title: 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.affiliation: College of Pharmacy, University of Hawaii at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Tamara P
authors.initials: TP
authors.lastname: Kondratyuk
authors.forename: Andrew
authors.initials: A
authors.lastname: Morrell
authors.forename: Evgeny
authors.initials: E
authors.lastname: Kiselev
authors.forename: Martin
authors.initials: M
authors.lastname: Conda-Sheridan
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: Soyoun
authors.initials: S
authors.lastname: Ahn
authors.forename: Yongsoo
authors.initials: Y
authors.lastname: Choi
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: White
authors.forename: Richard B
authors.initials: RB
authors.lastname: van Breemen
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007192:Indenes / Q000494:pharmacology*; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D047488:Retinoid X Receptors / Q000819:agonists*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: C559481:3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno(1,2-c)isoquinoline; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007192:Indenes; D007546:Isoquinolines; D047488:Retinoid X Receptors