Fenretinide: a p53-independent way to kill cancer cells.
The synthetic retinoid fenretinide [N-(4 hydroxyphenyl)retinamide] induces apoptosis of cancer cells and acts synergistically with chemotherapeutic drugs, thus providing opportunities for novel approaches to cancer therapy. The upstream signaling events induced by fenretinide include an increase in intracellular levels of ceramide, which is subsequently metabolized to GD3. This ganglioside triggers the activation of 12-Lox (12-lipoxygenase) leading to oxidative stress and apoptosis via the induction of the transcription factor Gadd153 and the Bcl-2-family member protein Bak. Increased evidence suggests that the apoptotic pathway activated by fenretinide is p53-independent and this may represent a novel way to treat tumors resistant to DNA-damaging chemotherapeutic agents. Therefore, fenretinide offers increased clinical benefit as a novel agent for cancer therapy, able to complement the action of existing chemotherapeutic treatment regimes. Furthermore, synergy between fenretinide and chemotherapeutic drugs may facilitate the use of chemotherapeutic drugs at lower concentrations, with possible reduction in treatment-associated morbidity.
Corazzari
Marco
M
INMI-IRCCS Lazzaro Spallanzani, Rome, Italy.
Lovat
Penny E
PE
Oliverio
Serafina
S
Di Sano
Federica
F
Donnorso
Raffaele Perrone
RP
Redfern
Christopher P F
CP
Piacentini
Mauro
M
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002518:Ceramides / Q000502:physiology; D004789:Enzyme Activation; D017313:Fenretinide / Q000627:therapeutic use*; D005732:Gangliosides / Q000502:physiology; D016158:Genes, p53; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D009447:Neuroblastoma / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D012799:Sialyltransferases / Q000378:metabolism; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000502:physiology; D050998:bcl-2 Homologous Antagonist-Killer Protein
D000970:Antineoplastic Agents; C494772:BAK1 protein, human; D022762:CCAAT-Enhancer-Binding Proteins; D002518:Ceramides; C497249:DDIT3 protein, human; D005732:Gangliosides; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051742:Transcription Factor CHOP; D017313:Fenretinide; C026226:ganglioside, GD3; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase; D020169:Caspases