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

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

Research output: Contribution to journalArticle

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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 G2/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, p21WAF1/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.

Original languageEnglish (US)
Pages (from-to)592-607
Number of pages16
JournalCancer Prevention Research
Volume4
Issue number4
DOIs
StatePublished - Apr 1 2011

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Retinoid X Receptors
MCF-7 Cells
Up-Regulation
Breast Neoplasms
Response Elements
Luciferases
Growth
3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno(1,2-c)isoquinoline
Methylnitrosourea
Caco-2 Cells
G2 Phase
HL-60 Cells
Chemoprevention
Liver Microsomes
Tetradecanoylphorbol Acetate
Human Mammary Glands
Microarray Analysis
Oligonucleotide Array Sequence Analysis
S Phase
Reporter Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Induction of retinoid X receptor activity and consequent upregulation of p21WAF1/CIP1 by indenoisoquinolines in MCF7 cells. / Park, Eun Jung; Kondratyuk, Tamara P.; Morrell, Andrew; Kiselev, Evgeny; Conda-Sheridan, Martin; Cushman, Mark; Ahn, Soyoun; Choi, Yongsoo; White, Jerry J.; Van Breemen, Richard B.; Pezzuto, John M.

In: Cancer Prevention Research, Vol. 4, No. 4, 01.04.2011, p. 592-607.

Research output: Contribution to journalArticle

Park, EJ, Kondratyuk, TP, Morrell, A, Kiselev, E, Conda-Sheridan, M, Cushman, M, Ahn, S, Choi, Y, White, JJ, Van Breemen, RB & Pezzuto, JM 2011, 'Induction of retinoid X receptor activity and consequent upregulation of p21WAF1/CIP1 by indenoisoquinolines in MCF7 cells', Cancer Prevention Research, vol. 4, no. 4, pp. 592-607. https://doi.org/10.1158/1940-6207.CAPR-10-0004
Park, Eun Jung ; Kondratyuk, Tamara P. ; Morrell, Andrew ; Kiselev, Evgeny ; Conda-Sheridan, Martin ; Cushman, Mark ; Ahn, Soyoun ; Choi, Yongsoo ; White, Jerry J. ; Van Breemen, Richard B. ; Pezzuto, John M. / Induction of retinoid X receptor activity and consequent upregulation of p21WAF1/CIP1 by indenoisoquinolines in MCF7 cells. In: Cancer Prevention Research. 2011 ; Vol. 4, No. 4. pp. 592-607.
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