Bezafibrate induces myotoxicity in human rhabdomyosarcoma cells via peroxisome proliferator-activated receptor alpha signaling.
Fibrates, the ligands of peroxisome proliferator-activated receptor alpha (PPARalpha), are used as a class of lipid-lowering drugs in clinical practice for the treatment of dyslipidemia. Fibrates are well tolerated in most cases concomitantly with occasional adverse reactions including muscular toxicity, which is enhanced by the combination with statins. This study was designed to investigate the effects of bezafibrate as a PPARalpha agonist on human embryo rhabdomyosarcoma (RD) cells and possible mechanisms responsible for bezafibrate-mediated myopathy. The results revealed that bezafibrate caused a dose-dependent decrease in cell viability, which was fortified in association with atorvastatin at a pharmacological dose. Bezafibrate at toxic doses of 300 and 1000microM upregulated PPARalpha at the mRNA level, counteracted by a PPARalpha antagonist (MK886). Bezafibrate at a toxic dose induced typical apoptotic characteristics related to the inhibition of phosphorylation of Akt which was blocked by PPARalpha antagonist. Toxic doses of bezafibrate initiated a significant increase in pyruvate dehydrogenase kinase 4 mRNA and protein levels, compromised by MK886. These results suggest the critical roles of PPARalpha signaling in bezafibrate-induced myotoxicity and the involvement of apoptosis through Akt pathway.
Zhao
Yan
Y
Department of Nutrition and Food, Harbin Medical University, Heilongjiang, China. amyzhaosb@126.com
Okuyama
Manabu
M
Hashimoto
Hiroyuki
H
Tagawa
Yoshiaki
Y
Jomori
Takahito
T
Yang
Baofeng
B
D017209:Apoptosis / Q000187:drug effects; D001629:Bezafibrate / Q000633:toxicity*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000960:Hypolipidemic Agents / Q000633:toxicity*; D047468:Immunoprecipitation; D051058:Oncogene Protein v-akt / Q000096:biosynthesis / Q000235:genetics; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012208:Rhabdomyosarcoma / Q000473:pathology*
D000960:Hypolipidemic Agents; D047493:PPAR alpha; D012333:RNA, Messenger; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D051058:Oncogene Protein v-akt; D001629:Bezafibrate