCF4, pAKT, pSTAT3, and PCNA and delayed tumor growth in nude mice harboring subcutaneous LN229 xenografts.
  
  
  CONCLUSIONS
  Aspirin sensitized TMZ chemotherapy efficacy through inhibition of β-catenin transactivation; furthermore, the coloaded microspheres achieved a sustained release action to reduce the TMZ dosage, offering the potential for improved treatment of glioblastomas.
authors.affiliation: Laboratory of Neuro-Oncology, Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, China.
authors.forename: Zhen-Dong
authors.initials: ZD
authors.lastname: Shi
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Qian
authors.forename: Chao-Yong
authors.initials: CY
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.forename: Kai-Liang
authors.initials: KL
authors.lastname: Zhang
authors.forename: Lu-Yue
authors.initials: LY
authors.lastname: Chen
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Zhang
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Pu
authors.forename: Xu-Bo
authors.initials: XB
authors.lastname: Yuan
authors.forename: Chun-Sheng
authors.initials: CS
authors.lastname: Kang
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D001241:Aspirin / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004337:Drug Carriers / Q000008:administration & dosage; D004357:Drug Synergism; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008863:Microspheres; D011897:Random Allocation; D000077204:Temozolomide; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004337:Drug Carriers; D051176:beta Catenin; D003606:Dacarbazine; D001241:Aspirin; D000077204:Temozolomide