Bartels Lauren E, Mattheolabakis George, Vaeth Brandon M, LaComb Joseph F, Wang Ruixue, Zhi Jizu, Komninou Despina, Rigas Basil, Mackenzie Gerardo G
Department of Family, Population and Preventive Medicine.
Department of Medicine and.
Carcinogenesis. 2016 Apr;37(4):420-429. doi: 10.1093/carcin/bgw017. Epub 2016 Feb 10.
Given that glioblastoma multiforme (GBM) is associated with poor prognosis, new agents are urgently needed. We developed phospho-glycerol-ibuprofen-amide (PGIA), a novel ibuprofen derivative, and evaluated its safety and efficacy in preclinical models of GBM, and its mechanism of action using human GBM cells and animal tumor models. Furthermore, we explored whether formulating PGIA in polymeric nanoparticles could enhance its levels in the brain. PGIA was 3.7- to 5.1-fold more potent than ibuprofen in suppressing the growth of human GBM cell lines. PGIA 0.75× IC50 inhibited cell proliferation by 91 and 87% in human LN-229 and U87-MG GBM cells, respectively, and induced strong G1/S arrest.In vivo, compared with control, PGIA reduced U118-MG and U87-MG xenograft growth by 77 and 56%, respectively (P< 0.05), and was >2-fold more efficacious than ibuprofen. Normal human astrocytes were resistant to PGIA, indicating selectivity. Mechanistically, PGIA reduced cyclin D1 levels in a time- and concentration-dependent manner in GBM cells and in xenografts. PGIA induced cyclin D1 degradation via the proteasome pathway and induced dephosphorylation of GSK3β, which was required for cyclin D1 turnover. Furthermore, cyclin D1 overexpression rescued GBM cells from the cell growth inhibition by PGIA. Moreover, the formulation of PGIA in poly-(L)-lactic acid poly(ethylene glycol) polymeric nanoparticles improved its pharmacokinetics in mice, delivering PGIA to the brain. PGIA displays strong efficacy against GBM, crosses the blood-brain barrier when properly formulated, reaching the target tissue, and establishes cyclin D1 as an important molecular target. Thus, PGIA merits further evaluation as a potential therapeutic option for GBM.
鉴于多形性胶质母细胞瘤（GBM）预后较差，迫切需要新的治疗药物。我们研发了一种新型布洛芬衍生物——磷酸甘油-布洛芬酰胺（PGIA），并在GBM临床前模型中评估了其安全性和有效性，同时利用人GBM细胞和动物肿瘤模型研究了其作用机制。此外，我们还探讨了将PGIA制成聚合物纳米颗粒是否能提高其在脑内的浓度。在抑制人GBM细胞系生长方面，PGIA的效力比布洛芬高3.7至5.1倍。PGIA 0.75×IC50分别抑制人LN-229和U87-MG GBM细胞的增殖91%和87%，并诱导强烈的G1/S期阻滞。在体内，与对照组相比，PGIA分别使U118-MG和U87-MG异种移植瘤的生长减少77%和56%（P<0.05），且疗效比布洛芬高2倍以上。正常人星形胶质细胞对PGIA具有抗性，表明其具有选择性。从机制上讲，PGIA在GBM细胞和异种移植瘤中以时间和浓度依赖性方式降低细胞周期蛋白D1水平。PGIA通过蛋白酶体途径诱导细胞周期蛋白D1降解，并诱导GSK3β去磷酸化，这是细胞周期蛋白D1周转所必需的。此外，细胞周期蛋白D1过表达可使GBM细胞免受PGIA对细胞生长的抑制。此外，将PGIA制成聚（L）-乳酸聚乙二醇聚合物纳米颗粒可改善其在小鼠体内的药代动力学，使PGIA能够进入脑内。PGIA对GBM显示出强大的疗效，在适当制剂的情况下可穿过血脑屏障，到达靶组织，并确定细胞周期蛋白D1为重要的分子靶点。因此，PGIA作为GBM的潜在治疗选择值得进一步评估。
