2026-04-26T23:12:03Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/260142025-12-18T12:52:28Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587
Repisalud
author
Jiménez-Alcázar, Miguel
author
Curiel-García, Álvaro
author
Nogales, Paula
author
Perales-Patón, Javier
author
Schuhmacher, Alberto J
author
Galán-Ganga, Marcos
author
Zhu, Lucía
author
Lowe, Scott W
author
Al-Shahrour, Fatima
author
Squatrito, Massimo
funder
Fundación Seve Ballesteros
funder
Asociación Española Contra el Cáncer
funder
European Molecular Biology Organization
funder
Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
funder
Ministerio de Economía, Industria y Competitividad (España)
funder
Fundación La Caixa
2025-01-14T10:36:31Z
2025-01-14T10:36:31Z
2021-06
Mol Cancer Ther. 2021 Jun;20(6):1029-1038.
https://hdl.handle.net/20.500.12105/26014
33846235
Molecular Cancer Therapeutics
Glioblastoma (GBM) is the most frequent and aggressive primary tumor type in the central nervous system in adults. Resistance to chemotherapy remains one of the major obstacles in GBM treatment. Identifying and overcoming the mechanisms of therapy resistance is instrumental to develop novel therapeutic approaches for patients with GBM. To determine the major drivers of temozolomide (TMZ) sensitivity, we performed shRNA screenings in GBM lines with different O6-methylguanine-DNA methyl-transferase (MGMT) status. We then evaluated dianhydrogalactitol (Val-083), a small alkylating molecule that induces interstrand DNA crosslinking, as a potential treatment to bypass TMZ-resistance mechanisms. We found that loss of mismatch repair (MMR) components and MGMT expression are mutually exclusive mechanisms driving TMZ resistance Treatment of established GBM cells and tumorsphere lines with Val-083 induces DNA damage and cell-cycle arrest in G-M phase, independently of MGMT or MMR status, thus circumventing conventional resistance mechanisms to TMZ. Combination of TMZ and Val-083 shows a synergic cytotoxic effect in tumor cells , and We propose this combinatorial treatment as a potential approach for patients with GBM.
eng
Dianhydrogalactitol Overcomes Multiple Temozolomide Resistance Mechanisms in Glioblastoma.
research article
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URL
https://repisalud.isciii.es/bitstreams/b14b141d-cbc3-46d2-8b8b-64dab8277a05/download
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75e8bf8c29686d8d98a62ab4ea294765
1784792
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Dianhydrogalactitol Overcomes_Mol Cancer Ther_2021.pdf