Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

Abstract

e Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPAR␣). FF and several other agonists of PPAR␣ have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPAR␣-independent mechanism explaining FF's cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPAR␣-dependent metabolic switch from glycolysis to fatty acid ␤-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase-mammalian target of rapamycin-autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells. F enofibrate (FF) is a common lipid-lowering drug and a potent agonist of peroxisome proliferator-activated receptor alpha (PPAR␣). Multiple reports indicate a beneficial role for lipid-lowering drugs, including fibrates and statins, as anticancer agents (1-7). For example, a 10-year, all-cause mortality study involving 7,722 patients treated with different fibrates revealed that the use of these drugs is associated with a significantly lower total mortality rate and a reduced probability of death from cancer (8). In cell culture and animal studies, various members of the fibrate family, which are all agonists of PPAR␣, demonstrate interesting anticancer effects, which are not fully understood. FF inhibited tumor growth by reducing both inflammation and angiogenesis in host tissue (5). Clofibrate attenuated ovarian cancer cell proliferation (9, 10), and gemfibrozil (GEM) inhibited the invasiveness of glioblastoma cells (11). In our previous work, FF synergized with staurosporine to reduce melanoma lung metastases (3, 12), significantly reduced glioblastoma invasiveness (13), and triggered apoptotic death in medulloblastoma (14) and human glioblastoma cell lines by inducing the FOXO3A-Bim apoptotic pathway (15). All of these studies encouraged the use of FF as a supplemental anticancer drug, a concept supported by recent clinical trials in which chronic administration of FF along with chemotherapeutic agents used at relatively low doses minimizes the toxicity and acute side effects of chemotherapy while maintaining efficacy for patients wit...

Fenofibrate reduces cisplatin-induced apoptosis of renal proximal tubular cells via inhibition of JNK and p38 pathways

“…This attention prompts us to investigate whether the protective effect of fenofibrate in cisplatin-induced toxicity in renal proximal tubular cells, alters the anticancer effect of cisplatin. Interestingly, fenofibrate alone reduced cell viability of tested cancer cells including colon, lung, and liver, correlating well with a recent study showing fenofibrate has antitumor activity (Wilk et al, 2015). In addition, fenofibrate did not alter the anticancer activity of cisplatin.…”

“…Potentially, cytotoxicity following high concentration cisplatin exposure was attenuated by fenofibrate but no other fibrates. As fenofibrate acts via a PPARα-independent mechanism (Asavapanumas et al, 2012;Wilk et al, 2015), checking whether the renoprotective effect of fenofibrate is mediated by PPARα activation was essential. Employing PPARα inhibition via a PPARα antagonist, GW6471, fenofibrate's protective effect was maintained, suggesting PPARα activation is not required.…”

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

“…Fenofibrate has anti-glioma effects also via PPARalpha agonism [111][112][113][114] and by related adenosine triphosphate (ATP) depletion in glioma cells. 113 Empirical evidence indicated a fenofibrate-mediated decrease in stemness mediators CD133 and transcription factor Oct4 in glioma cell populations.…”

“…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).…”

Fenofibrate in cancer: mechanisms involved in anticancer activity

“…Wilk et al 157 found that FF accumulated in mitochondria instead of the active form of the drug, the fenofibric acid, so that unchanged FF was the responsible of the activity on this organelle. This finding shows that FF and fenofibric acid may exhibit different pharmacologic activities (Figure 8), and explains the efforts done to find a suitable carrier to FF that would permit the arrival of this pharmaceutical to the tumor before being cleaved to FA 174 .…”