Aspirin-/TMZ-coloaded microspheres exert synergistic antiglioma efficacy via inhibition of β-catenin transactivation.

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.