Abstract
Objective: To review the mechanisms of anti-cancer activity of fenofibrate (FF) and other Peroxisome Proliferator Activator Receptor α (PPARα) agonists based on evidences reported in the published literature.Methods: We extensively reviewed the literature concerning FF as an off target anti-cancer drug. Controversies regarding conflicting findings were also addressed.Results:The main mechanism involved in anti-cancer activity is anti-angiogenesis through down-regulation of Vascular Endothelial Growth Factor (VEGF), Vascular Endothelial Growth Factor Receptor (VEGFR) and Hypoxia Inducible factor-1 α (HIF-1α), inhibition of endothelial cell migration, up-regulation of endostatin and thrombospondin-1, but there are many other contributing mechanisms like apoptosis and cell cycle arrest, down-regulation of Nuclear Factor Kappa B (NF-kB) and Protein kinase B (Akt) and decrease of cellular energy by impairing mitochondrial function. Growth impairment is related to down-regulation of Phospho-Inositol 3 Kinase (PI3K)/Akt axis and down-regulation of the p38 map kinase (MAPK) cascade. A possible role should be assigned to FF stimulated over-expression of Tribbles Homolog-3 (TRIB3) which inhibits Akt phosphorylation. Important anti-cancer and anti-metastatic activities are due to down-regulation of MCP-1 (monocyte chemotactic protein-1), decreased Metalloprotease-9 (MMP-9) production, weak down-regulation of adhesion molecules like E selectin, intercellular adhesion molecules (ICAM) and Vascular Endothelial Adhesion Molecules (VCAM), and decreased secretion of chemokines like Interleukin-6 (IL-6), and down-regulation of cyclin D-1. There is no direct link between FF activity in lipid metabolism and anticancer activity, except for the fact that many anticancer actions are dependent from PPARα agonism. FF exhibits also PPARα independent anti-cancer activities.Conclusions: There are strong evidences indicating that FF can disrupt growth-related activities in many different cancers, due to anti-angiogenesis and anti-inflammatory effects. Therefore FF may be useful as a complementary adjunct treatment of cancer, particularly included in anti-angiogenic protocols like those currently increasingly used in glioblastoma. There are sound reasons to initiate well planned phase II clinical trials for FF as a complementary adjunct treatment of cancer.
Highlights
Fenofibrate (FF) is a drug of the fibrate class that has been used since 1975 to reduce cholesterol (LDL and VLDL) and triglyceride levels and increase HDL in patients at risk of cardiovascular disease and for treatment of atherosclerosis (1 and 47).Fenofibrate /HUVEC (FF) is one of the most commonly prescribed fibrates, and has a well known efficacy and tolerability profile1.FF seems to lower lipid levels by activating peroxisome proliferatoractivated receptor alpha (PPARα), a nuclear receptor which acts as a ligand activated transcriptional factor and activates lipoprotein lipase and reducing apolipoprotein CIII expression
Important anti-cancer and anti-metastatic activities are due to down-regulation of MCP-1, decreased Metalloprotease-9 (MMP-9) production, weak down-regulation of adhesion molecules like E selectin, intercellular adhesion molecules (ICAM) and Vascular Endothelial Adhesion Molecules (VCAM), and decreased secretion of chemokines like Interleukin-6 (IL-6), and down-regulation of cyclin D-1
There is no direct link between FF activity in lipid metabolism and anticancer activity, except for the fact that many anticancer actions are dependent from Peroxisome Proliferator Activator Receptor α (PPARα) agonism
Summary
FF seems to lower lipid levels by activating peroxisome proliferatoractivated receptor alpha (PPARα), a nuclear receptor which acts as a ligand activated transcriptional factor and activates lipoprotein lipase and reducing apolipoprotein CIII expression. These activities increase lipolysis and eliminate triglyceride-rich particles. Three isoforms have been identified: PPARα, PPARβ/δ, and PPARγ. Ligand binding activates these receptors that play key roles in cellular energy homeostasis, modulating glucose and lipid metabolism
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