ArticleInternational journal of molecular sciences2026
A Sequence-Dependent Combination of Photodynamic Therapy and Carboxyamidotriazole Orotate for Enhanced Treatment of Glioblastoma.
Article in International journal of molecular sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Glioblastoma (GBM) remains a highly lethal malignancy characterized by profound treatment resistance and metabolic plasticity. While photodynamic therapy (PDT) and the mitochondrial complex I inhibitor carboxyamidotriazole orotate (CTO) have individually shown promise, their combined potential requires further exploration and optimization. This study systematically investigated the interaction between 5-aminolevulinic acid (5-ALA)-mediated PDT and CTO in U87 GBM models. Intriguingly, we discovered a sequence-dependent interaction under the tested treatment schedules: CTO pre-incubation before PDT resulted in attenuated PDT-induced cytotoxicity, possibly due to CTO-mediated suppression of reactive oxygen species (ROS) accumulation. In contrast, a sequential "PDT→CTO" regimen enhanced anti-tumor efficacy both in vitro and in vivo. Mechanistically, the sequential approach was associated with enhanced mitochondrial depolarization and reduced expression of glycolysis-related genes, suggesting a potential metabolic "dual-hit" involving disturbance of mitochondrial function and compensatory glycolytic adaptation. These results highlight treatment sequence as a critical determinant of PDT-CTO interaction and provide a basis for further preclinical investigation of PDT followed by metabolic intervention as a combination strategy with potential translational relevance.
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