Purine metabolism rewiring improves glioblastoma susceptibility to temozolomide treatment

D'Aprile, Simona (author), Denaro, Simona (author), Torrisi, Filippo (author), Longhitano, Lucia (author), Giallongo, Sebastiano (author), Giallongo, Cesarina (author), Bontempi, Vittorio (author), Bucolo, Claudio (author), Drago, Filippo (author), Mione, Maria Caterina (author), Potokar, Maja (author), Jorgačevski, Jernej (author), Zorec, Robert (author)

Glioblastoma (GBM) is among the deadliest cancers, characterized by poor prognosis and median survival of 12-15 months post-diagnosis. Despite aggressive therapeutic regimens, GBM treatment is still an unmet clinical need due to heterogeneity, recurrencies, and resistance. Metabolic reshaping is emerging as a critical mechanism supporting cell proliferation and sustaining chemoresistance. In this study, we explored metabolic changes induced by chemotherapy in temozolomide (TMZ)-sensitive and TMZ-resistant GBM cell lines. We found that purine levels were altered in sensitive versus resistant GBM cells, highlighting a critical role of guanosine and inosine metabolism. By using a mesenchymal-like GBM zebrafish model, we uncovered dysregulated pathways involved in purine metabolism, with a downregulation of catabolic processes. Our data indicate that combined treatment with TMZ plus guanosine and inosine increased cytotoxicity, enhancing chemotherapy effectiveness in TMZ-resistant cells. These effects correlated with alterations in mitochondrial dynamics and activity. Specifically, the combinatorial effectiveness of TMZ with guanosine and inosine was linked to Mitofusin-2 overexpression, enhancing mitochondrial fusion, typically associated with a better prognosis. Therefore, our findings suggest that purine metabolism is involved in the metabolic rewiring of TMZ-resistant cells, suggesting guanosine and inosine as potential adjuvant treatments to improve the cytotoxicity effects of chemotherapy in resistant GBM.

• Language: English
• Keywords: metabolism, purine, glioblastoma, temozolomide, treatment
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: 12 str.
• Numbering: Vol. 16, iss. 1, art. 336
• PID: 20.500.12556/RUL-181456
• UDC: 616-092
• ISSN on article: 2041-4889
• DOI: 10.1038/s41419-025-07667-0
• COBISS.SI-ID: 237002499
• Publication date in RUL: 08.04.2026

Record is a part of a journal

• Title: Cell death & disease
• Publisher: Springer Nature
• ISSN: 2041-4889
• COBISS.SI-ID: 24434727

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: presnova, purin, glioblastom, temozolomid, zdravljenje