Aspirin‐/TMZ‐coloaded Microspheres Exert Synergistic Antiglioma Efficacy via Inhibition of β‐catenin Transactivation

Authors:
  • C(Chinese Glioma Cooperative Group (CGCG)
    Chinese Glioma Cooperative Group (CGCG)
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Abstract
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 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.
Funding Information
  • China National Natural Scientific Fund (81001128, 81172406, 51073118)
  • Tianjin Municipal Science and Technology Committee (09JCZDJC17600, 10SYSYJC28800, NCET-08-0334)
  • National High Technology Research and Development Program (2012AA02A508)

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