Abstract 776: Sensitization of glioblastoma cells to temozolomide induced antitumor effect by PLGA-aspirin microsphere through modulation of β-catenin transactivation

Abstract

Abstract Malignant gliomas are the most prevalent and deadliest brain neoplasms. Although temozolomide (TMZ) was currently used for treating glioblastoma patients, the recurrence was commonly existed due to the acquired therapeutic resistance. Thus the combination chemotherapy with TMZ is considered a promising therapeutic strategy in overcoming therapeutic resistance and improving treatment efficacy. In this study, we performed PLGA microspheres of aspirin and TMZ by spray drying technique and detected their cytotoxicity to glioblastoma cells. In vitro assay, PLGA-aspirin (PLGA-A) microsphere treatment revealed a slight inhibition of proliferation, invasion, as well as slightly induced apoptosis of A172 and U87 cells through inhibition of β-catenin transactivation in comparison with PLGA microsphere and Control group. In addition, the limited antitumor effect was also demonstrated in vivo. However, PLGA-aspirin-temozolomide (PLGA-A-T) microsphere treatment group displayed enhancing antitumor efficacy compared with PLGA-temozolomide (PLGA-T) microsphere group. IC50 values were dramatically decreased in cells treated with PLGA-A-T microsphere, to a greater extent than those treated with PLGA-A microsphere. Meanwhile, the PLGA-A-T microsphere significantly enhanced apoptosis in both A172 cells and U87 cells, and cell proliferation and invasiveness were obviously weakened. In response to the inhibition of β-catenin signaling, β-catenin/TCF4 transcriptional activity and STAT3 luciferase activity was strongly inhibited, as well as a greater decrease of mRNA and protein expression levels of β-catenin, TCF4, pAKT and pSTAT3.Similar results were also observed in vivo, intratumoral injection of PLGA-A-T microsphere significantly downregulated expression of β-catenin, TCF4, pAKT, pSTAT3 and PCNA, and also delayed tumor growth in nude mice harboring subcutaneous U87 xenografts. These results indicated that the synergistic cytotoxic effect of aspirin and temozolomide was achieved by aspirin- temozolomide -loaded PLGA nanoparticles through inhibition of β-catenin transactivation, offering the potential for improved treatment of glioblastomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 776. doi:1538-7445.AM2012-776