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首页> 外文期刊>CNS neuroscience & therapeutics. >Aspirin‐/ TMZ ‐coloaded Microspheres Exert Synergistic Antiglioma Efficacy via Inhibition of β‐catenin Transactivation
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Aspirin‐/ TMZ ‐coloaded Microspheres Exert Synergistic Antiglioma Efficacy via Inhibition of β‐catenin Transactivation

机译：阿司匹林/ TMZ载药微球通过抑制β-连环蛋白反式激活发挥协同抗胶质瘤功效

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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.
机译：发明背景和目的目前，替莫唑胺（TMZ）作为有效剂被广泛用于治疗多形性胶质母细胞瘤（GBM），而由于固有或获得的治疗抗性经常复发。联合化疗与TMZ可能是改善治疗效果的有前途的治疗策略。方法通过喷雾干燥制备阿司匹林，TMZ和阿司匹林/ TMZ负载的聚L-丙交酯-乙交酯（PLGA）微球，并测定胶质母细胞瘤细胞的细胞毒性。结果阿司匹林微球治疗可通过抑制β-catenin反式激活在体外和体内诱导轻度凋亡并适度抑制LN 229和U 87细胞的增殖。然而，与单个TMZ装载的微球相比，阿司匹林/ TMZ装载的微球具有协同的抗肿瘤功效。阿司匹林/ TMZ微球诱导更多的凋亡并抑制LN 229和U 87细胞的增殖。与抑制β-catenin信号传导相对应，β-catenin/ TCF 4转录活性和STAT 3荧光素酶活性被强烈抑制，下游靶标表达降低。此外，阿司匹林/ TMZ微球瘤内注射下调了皮下LN 229异种移植裸鼠的β-catenin，TCF 4，pAKT，pSTAT 3和PCNA的表达，并延迟了肿瘤的生长。结论阿司匹林通过抑制β-catenin反式激活而提高了TMZ化疗的疗效。此外，负载的微球实现了缓释作用以减少TMZ剂量，为胶质母细胞瘤的治疗提供了潜力。

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