Abstract:
Soloxolone amides are semisynthetic triterpenoids that can cross the blood-brain barrier and inhibit glioblastoma growth both in vitro and in vivo. Here we investigate the impact of these compounds on processes associated with glioblastoma invasiveness and therapy resistance. Screening of soloxolone amides against glioblastoma cells revealed the ability of compound 7 (soloxolone para-methylanilide) to inhibit transforming growth factor-beta 1 (TGF-β1)-induced glial-mesenchymal transition Compound 7 inhibited morphological changes, wound healing, transwell migration, and expression of mesenchymal markers (N-cadherin, fibronectin, Slug) in TGF-β1-induced U87 and U118 glioblastoma cells, while restoring their adhesiveness. Confocal microscopy and molecular docking showed that 7 reduced SMAD2/3 nuclear translocation probably by direct interaction with the TGF-β type I and type II receptors (TβRI/II). In addition, 7 suppressed stemness of glioblastoma cells as evidenced by inhibition of colony forming ability, spheroid growth, and aldehyde dehydrogenase (ALDH) activity. Furthermore, 7 exhibited a synergistic effect with temozolomide (TMZ) on glioblastoma cell viability. Using N-acetyl-L-cysteine (NAC) and flow cytometry analysis of Annexin V-FITC-, propidium iodide-, and DCFDA-stained cells, 7 was found to synergize the cytotoxicity of TMZ by inducing ROS-dependent apoptosis. Further in vivo studies showed that 7, alone or in combination with TMZ, effectively suppressed the growth of U87 xenograft tumors in mice. Thus, 7 demonstrated promising potential as a component of combination therapy for glioblastoma, reducing its invasiveness and increasing its sensitivity to chemotherapy.
摘要:
索洛酮酰胺是半合成的三萜类化合物,可以在体外和体内穿过血脑屏障并抑制胶质母细胞瘤的生长。在这里,我们研究了这些化合物对胶质母细胞瘤侵袭性和治疗抗性相关过程的影响。针对胶质母细胞瘤细胞的索洛酮酰胺的筛选揭示了化合物7(索洛酮对甲基苯胺)抑制转化生长因子β1(TGF-β1)诱导的神经胶质间质转化的能力化合物7抑制了形态学变化,伤口愈合,Transwell迁移,和间充质标志物(N-cadherin,纤连蛋白,Slug)在TGF-β1诱导的U87和U118胶质母细胞瘤细胞中,同时恢复它们的粘附性。共聚焦显微镜和分子对接显示,7可能通过与TGF-βI型和II型受体(TβRI/II)的直接相互作用来减少SMAD2/3核易位。此外,7抑制胶质母细胞瘤细胞的干性,如集落形成能力的抑制所证明,球体生长,和醛脱氢酶(ALDH)活性。此外,图7显示了与替莫唑胺(TMZ)对成胶质细胞瘤细胞活力的协同作用。使用N-乙酰-L-半胱氨酸(NAC)和流式细胞术分析膜联蛋白V-FITC-,碘化丙啶-,和DCFDA染色的细胞,发现7通过诱导ROS依赖性凋亡协同TMZ的细胞毒性。进一步的体内研究表明,7,单独或与TMZ联合使用,有效抑制小鼠U87异种移植瘤的生长。因此,7证明了作为胶质母细胞瘤联合治疗的组成部分的有希望的潜力,降低其侵袭性并增加其对化疗的敏感性。