title: Inhibition of acid ceramidase by a 2-substituted aminoethanol amide synergistically sensitizes prostate cancer cells to N-(4-hydroxyphenyl) retinamide.
abstract: BACKGROUND
  The purpose of this study was to determine whether the therapeutic efficacy of fenretinide (4-HPR), a ceramide-generating anticancer agent, could be enhanced in prostate cancer cells by inclusion of a novel synthetic acid ceramidase (AC) inhibitor, DM102, a pivaloylamide of a 2-substituted aminoethanol. In prostate cancer, AC plays a role in progression and resistance to chemotherapy.
  
  
  METHODS
  PC-3 and DU 145 hormone-refractory human prostate cancer cell lines were used. Cells were exposed to 4-HPR, DM102, and combinations; viability, apoptosis, cell migration, ceramide metabolism, and levels of reactive oxygen species (ROS) were assessed.
  
  
  RESULTS
  Single agent 4-HPR and DM102 (2.5-10 µM) were weakly cytotoxic; however, combinations synergistically decreased cell viably to as low as 1.5% of control. N-oleoylethanolamine (NOE), a frequently employed AC inhibitor, was not effective in producing synergy. The 4-HPR/DM102 regimen enhanced caspase activity and increased [(3) H](dihydro)ceramide and ROS levels 6- and 30-fold over control, respectively. The antioxidant vitamin E, but not the de novo ceramide synthesis inhibitor myriocin, partially rescued cells from 4-HPR/DM102 cytotoxicity. The 4-HPR/DM102 combination also elicited synergistic cytotoxicity in DU 145 cells, another human hormone-refractory prostate cancer cell line.
  
  
  CONCLUSIONS
  This study shows that 4-HPR cytotoxicity is enhanced in a synergistic fashion by inclusion of the AC inhibitor DM102, by a mechanism that enlists generation of ROS, and thus provides a system to raise 4-HPR therapeutic potential. The role of ceramide however in the cytotoxic response is not clear, as blocking ceramide generation failed to rescue PC-3 cells from 4-HPR/DM102 cytotoxicity.
authors.affiliation: John Wayne Cancer Institute, Santa Monica, California 90404, USA.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gouazé-Andersson
authors.forename: Margaret
authors.initials: M
authors.lastname: Flowers
authors.forename: Ramin
authors.initials: R
authors.lastname: Karimi
authors.forename: Gemma
authors.initials: G
authors.lastname: Fabriás
authors.forename: Antonio
authors.initials: A
authors.lastname: Delgado
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.forename: Myles C
authors.initials: MC
authors.lastname: Cabot
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D055572:Ceramidases / Q000037:antagonists & inhibitors*; D004347:Drug Interactions; D063388:Endocannabinoids; D004983:Ethanolamines / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D009829:Oleic Acids; D017382:Reactive Oxygen Species / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology
chemical_list: C559741:(2R,3Z)-N-(1-hydroxyoctadec-3-en-2-yl)pivalamide; D000577:Amides; D000970:Antineoplastic Agents; D063388:Endocannabinoids; D004983:Ethanolamines; D005231:Fatty Acids, Unsaturated; D009829:Oleic Acids; D017382:Reactive Oxygen Species; C033595:N-oleoylethanolamine; D014810:Vitamin E; D017313:Fenretinide; D020169:Caspases; D055572:Ceramidases