ArticleJournal of cellular physiology2025
Bypassing Blood-Brain Barrier and Glucose Dependency of Anti-Glioblastoma Drug Candidates Targeting Mitochondrial Respiration.
Article in Journal of cellular physiology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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The trial behind it
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Who cites it
1 citing paper in PubMed.
- Targeting Metabolic Vulnerabilities in Glioblastoma: a Framework for Multi-node Combination Therapy.Current oncology reports · 2026Review
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Authors and funding
13 authors.
Funding
Abstract
We attempt to address two key therapeutic obstacles affecting glioblastoma patients: low ability of anticancer drugs to penetrate the blood-brain barrier (BBB), and temozolomide (TMZ) resistance, by targeting mitochondrial respiration of glioblastoma cells. We designed and tested over 100 new compounds based on the chemical structure of fenofibrate (FF), which in its prodrug form is cytotoxic to cancer cells by causing severe impairment of mitochondrial respiration. The compounds were designed using two key predictive tools: central nervous system-multiparameter optimization (CNS-MPO) and BBB_SCORE. These algorithms assess how effectively compounds can penetrate the BBB. We initially selected PP1 as a lead compound by testing its BBB penetration, metabolic performance, and antitumoral efficacy. PP1 accumulated in brain tumors and triggered glioblastoma cell death. However, PP1-induced inhibition of mitochondrial respiration was followed by an immediate glycolytic response, which attenuated PP1 toxicity in a glucose-dependent manner. To bypass this limitation, we tested two strategies: (1) the use of PP1 in combination with glycolysis inhibitors; and (2) introduction of a new compound, PP211, which inhibited mitochondrial respiration in the absence of a concomitant increase of glycolysis. Although the combination of PP1 with glycolysis inhibitors was very effective in vitro, this drug combination demonstrated elevated toxicity in mice. PP211, instead, attenuated TMZ-resistant tumor growth and prolonged mouse survival with only minimal general animal toxicity. In summary, we developed and tested a novel mitochondria-targeting drug candidate, PP211, which effectively crosses the BBB, overcomes TMZ resistance, and induces tumor cell death independently of glucose levels-while exhibiting minimal systemic toxicity in preclinical models. These findings support further development of PP211 for glioblastoma therapy.
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