Chiou Jennifer, Impedovo Valeria, Huynh Yen Bao, Gorgoglione Ruggiero, Penalva Luiz O F, Lodi Alessia, Brenner Andrew J, Tiziani Stefano
Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX 78712, USA.
Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX 78723, USA.
Int J Mol Sci. 2025 Jan 8;26(2):474. doi: 10.3390/ijms26020474.
Glioblastoma (GBM), the most prevalent primary malignant brain tumor, remains challenging to treat due to extensive inter- and intra-tumor heterogeneity. This variability demands combination treatments to improve therapeutic outcomes. A significant obstacle in treating GBM is the expression of O-methylguanine-DNA methyltransferase, a DNA repair enzyme that reduces the efficacy of the standard alkylating agent, temozolomide, in about 50% of patients. This underscores the need for novel, more targeted therapies. Our study investigates the metabolic-epigenetic impact of combining SN-38, a novel topoisomerase inhibitor inducing DNA double-strand breaks, with rabusertib, a checkpoint kinase 1 inhibitor. We identified this synergistic combination through high-throughput drug screening across a panel of GBM cell lines using a cancer drug library combined with SN-38. A secondary metabolic screening with the PEDS algorithm demonstrated a synergistic modulation of purine, one-carbon, and redox metabolism. Furthermore, the combined treatment led to the significant depletion of epigenetically relevant metabolites such as 5-methyl-cytosine, acetyl-lysine, and trimethyl-lysine. Reduced intermediates of the glutathione cycle indicated increased cellular stress following combinatorial treatment. Overall, the combination of SN-38 and rabusertib synergistically disrupts metabolites associated with epigenetic adaptations, leading to cytotoxicity independent of O-methylguanine-DNA methyltransferase status, thereby underpinning this combination as a promising candidate for combinatorial therapy in GBM.
胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，由于肿瘤间和肿瘤内广泛的异质性，其治疗仍然具有挑战性。这种变异性需要联合治疗来改善治疗效果。治疗GBM的一个重大障碍是O-甲基鸟嘌呤-DNA甲基转移酶的表达，这是一种DNA修复酶，在约50%的患者中会降低标准烷化剂替莫唑胺的疗效。这凸显了对新型、更具针对性疗法的需求。我们的研究调查了新型拓扑异构酶抑制剂SN-38（可诱导DNA双链断裂）与检查点激酶1抑制剂瑞博西尼联合使用对代谢-表观遗传的影响。我们通过使用癌症药物库与SN-38对一组GBM细胞系进行高通量药物筛选，确定了这种协同组合。使用PEDS算法进行的二次代谢筛选显示嘌呤、一碳和氧化还原代谢受到协同调节。此外，联合治疗导致表观遗传相关代谢物如5-甲基胞嘧啶、乙酰赖氨酸和三甲基赖氨酸显著减少。谷胱甘肽循环中间产物的减少表明联合治疗后细胞应激增加。总体而言，SN-38和瑞博西尼的联合使用可协同破坏与表观遗传适应相关的代谢物，导致细胞毒性，且与O-甲基鸟嘌呤-DNA甲基转移酶状态无关，从而支持这种联合用药作为GBM联合治疗的一个有前景的候选方案。
