Comparison of N-(4-hydroxyphenyl)retinamide and all-trans-retinoic acid in the regulation of retinoid receptor-mediated gene expression in human breast cancer cell lines.

Abstract

The activities of N-(4-hydroxyphenyl)retinamide [(4-HPR), Fenretinide] and all-trans-retinoic acid (RA) were determined for (a) the inhibition of cell proliferation; (b) the activation of human retinoid receptor-mediated target gene expression; (c) the inhibition of estradiol- and progesterone-induced gene activation in breast cancer cell lines; and (d) the regulation of the expression of tumor suppressor retinoblastoma protein. Similar to RA, both 4-HPR and its active metabolite N-(4-methoxyphenyl)retinamide (4-MPR) effectively impeded the growth of MCF7 and T-47D human breast cancer cell lines, except that 4-HPR also inhibited the proliferation of RA-resistant BT-20 cells. However, when tested in human recombinant retinoic acid receptor (RAR-alpha, RAR-beta, and RAR-gamma)-induced reporter gene assays, RA was much more potent (>100-fold) than either 4-HPR or 4-MPR. 4-HPR induced transcriptional activation through all three RAR subtypes at 1-10microM, while RA showed comparable activity at 10-100microM. Despite the apparent weak interaction at the RAR level, 4-HPR was comparable to RA in the inhibition of both estrogen receptor- and progesterone receptor-mediated transcriptional activation in MCF7 and T-47D cells, respectively. Moreover, similar to RA, 4-HPR and 4-MPR caused marked up-regulation of tumor suppressor retinoblastoma protein in both MCF7 and T-47D cells. Since RA and 4-HPR showed comparable activity in the inhibition of estrogen recptor- and progesterone receptor-induced gene transcription and in the stimulation of retinoblastoma protein expression in MCF7 and T-47D cells, the reduced RAR activation by 4-HPR may result in the lack of hepatic toxicity and therefore the improved therapeutic efficacy relative to RA.

• Authors: S M Kazmi, R K Plante, V Visconti, C Y Lau
• Journal: Cancer research (Cancer Res) Vol. 56 Issue 5 Pg. 1056-62 (Mar 01 1996) ISSN: 0008-5472 [Print] United States
• PMID: 8640761 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antineoplastic Agents
• Keratolytic Agents
• RARA protein, human
• Receptors, Retinoic Acid
• Retinoblastoma Protein
• Retinoic Acid Receptor alpha
• retinoic acid receptor beta
• retinoic acid receptor gamma
• Fenretinide
• Tretinoin

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Division (drug effects)
• Female
• Fenretinide (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Keratolytic Agents (pharmacology)
• Receptors, Retinoic Acid (metabolism)
• Retinoblastoma Protein (biosynthesis)
• Retinoic Acid Receptor alpha
• Transcriptional Activation
• Tretinoin (pharmacology)
• Tumor Cells, Cultured