Metabolic Vulnerabilities of Temozolomide-Resistant Glioblastoma Cells: Implications for Targeted Therapies and Overcoming Chemoresistance

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Abstract Chemoresistance is a major clinical challenge in the management of glioblastoma (GB), making it difficult to achieve long-term success with traditional treatments. Therefore, there is a need for the development of novel drugs. We explored the metabolic vulnerabilities of temozolomide (TMZ)-resistant GB and their potential implications for targeted therapies. In monolayer and tumoroid cultures, we found elevated reliance on oxidative phosphorylation in TMZ-resistant cells. Notably, iron reduction in TMZ-resistant cells reduced viability and proliferation, upregulated hypoxia-inducible factor 1-α (Hif1-α) expression, induced autophagy, inhibited autophagic flux, and increased reactive oxygen species (ROS) generation, indicating the significance of iron in metabolic vulnerabilities of these cells. Hypoxic cells showed acquired resistance to iron chelation compared to their normoxic state, suggesting an adaptive mechanism associated to hypoxia. Viability, size, and invasion were reduced in TMZ-resistant tumoroids. Additionally, we reported IC50 for the combination of TMZ with a range of DFO and DFP, making the combination therapy a promising drug candidate to improve therapeutic treatments. Teaser Combining iron reduction and chemotherapy in drug-resistant glioblastoma cells enhances therapeutic outcomes.

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