Characterization of fenofibrate-mediated anti-proliferative pro-apoptotic effects on high-grade gliomas and anti-invasive effects on glioma stem cells

Abstract

Glioblastoma is the most common, and at the same time, most aggressive type of high-grade glioma (HGG). The prognosis of glioblastoma patients treated with standard therapy including surgery, temozolomide and radiation therapy remains poor. Peroxisome proliferator-activated receptor-α (PPARα) agonists are in widespread clinical use for the treatment of hyperlipidemia. Recent evidence has suggested a potential role in various cancers including glioblastoma. In this study, we characterized the effects of PPARα agonist, fenofibrate, directly on HGG cells and glioma stem cells (GSC). Fenofibrate exhibited dose-dependent p53-independent anti-proliferative effects on HGG starting at 25 μM and pro-apoptotic effects starting at 50 μM, suggesting that the anti-proliferative actions are present only at 25 μM. PPARα was expressed in all HGG cell lines. Inhibition of PPARα with specific inhibitor GW6471 did not affect either proliferation or apoptosis suggesting that these are PPARα-independent effects. Fenofibrate treatment of HGG cells robustly diminished the expression of key signaling pathways, including NF-κB and cyclin D1. Phosphorylation of Akt was also diminished, with no change in total Akt. Effects on apoptotic signaling molecules, Bax and Bcl-xL, had a trend towards pro-apoptotic effects. With respect to GSC, fenofibrate treatment at 25 μM significantly decreased invasion in association with a decrease in CD133 and Oct4 expression. Overall, results support consideration of fenofibrate as an anti-glioma agent and establish its potential as an adjunct treatment strategy for HGG. Translation to the clinical setting could be rapid given its current use as a clinical agent and its low toxicity profile.

Precursor N-cadherin mediates glial cell line-derived neurotrophic factor-promoted human malignant glioma

“…This is consistent with the total N-cadherin contents in various glioma surgical specimens. However, for different glial cell lines in vitro , both U87 and U251 cells express abundant proN-cadherin on the cell surface, although U251 is p53 mutant glioma cell line, HA, U343, and U87 are all p53 wild-type [27]. …”

Anticancer Properties of Fenofibrate: A Repurposing Use

“…Fenofibrate can also affect apoptotic signaling molecules by upregulation of Bax and downregulation of Bcl-xL. Furthermore, the drug obviously reduced glioma stem cells (GSC) invasion probably through decreasing the expression of CD133 (classical stem-cell markers) and Oct4GSC (associated with a poor prognosis in GSC) 46 .…”

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

“…113 Empirical evidence indicated a fenofibrate-mediated decrease in stemness mediators CD133 and transcription factor Oct4 in glioma cell populations. 114 A seven-drug cocktail to treat a G-CSF producing tumor-progressive medulloblastoma using fibrate is in current clinical trial in Austria (ClinicalTrials.gov Identifier: NCT01356290, the MEMMAT regimen). MEMMAT uses four adjuvants-bevacizumab, thalidomide, celecoxib, and fenofibric acid-to augment three traditional cytotoxic drugs-etoposide, cyclophosphamide, and cytarabine.…”