Nuclear retinoid receptors are involved in N-(4-hydroxyphenyl) retinamide (Fenretinide)-induced gene expression and growth inhibition in HL-60 acute myeloid leukemia cells

Leuk Lymphoma. 2004 May;45(5):979-85. doi: 10.1080/1042819031000151833.


N-(4-hydroxyphenyl) retinamide (Fenretinide, 4-HPR) inhibits cell growth by inducing apoptosis in numerous tumor cell types including all-trans-retinoic acid (ATRA)-resistant tumor cells. However, the mechanism(s) by which 4-HPR mediates its anti-proliferative effects remains unclear. Here, we determined whether 4-HPR induced growth inhibition and gene expression involve retinoid receptors in human acute myeloid leukemia (AML) cells (HL-60). We treated HL-60 and ATRA-resistant HL-60 (HL-60R) cells that express mutated RARalpha and very low levels of RARbeta, RARgamma and RXRalpha with 4-HPR (2 microM) for 3 days. 4-HPR showed significant anti-proliferative effects against both cell types and induced growth inhibition (92.7%) in HL-60 cells. However, at the same dose, 4-HPR induced only 53.4% growth inhibition in HL-60R cells. Growth inhibition by 4-HPR was significantly enhanced in HL-60R cells that were retroviraly transduced to express human RARalpha, RARbeta or RXRalpha (95.6%, 97.1%, and 75.6%, respectively), in comparison to HL-60R cells (P < 0.05), but not in HL-60R cells expressing RARgamma. Although ATRA and 4-HPR induced expression of CYP26, an ATRA-inducible gene encoding a cytochrome P450 enzyme, in HL-60 cells, both retinoids failed to induce CYP26 in HL-60R cells. However, induction of CYP26 mRNA by 4-HPR was restored in HL-60R cells expressing RARalpha and RARgamma, but not RARbeta and RXRalpha. In conclusion, our data suggest that nuclear retinoid receptors are involved in 4-HPR-induced growth inhibition and gene expression, and that 4-HPR can mediate its anti-proliferative effects through retinoid receptor-dependent mechanisms in HL-60 cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Cell Proliferation / drug effects
  • Cytochrome P-450 Enzyme System / genetics
  • Fenretinide / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • HL-60 Cells
  • Humans
  • Leukemia, Myeloid / pathology*
  • RNA, Messenger / drug effects
  • Receptors, Retinoic Acid / physiology*
  • Retinoic Acid 4-Hydroxylase
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptor alpha / physiology


  • RARA protein, human
  • RNA, Messenger
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptor alpha
  • retinoic acid receptor beta
  • retinoic acid receptor gamma
  • Fenretinide
  • Cytochrome P-450 Enzyme System
  • Retinoic Acid 4-Hydroxylase