title: The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes.
abstract: Fenretinide remains the most investigated retinoid compound for the prevention of cancer. Its clinical use remains a genuine possibility due to a favourable toxicological profile and accumulation in fatty tissues. Like other well-characterised pharmacological therapies, Fenretinide has been shown to affect multiple signalling pathways. Recent findings have discovered additional beneficial properties the synthetic retinoid was not intentionally designed for, including the prevention of high-fat diet-induced obesity and insulin resistance. These preclinical findings in rodents are timely since obesity has reached pandemic proportions and safe effective therapeutics are severely lacking. Recent investigations have proposed various mechanisms of action for the beneficial effects of Fenretinide. This review covers the current knowledge about Fenretinide's use as a therapy for cancer and potential to treat obesity, insulin resistance and glucose intolerance. An overview of the signalling pathways manipulated by Fenretinide including retinoid homeostasis, reactive oxygen species generation and inhibition of ceramide synthesis will be presented and insights into apoptosis and/or autophagy induction by Fenretinide will also be discussed. The largely unexplored area of Fenretinide metabolites as alternative therapeutic options and how these may be relevant will also be presented. Fenretinide shows great promise, but unfortunately evidence is lacking from clinical trials on Fenretinide's effectiveness in humans. Finally we identify what action can be taken to further progress the investigation of this extremely important retinoid.
authors: Institute of Medical Sciences, College of Life Sciences & Medicine, University of Aberdeen, Aberdeen, UK. Electronic address: n.mody@abdn.ac.uk.
authors: Nimesh
authors: N
authors: Mody
authors: Institute of Medical Sciences, College of Life Sciences & Medicine, University of Aberdeen, Aberdeen, UK.
authors: George D
authors: GD
authors: Mcilroy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002986:Clinical Trials as Topic; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control*; D004579:Electron Transport / Q000187:drug effects; D017313:Fenretinide / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D009765:Obesity / Q000517:prevention & control*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014801:Vitamin A / Q000097:blood / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C101326:RBP4 protein, human; D017382:Reactive Oxygen Species; D054839:Retinol-Binding Proteins, Plasma; D014801:Vitamin A; D017313:Fenretinide; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase
keywords: Adipogenesis; Apoptosis; Autophagy; Obesity; Reactive oxygen species; Retinoic acid; Type-2 diabetes