Abstract
This study demonstrated that fenofibrate, a lipid-lowering drug, induced a significant time-dependent cytotoxicity of hepatoma Hep3B cells. Hep3B cells are significantly more sensitive to cell killing by fenofibrate than hepatoma HepG2, lung cancer CH27 and oral cancer HSC-3 cells. From the result of docking simulation, fenofibrate can bind excellently to the thioesterase domain of fatty acid synthase (FASN) binding site as orlistat, a FASN inhibitor, acts. The fenofibrate-induced cell cytotoxicity was protected by addition of palmitate, indicating that the cytotoxic effect of fenofibrate is due to starvation of Hep3B cells by inhibiting the formation of end product in the FASN reaction. Inhibition of lipid metabolism-related proteins expression, such as proteins containing thioesterase domain and fatty acid transport proteins, was involved in the fenofibrate-induced Hep3B cell death. Fenofibrate caused S and G2/M cell cycle arrest by inducing cyclin A/Cdk2 and reducing cyclin D1 and E protein levels in Hep3B cells. The anti-tumor roles of fenofibrate on Hep3B cells by inducing apoptosis and necroptosis were dependent on the expression of Bcl-2/caspase family members and RIP1/RIP3 proteins, respectively. These results suggest that fenofibrate has an anti-cancer effect in Hep3B cells and inhibition of lipid metabolism may be involved in fenofibrate-induced Hep3B cells apoptosis and necroptosis.
Highlights
Fibric acid derivatives are effective lipid-lowering drugs
Fenofibrate was docked with 2px[6], the crystal structure of thioesterase domain of fatty acid synthase (FASN) bound to orlistat
Based on the above reasons, we suggest that fenofibrate, like orlistat, binds to the thioesterase domain of FASN well, which could inhibit the activity of FASN
Summary
Fibric acid derivatives are effective lipid-lowering drugs. Chen et al (2012) have demonstrated that a decrease of triglyceride accumulation induced by fenofibrate, a fibric acid derivative, resulted from increase of adipose triglyceride lipase expression and decrease of fatty acid synthase (FASN) level under high-glucose condition in myoblast cells[1]. In addition to being lipid-lowering agents, fibric acid derivatives were found to have anti-cancer effects through inhibition of FASN activity[2]. A fibric acid derivative, significantly induced a decrease of the protein expression of active FASN and an increase in the amounts of free fatty acids in breast cancer[2]. Associated with increasing tumor progression, poor prognosis and risk of death[14,15,16] These observations indicate that FASN plays a critical role in tumor lipid metabolism, and FASN-catalyzed biosynthesis of fatty acid should be a good target for tumor therapy. A FDA-approved drug for obesity, was reported to bind the thioesterase domain of FASN, which can inhibit tumor growth and induce tumor cell death[22,23,24]. It interests us to investigate whether fenofibrate inhibits cancer cell growth through inhibition of FASN activity
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