PDF(Pubmed)
Abstract：
Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this study, we investigated the potential of PBI-05204 in targeting GBM stem cells (GSCs) and the underlying mechanisms. Treatment with PBI-05204 significantly reduced both the number and size of tumor spheres derived from patient-derived GSCs (GBM9, GSC28 and TS543), and suppressed the tumorigenesis of GBM9 xenografts. Moreover, PBI-05204 treatment led to a significant decrease in the expression of CD44 and NANOG, crucial markers of progenitor stem cells, in GBM9 and GSC28 GSCs. This treatment also down-regulated GRP78 expression in both GSC types. Knocking down GRP78 expression through GRP78 siRNA transfection in GBM9 and GSC28 GSCs also resulted in reduced spheroid size and CD44 expression. Combining PBI-05204 with GRP78 siRNA further decreased spheroid numbers compared to GRP78 siRNA treatment alone. PBI-05204 treatment led to increased expression of pRIP1K and pRIP3K, along with enhanced binding of RIPK1/RIPK3 in GBM9 and GSC28 cells, resembling the effects observed in GRP78-silenced GSCs, suggesting that PBI-05204 induced necroptosis in these cells. Furthermore, oleandrin, a principle active cardiac glycoside component of PBI-05204, showed the ability to inhibit the self-renewal capacity in GSCs. These findings highlight the potential of PBI-05204 as a promising candidate for the development of novel therapies that target GBM stem cells.
摘要：
多形性胶质母细胞瘤（GBM）的成功治疗，一种侵袭性的原发性脑肿瘤,要求开发新的治疗策略。在这项研究中,我们研究了PBI-05204靶向GBM干细胞(GSCs)的潜力和潜在机制.用PBI-05204治疗显著减少了源自患者来源的GSC（GBM9、GSC28和TS543）的肿瘤球体的数量和大小，并抑制了GBM9异种移植物的肿瘤发生。此外，PBI-05204处理导致CD44和NANOG的表达显著降低,祖细胞的关键标记，在GBM9和GSC28GSC中。该处理还下调两种GSC类型中的GRP78表达。通过GRP78siRNA转染在GBM9和GSC28GSC中抑制GRP78表达也导致球状体大小和CD44表达减少。与单独的GRP78siRNA处理相比,将PBI-05204与GRP78siRNA组合进一步减少球状体数目。PBI-05204处理导致pRIP1K和pRIP3K的表达增加,随着GBM9和GSC28细胞中RIPK1/RIPK3的结合增强，类似于在GRP78沉默的GSC中观察到的效果，提示PBI-05204在这些细胞中诱导坏死。此外，夹竹桃,PBI-05204的主要活性强心苷成分，显示出抑制GSCs自我更新能力的能力。这些发现凸显了PBI-05204作为开发靶向GBM干细胞的新疗法的有希望的候选者的潜力。
