PPAR-α Activators Remodel U87 Cells and Enhance Sunitinib Cytotoxicity via Modulation of Cell Cycle, Apoptosis, TAOKs/Cadherins Gene Expression and Histone Demethylase

Background: Glioblastoma multiforme (GBM) is an aggressive and highly invasive primary brain tumor characterized by poor clinical outcomes and limited therapeutic options, emphasizing the need for novel treatment strategies. Fenofibrate (FEN), a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist widely used for dyslipidemia, has demonstrated anticancer effects through the modulation of cellular proliferation, apoptosis, and metabolic pathways. This study explored the therapeutic potential of FEN alone and in combination with sunitinib (SNB) against U87 glioblastoma (GB) cells. Methods: U87 cells were treated with FEN, SNB, or their combination. Cell viability, apoptosis, and cell-cycle progression were evaluated. The expression of tumor protein 53 (TP53), BCL2 associated X, apoptosis regulator (BAX), epithelial cadherin (CDH1), neural cadherin (CDH2), thousand and one kinase 1 (TAOK1), and thousand and one kinase 2 (TAOK2) was assessed using quantitative reverse transcription polymerase chain reaction (RT-PCR). Molecular docking was performed to examine the potential interactions of fenofibric acid (FFA) and SNB with GBM-related molecular targets. Results: FEN and SNB reduced U87 cell viability in a dose-dependent manner, while combined treatment produced greater cytotoxicity than either agent alone. The combination induced the highest level of apoptosis and enhanced G1-phase cell-cycle arrest. Treatment also increased TP53, BAX, and CDH1 expression while decreasing CDH2, TAOK1, and TAOK2 expression. Molecular docking demonstrated favorable interactions of FFA and SNB with multiple targets implicated in GBM progression. Conclusions: FEN combined with SNB exhibited enhanced anticancer activity against U87 GB cells through induction of apoptosis, cell-cycle arrest, and modulation of tumorrelated genes. These findings support the potential of FEN/SNB combination therapy as a promising therapeutic strategy for GBM and provide a basis for further preclinical investigation.