Retinoid receptor-dependent and independent biological activities of novel fenretinide analogues and metabolites

Clin Cancer Res. 2003 Oct 1;9(12):4606-13.

Abstract

Fenretinide (4-HPR) is a retinoid analogue with antitumor and chemopreventive activities. In addition to 4-HPR, there are several other new phenylretinamides bearing hydroxyl, carboxyl, or methoxyl residues on carbons 2, 3, and 4 of the terminal phenylamine ring [N-(2-hydroxyphenyl)retinamide (2-HPR), N-(3-hydroxyphenyl)retinamide, N-(2-carboxyphenyl)retinamide, N-(3-carboxyphenyl)retinamide, N-(4-carboxyphenyl)retinamide, and N-(4-methoxyphenyl)retinamide (4-MPR) ]. It is hypothesized that these agents can act independent of the nuclear retinoid receptor pathway. To test this hypothesis directly, we have analyzed the activity of these phenylretinamides in vitro on a panel of F9 murine embryonal carcinoma cell lines, which includes wild-type (F9-WT) and mutant cells that have disrupted genes for both retinoid X receptor alpha and retinoic acid receptor gamma retinoid receptors (F9-KO). The F9-KO cells lack almost all measurable response to all-trans-retinoic acid, the primary biologically active retinoid. Two distinct effects of retinamides were identified. The first is a rapid, dose-dependent induction of cell growth inhibition (reduced cell viability), and the second is a slower induction of differentiation and accumulation of cells in the G(1) phase of the cell cycle that was observed with a concentration of 1 micro M, for only those phenylretinamides bearing charged (hydroxyl or carboxyl) groups on the terminal phenylamine ring. The induction of differentiation and G(1) accumulation was only observed in the F9-WT cells, indicating that this effect is receptor-dependent. 4-MPR, a major metabolite of 4-HPR, lacks a charged group on the terminal phenylamine ring and did not induce retinoid receptor-dependent effects, but did induce cell growth inhibition. Thus, 4-MPR may play a role in the clinical activity of 4-HPR. This study further reveals the mechanism of action of these novel phenylretinamides and supports continued investigation into their development as chemopreventive drugs.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Carcinoma, Embryonal / metabolism*
  • Carcinoma, Embryonal / pathology
  • Cell Death / drug effects
  • Cell Differentiation / drug effects
  • Fenretinide / analogs & derivatives
  • Fenretinide / pharmacology*
  • G1 Phase / drug effects*
  • Immunoenzyme Techniques
  • Mice
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Retinoid X Receptors
  • S Phase / drug effects
  • Signal Transduction / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tretinoin / pharmacology
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Transcription Factors
  • retinoic acid receptor gamma
  • Fenretinide
  • Tretinoin