title: Retinoid receptor-dependent and independent biological activities of novel fenretinide analogues and metabolites.
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.
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Anita L
authors.initials: AL
authors.lastname: Sabichi
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Susan
authors.initials: S
authors.lastname: Fischer
authors.forename: Changchan
authors.initials: C
authors.lastname: Zou
authors.forename: Xiulan
authors.initials: X
authors.lastname: Yang
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Kelloff
authors.forename: Reuben
authors.initials: R
authors.lastname: Lotan
authors.forename: John L
authors.initials: JL
authors.lastname: Clifford
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D018236:Carcinoma, Embryonal / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D017313:Fenretinide / Q000031:analogs & derivatives / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects*; D007124:Immunoenzyme Techniques; D051379:Mice; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000097768:Retinoic Acid Receptor gamma
chemical_list: D000970:Antineoplastic Agents; D017313:Fenretinide; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma