Gaiaschi Ludovica, Casali Claudio, Stabile Andrea, D'Amico Sharon, Ravera Mauro, Gabano Elisabetta, Galluzzo Andrea, Favaron Cristina, Gola Federica, De Luca Fabrizio, Pellegatta Serena, Bottone Maria Grazia
Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
Department of Sciences and Technological Innovation (DiSIT), University of Piemonte Orientale "A. Avogadro", Alessandria, Italy.
Cell Prolif. 2025 Jun;58(6):e13815. doi: 10.1111/cpr.13815. Epub 2025 Jan 27.
Due to the lack of effective therapeutic approach, glioblastoma (GBM) remains one of the most malignant brain tumour. By in vitro investigations on primary GBM stem cells, we highlighted one of the underlying mechanisms of drug resistance to alkylating agents, the DNA damage responses. Here, flow cytometric analysis and viability and repopulation assays were used to assess the long-term cytotoxic effect induced by the administration of a fourth-generation platinum prodrug, the (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato) platinum(IV) named Pt(IV)Ac-POA, in comparison to the most widely used Cisplatin. The immunofluorescence studies revealed changing pathways involved in the DNA damage response mechanisms in response to the two chemotherapies, suggesting in particular the role of Poly (ADP-Ribose) polymerases in the onset of resistance to Cisplatin-induced cytotoxicity. Thus, this research provides a proof of concept for how the use of a prodrug which allows the co-administration of Cisplatin and an Histone DeACetylase inhibitors, could suppress DNA repair mechanisms, suggesting a novel effective approach in GBM treatment.
由于缺乏有效的治疗方法，胶质母细胞瘤（GBM）仍然是最恶性的脑肿瘤之一。通过对原发性GBM干细胞进行体外研究，我们揭示了对烷化剂耐药的潜在机制之一，即DNA损伤反应。在这里，与最广泛使用的顺铂相比，我们使用流式细胞术分析以及活力和再增殖试验来评估给予第四代铂前药（OC-6-44）-乙酸二氨二氯（2-（2-丙炔基）辛酸酯）铂（IV）（简称Pt（IV）Ac-POA）所诱导的长期细胞毒性作用。免疫荧光研究揭示了两种化疗药物作用下DNA损伤反应机制中涉及的变化途径，特别表明了聚（ADP-核糖）聚合酶在顺铂诱导的细胞毒性耐药发生中的作用。因此，本研究为使用一种能同时给予顺铂和组蛋白去乙酰化酶抑制剂的前药如何抑制DNA修复机制提供了概念验证，为GBM治疗提出了一种新的有效方法。
