Yadav Niket, Xiao Aizhen, Zhong Qing, Kumar Pankaj, Konduru Guruprasad, Hart William, Lazzara Matthew, Purow Benjamin
Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA.
Medical Scientist Training Program (MSTP), University of Virginia School of Medicine, Charlottesville, VA, 22903, USA.
J Neurooncol. 2025 May 28. doi: 10.1007/s11060-025-05089-8.
This study investigates the synergistic therapeutic potential of a novel combination of the repurposed drug simvastatin with irinotecan chemotherapy towards glioblastoma (GBM) and the underlying molecular mechanisms.
In vitro efficacy of simvastatin and irinotecan alone and in combination against diverse GBM lines (U251MG, G34, SB28) was assessed using mechanistically distinct cell viability assays. RNA-Sequencing was performed to uncover the top pathways and genes affected by these drugs, followed by validation of promising pathways (TGF-β signaling and cell death) using targeted phosphoproteomics and in vitro genetic manipulation and functional assays.
We observed robust in vitro synergy at nanomolar concentrations between simvastatin and irinotecan across diverse GBM lines. Notably, irinotecan alone and in combination with simvastatin reduced mRNA expression of TGF-β family members. Targeted phosphoproteomics and functional experiments further showed significant inhibition of TGF-β signaling with both treatment types. Additionally, a role for apoptosis and enrichment of caspase-independent cell death pathways (autophagy, ferroptosis) as well as immunological (interferons, complement, inflammatory responses, TNF-α) and oncogenic (K-RAS/ERK) signaling pathways were observed with the combination treatment.
Besides the first detailed demonstration of a robust synergy between simvastatin and irinotecan against GBM lines, this study shows for the first time that both irinotecan and the combination treatment converge on inhibition of TGF-β signaling. This is notable given the lack of TGF-β inhibitors in the clinic. Collectively, this study provides preclinical data suggesting this novel drug combination be tested in patients with GBM and TGF-β driven cancers.
本研究探讨重新利用的药物辛伐他汀与伊立替康化疗的新型组合对胶质母细胞瘤（GBM）的协同治疗潜力及其潜在分子机制。
使用机制不同的细胞活力测定法评估辛伐他汀和伊立替康单独及联合对多种GBM细胞系（U251MG、G34、SB28）的体外疗效。进行RNA测序以揭示受这些药物影响的主要信号通路和基因，随后使用靶向磷酸蛋白质组学以及体外基因操作和功能测定法验证有前景的信号通路（TGF-β信号传导和细胞死亡）。
我们观察到在纳摩尔浓度下，辛伐他汀和伊立替康在多种GBM细胞系中具有强大的体外协同作用。值得注意的是，单独使用伊立替康以及与辛伐他汀联合使用时，均可降低TGF-β家族成员的mRNA表达。靶向磷酸蛋白质组学和功能实验进一步表明，两种治疗方式均能显著抑制TGF-β信号传导。此外，联合治疗还观察到细胞凋亡的作用以及半胱天冬酶非依赖性细胞死亡途径（自噬、铁死亡）的富集，以及免疫（干扰素、补体、炎症反应、TNF-α）和致癌（K-RAS/ERK）信号通路。
除了首次详细证明辛伐他汀和伊立替康对GBM细胞系具有强大的协同作用外，本研究还首次表明伊立替康和联合治疗均能抑制TGF-β信号传导。鉴于临床上缺乏TGF-β抑制剂，这一点值得关注。总体而言，本研究提供了临床前数据，表明这种新型药物组合可在GBM和TGF-β驱动的癌症患者中进行测试。
