Fenretinide induces mitochondrial ROS and inhibits the mitochondrial respiratory chain in neuroblastoma.
Fenretinide induces apoptosis in neuroblastoma by induction of reactive oxygen species (ROS). In this study, we investigated the role of mitochondria in fenretinide-induced cytotoxicity and ROS production in six neuroblastoma cell lines. ROS induction by fenretinide was of mitochondrial origin, demonstrated by detection of superoxide with MitoSOX, the scavenging effect of the mitochondrial antioxidant MitoQ and reduced ROS production in cells without a functional mitochondrial respiratory chain (Rho zero cells). In digitonin-permeabilized cells, a fenretinide concentration-dependent decrease in ATP synthesis and substrate oxidation was observed, reflecting inhibition of the mitochondrial respiratory chain. However, inhibition of the mitochondrial respiratory chain was not required for ROS production. Co-incubation of fenretinide with inhibitors of different complexes of the respiratory chain suggested that fenretinide-induced ROS production occurred via complex II. The cytotoxicity of fenretinide was exerted through the generation of mitochondrial ROS and, at higher concentrations, also through inhibition of the mitochondrial respiratory chain.
Cuperus
Roos
R
Laboratory Genetic Metabolic Diseases, Department of Pediatrics/Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands.
Leen
René
R
Tytgat
Godelieve A M
GA
Caron
Huib N
HN
van Kuilenburg
André B P
AB
D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004579:Electron Transport / Q000187:drug effects*; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology
D000970:Antineoplastic Agents; D000975:Antioxidants; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D014451:Ubiquinone; D017313:Fenretinide; C429014:mitoquinone