Open AccessAspirin‐/ TMZ ‐coloaded Microspheres Exert Synergistic Antiglioma Efficacy via Inhibition of β‐catenin Transactivation
Author(s) -
Shi ZhenDong,
Qian XiaoMin,
Liu ChaoYong,
Han Lei,
Zhang KaiLiang,
Chen LuYue,
Zhang JunXia,
Pu PeiYu,
Yuan XuBo,
Kang ChunSheng
Publication year - 2013
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12041
Subject(s) - transactivation , temozolomide , aspirin , chemistry , cancer research , apoptosis , in vivo , pharmacology , catenin , growth inhibition , medicine , signal transduction , biology , glioblastoma , gene expression , biochemistry , wnt signaling pathway , microbiology and biotechnology , gene
Summary Background and Aims 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 LN 229 and U 87 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 LN 229 and U 87 cells. Corresponding to inhibition of β‐catenin signaling, β‐catenin/ TCF 4 transcriptional activity and STAT 3 luciferase activity were strongly suppressed, and downstream targets expression was decreased. Furthermore, aspirin/ TMZ microsphere intratumoral injection downregulated the expression of β‐catenin, TCF 4, pAKT , pSTAT 3, and PCNA and delayed tumor growth in nude mice harboring subcutaneous LN 229 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.