Induction of retinoid X receptor activity and consequent upregulation of p21WAF1/CIP1 by indenoisoquinolines in MCF7 cells.

Abstract

Retinoid X receptor (RXR) has been targeted for the chemoprevention and treatment of cancer. To discover potential agents acting through RXRs, we utilized an RXR response element (RXRE)-luciferase reporter gene assay. Following extensive screening, 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline dihydrochloride (AM6-36) was found to induce RXRE-luciferase activities. AM6-36 inhibited COX-2 expression and anchorage-independent growth with 12-O-tetradecanoylphorbol 13-acetate-stimulated JB6 Cl41 cells, induced the expression of CD38 in HL-60 cells, and attenuated the growth of N-methyl-N-nitrosourea-induced mammary tumors in rats. Consistent with other reports describing the antiproliferative effects of RXR agonists in breast cancers, AM6-36 showed growth inhibition with cultured MCF7 breast cancer cells, accompanied by G(2)/M-phase arrest at lower concentrations and enhanced S-phase arrest at higher concentrations. On the basis of DNA microarray analysis, AM6-36 upregulated the expression of CDKN1A, a target gene of RXR, by 35-fold. In accord with this response, the expression of the corresponding protein, p21(WAF1/CIP1), was increased in the presence of AM6-36. Induction of p21 by AM6-36 was abrogated following transient knockdown of RXRα, demonstrating that the effect of AM6-36 on the expression of p21 is closely related to modulation of RXRα transcriptional activity. Intestinal permeability was suggested with Caco-2 cells and limited metabolism resulted when AM6-36 was incubated with human liver microsomes. Oral administration with rats resulted in 0.8 μg/mL, 4.3 μg/g, and 0.3 μg/g in serum, liver, and mammary gland, respectively. In sum, these data suggest that AM6-36 is a promising lead for the treatment or prevention of breast cancer and provide a strong rationale for testing in more advanced antitumor systems.

• Authors: Eun-Jung Park, Tamara P Kondratyuk, Andrew Morrell, Evgeny Kiselev, Martin Conda-Sheridan, Mark Cushman, Soyoun Ahn, Yongsoo Choi, Jerry J White, Richard B van Breemen, John M Pezzuto
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 4 Issue 4 Pg. 592-607 (Apr 2011) ISSN: 1940-6215 [Electronic] United States
• PMID: 21464033 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2011 AACR.

Chemical References

• 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno(1,2-c)isoquinoline
• Antineoplastic Agents
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Indenes
• Isoquinolines
• Retinoid X Receptors

Topics

• Animals
• Antineoplastic Agents (metabolism, pharmacology)
• Breast Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis)
• Female
• Gene Expression (drug effects)
• Humans
• Indenes (pharmacology)
• Isoquinolines (metabolism, pharmacology)
• Oligonucleotide Array Sequence Analysis
• Rats
• Rats, Sprague-Dawley
• Retinoid X Receptors (agonists)
• Transcription, Genetic (drug effects)
• Transcriptional Activation (drug effects)
• Up-Regulation
• Xenograft Model Antitumor Assays