Zając-Grabiec Anna, Czopek Anna, Pazdan Karolina, Jończyk Jakub, Michałkiewicz Filip, Skóra Tomasz, Krzyżowska Monika, Biesaga Beata, Wiśniewski Dominik, Ajersch Paula, Miszczyk Justyna
Department of Medical Physics, Cyclotron Centre Bronowice, Institute of Nuclear Physics, Polish Academy of Sciences, Radzikowskiego 152, Kraków, 31-342, Poland.
Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków, 30-688, Poland.
Pharmacol Rep. 2025 Sep 3. doi: 10.1007/s43440-025-00783-w.
Central nervous system (CNS) tumors, including gliomas, are among the most aggressive cancers, with glioblastoma multiforme (GBM) being the most common and lethal. This study explores the potential of multidrug repositioning as a modern chemotherapy strategy for GBM cell lines. It combines the standard GBM chemotherapeutic temozolomide (TMZ) with olaparib (OLA) and oxaliplatin (OXA), both repurposed from other cancer types. Most experimental drug therapy studies focus on just one or two selected high-grade GBM cell lines, but in this study, four such cell lines were used.
Glioblastoma (GBM) cell lines U118 MG, H4, U251 MG and U87 MG were treated for 72 h with oxaliplatin (OXA, 50-200 µM), olaparib (OLA, 1-100 µM), or temozolomide (TMZ, 10-100 µM). Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) assay. Half-maximal inhibitory concentration (IC₅₀) values were calculated using GraphPad Prism 8. A human fibroblast line (hFib) from a healthy donor was used as a control. The type of cell death following the above treatments was analysed using a fluorescence-based Apoptotic, Necrotic & Healthy Cells Quantification Kit.
The combination of OLA, OXA, and TMZ significantly reduced cell viability and survival, inducing apoptosis/necrosis more effectively than TMZ alone. These synergistic effects alter glioblastoma metabolism, promote apoptosis, and enhance antitumor activity in vitro.
The proposed multidrug repositioning chemotherapy produced a therapeutic effect at lower doses, suggesting that it is potentially a safer and more effective treatment option.
包括胶质瘤在内的中枢神经系统（CNS）肿瘤是最具侵袭性的癌症之一，多形性胶质母细胞瘤（GBM）最为常见且致命。本研究探索了多药重新定位作为GBM细胞系现代化疗策略的潜力。它将标准的GBM化疗药物替莫唑胺（TMZ）与从其他癌症类型重新利用的奥拉帕利（OLA）和奥沙利铂（OXA）联合使用。大多数实验性药物治疗研究仅关注一两种选定的高级别GBM细胞系，但在本研究中使用了四种此类细胞系。
用奥沙利铂（OXA，50 - 200 μM）、奥拉帕利（OLA，1 - 100 μM）或替莫唑胺（TMZ，10 - 100 μM）对胶质母细胞瘤（GBM）细胞系U118 MG、H4、U251 MG和U87 MG进行72小时处理。使用3 -（4,5 - 二甲基噻唑 - 2 - 基）- 5 -（3 - 羧基甲氧基苯基）- 2 -（4 - 磺基苯基）- 2H - 四唑（MTS）测定法评估细胞活力。使用GraphPad Prism 8计算半数最大抑制浓度（IC₅₀）值。将来自健康供体的人成纤维细胞系（hFib）用作对照。使用基于荧光的凋亡、坏死和健康细胞定量试剂盒分析上述处理后的细胞死亡类型。
OLA、OXA和TMZ的联合使用显著降低了细胞活力和存活率，比单独使用TMZ更有效地诱导凋亡/坏死。这些协同作用改变了胶质母细胞瘤的代谢，促进了凋亡，并增强了体外抗肿瘤活性。
所提出的多药重新定位化疗在较低剂量下产生了治疗效果，表明它可能是一种更安全、更有效的治疗选择。
