Inhibitory effects of fenretinide metabolites N-[4-methoxyphenyl]retinamide (MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (3-keto-HPR) on fenretinide molecular targets β-carotene oxygenase 1, stearoyl-CoA desaturase 1 and dihydroceramide Δ4-desaturase 1

PLoS One. 2017 Apr 27;12(4):e0176487. doi: 10.1371/journal.pone.0176487. eCollection 2017.

Abstract

The therapeutic capacity of fenretinide (N-[4-hydroxyphenyl] retinamide; 4-HPR) has been demonstrated for several conditions, including cancer, obesity, diabetes, and ocular disease. Yet, the mechanisms of action for its pleiotropic effects are still undefined. We hypothesized that investigation of two of the major physiological metabolites of fenretinide, N-[4-methoxyphenyl]retinamide (MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (3-keto-HPR), might begin to resolve the multifaceted effects of this synthetic retinoid. We analyzed the effects of fenretinide, MPR, 3-keto-HPR, and the non-retinoid RBP4 ligand A1120, on the activity of known targets of fenretinide, stearoyl-CoA desaturase 1 (SCD1) and dihydroceramide Δ4-desaturase 1 (DES1) in ARPE-19 cells, and purified recombinant mouse beta-carotene oxygenase 1 (BCO1) in vitro. Lipids and retinoids were extracted and quantified by liquid chromatography-mass spectrometry and reversed phase HPLC, respectively. The data demonstrate that while fenretinide is an inhibitor of the activities of these three enzymes, that 3-keto-HPR is a more potent inhibitor of all three enzymes, potentially mediating most of the in vivo beneficial effects of fenretinide. However, while MPR does not affect SCD1 and DES1 activity, it is a potent specific inhibitor of BCO1. We conclude that a deeper understanding of the mechanisms of action of fenretinide and its metabolites provides new avenues for therapeutic specificity. For example, administration of 3-keto-HPR instead of fenretinide may be preferential if inhibition of SCD1 or DES1 activity is the goal (cancer), while MPR may be better for BCO1 modulation (carotenoid metabolism). Continued investigation of fenretinide metabolites in the context of fenretinide's various therapeutic uses will begin to resolve the pleotropic nature of this compound.

MeSH terms

  • Animals
  • Cell Line
  • Fenretinide / analogs & derivatives*
  • Fenretinide / metabolism*
  • Fenretinide / pharmacology
  • Humans
  • Membrane Proteins / antagonists & inhibitors*
  • Mice
  • Molecular Targeted Therapy*
  • Oxidoreductases / antagonists & inhibitors*
  • Receptors, Retinoic Acid / metabolism
  • Stearoyl-CoA Desaturase / antagonists & inhibitors*
  • Tretinoin / analogs & derivatives*
  • Tretinoin / metabolism
  • Tretinoin / pharmacology
  • beta-Carotene 15,15'-Monooxygenase / antagonists & inhibitors*

Substances

  • 4-oxofenretinide
  • Membrane Proteins
  • Receptors, Retinoic Acid
  • retinoic acid receptor beta
  • Fenretinide
  • Tretinoin
  • N-(4-methoxyphenyl)retinamide
  • Oxidoreductases
  • Bco1 protein, mouse
  • SCD1 protein, human
  • Stearoyl-CoA Desaturase
  • beta-Carotene 15,15'-Monooxygenase
  • Degs protein, mouse

Grants and funding

This work was supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health. Acucela Inc. provided support in the form of salaries for author NM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ‘author contributions’ section.