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<p>Fenofibrate, an active pharmaceutical ingredient (API) of the fibrate class approved by the U.S. Food and Drug Administration (FDA) for the treatment of hypercholesterolemia and hyperlipidemia, has emerged as a promising candidate for repurposing in cancer. Indeed, beyond its lipid-lowering effects, fenofibrate has demonstrated antitumor properties, including antiproliferative and cytotoxic effects in normoxia (21% O<sub>2</sub>) in preclinical models of GBM. In addition, fenofibrate may inhibit hypoxia-inducible factor-1 alpha (HIF-1α) and reduce the expression of hypoxia-inducible genes, potentially overcoming hypoxia-induced chemoresistance. These findings, combined with its established clinical safety profile, support further investigation of fenofibrate as a potential therapeutic strategy in GBM. On this basis, physico-chemical characterization of fenofibrate was assessed to determine its ability to cross the blood–brain barrier. We determined in vitro on GBM cell lines U251-MG, U87-MG and GL261, the efficacy of fenofibrate in decreasing GBM cell viability and proliferation under normoxia (21% O<sub>2</sub>) and hypoxia (1% and 0.2% O<sub>2</sub>). We investigated the kinetics of its internalization by HPLC. In addition, the safety of fenofibrate was evaluated on non-tumoral brain cells. Dunn’s post-hoc test was used after a significant Kruskal–Wallis. Being practically insoluble in water, fenofibrate was dissolved in dimethyl sulfoxide (DMSO) for studies. Primary astrocytes showed no signs of toxicity following treatment with fenofibrate. The effect of fenofibrate on GBM cell lines was studied at various time points and exhibited a cell type-, time- and concentration-dependent cytotoxicity with an LC<sub>50</sub> of 25, 43.7 and 49.6&#xa0;µM for U251-MG, U87-MG and GL261 cells, respectively. Interestingly, fenofibrate uptake was confirmed, 12.9 ± 5.7% and 14.2 ± 6.6% of fenofibrate was found in U251-MG and U87-MG cells, respectively. Intracellular concentrations of fenofibrate increased over time and no precipitation was observed. In hypoxia (1% and 0.2% of O<sub>2</sub>), the cytotoxic effect of fenofibrate was still present, albeit decreased. Furthermore, fenofibrate induced a cytostatic effect on U251-MG and U87-MG under both normoxia (21% O<sub>2</sub>) and hypoxia (1% and 0.2% O<sub>2</sub>), reducing their proliferation. Under the experimental conditions tested, namely in vitro studies, fenofibrate appeared more efficient compared with temozolomide, the standard treatment for GBM. This study demonstrated the cytotoxic and cytostatic effect of fenofibrate on GBM cells. These results indicate that fenofibrate may be a therapeutic alternative for GBM treatment. </p>

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Fenofibrate as an anti-cancer treatment: an in vitro study on glioblastoma cells at various oxygen levels and on normal astrocytes

  • 期刊论文

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  • 发表日期：

    2026年5月2日

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  • Yasmine Chokry,
  • Anne-Claire Groo,
  • Sophie Corvaisier,
  • Ons Ben Hadj Hassen,
  • Isis Blanchard,
  • Samuel Valable,
  • Aurélie Malzert-Fréon

摘要

Fenofibrate, an active pharmaceutical ingredient (API) of the fibrate class approved by the U.S. Food and Drug Administration (FDA) for the treatment of hypercholesterolemia and hyperlipidemia, has emerged as a promising candidate for repurposing in cancer. Indeed, beyond its lipid-lowering effects, fenofibrate has demonstrated antitumor properties, including antiproliferative and cytotoxic effects in normoxia (21% O2) in preclinical models of GBM. In addition, fenofibrate may inhibit hypoxia-inducible factor-1 alpha (HIF-1α) and reduce the expression of hypoxia-inducible genes, potentially overcoming hypoxia-induced chemoresistance. These findings, combined with its established clinical safety profile, support further investigation of fenofibrate as a potential therapeutic strategy in GBM. On this basis, physico-chemical characterization of fenofibrate was assessed to determine its ability to cross the blood–brain barrier. We determined in vitro on GBM cell lines U251-MG, U87-MG and GL261, the efficacy of fenofibrate in decreasing GBM cell viability and proliferation under normoxia (21% O2) and hypoxia (1% and 0.2% O2). We investigated the kinetics of its internalization by HPLC. In addition, the safety of fenofibrate was evaluated on non-tumoral brain cells. Dunn’s post-hoc test was used after a significant Kruskal–Wallis. Being practically insoluble in water, fenofibrate was dissolved in dimethyl sulfoxide (DMSO) for studies. Primary astrocytes showed no signs of toxicity following treatment with fenofibrate. The effect of fenofibrate on GBM cell lines was studied at various time points and exhibited a cell type-, time- and concentration-dependent cytotoxicity with an LC50 of 25, 43.7 and 49.6 µM for U251-MG, U87-MG and GL261 cells, respectively. Interestingly, fenofibrate uptake was confirmed, 12.9 ± 5.7% and 14.2 ± 6.6% of fenofibrate was found in U251-MG and U87-MG cells, respectively. Intracellular concentrations of fenofibrate increased over time and no precipitation was observed. In hypoxia (1% and 0.2% of O2), the cytotoxic effect of fenofibrate was still present, albeit decreased. Furthermore, fenofibrate induced a cytostatic effect on U251-MG and U87-MG under both normoxia (21% O2) and hypoxia (1% and 0.2% O2), reducing their proliferation. Under the experimental conditions tested, namely in vitro studies, fenofibrate appeared more efficient compared with temozolomide, the standard treatment for GBM. This study demonstrated the cytotoxic and cytostatic effect of fenofibrate on GBM cells. These results indicate that fenofibrate may be a therapeutic alternative for GBM treatment.