In vivo imaging of retinoic acid receptor β2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells

David Z. Qian, Mingqiang Ren, Yongfeng Wei, Xiaofei Wang, Fleur Van De Geijn, Camilla Rasmussen, Osamu Nakanishi, Nicoletta Sacchi, Roberto Pili

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

BACKGROUND. In retinoid resistant epithelial tumors, the lack of retinoic acid receptor β2 (RARβ2) expression due to epigenetic silencing impairs the activation of retinoid target genes including RARβ2, and has been associated with the development of cancer. In this study we developed a strategy to monitor the re-activation of RARβ2 by chromatin remodeling agents combined with retinoids in real time, and to correlate the RARβ2 re-activation with anti-tumor activity. METHODS. We selected the RARβ2-negative retinoid resistant human prostate carcinoma cell line PC3 and stably transfected it with a luciferase expression vector under the control of a functional segment of RARβ2 promoter (pGL2-RARβ2-PC3). Then, we used the bioluminescence technology to monitor the reporter gene expression in real time both in vitro and in vivo following combination treatment with the histone deacetylase inhibitor MS-275 and 13-cis retinoic acid (CRA). Based on the effective dose for the RARβ2 re-activation, we tested the antitumor activity of this drug combination. RESULTS. Following combination treatment with MS-275 and CRA, we observed endogenous RARβ2 re-expression, acetylation at the RARβ2 promoter level, and synergistic activation of the luciferase reporter gene by real time imaging both in vitro and in vivo. Combination treatment with MS-275 and CRA restored retinoid sensitivity in human prostate carcinoma cell lines, and had a greater inhibitory effect on tumor cell growth than single agents in vitro and in vivo. CONCLUSIONS. This study provides evidence that HDAC inhibitors restore retinoid sensitivity in prostate cancer cells, and in vivo real time imaging of RARβ2 activation may represent a useful tool to study the pharmacodynamics of combination therapy with HDAC inhibitors and retinoids.

Original languageEnglish (US)
Pages (from-to)20-28
Number of pages9
JournalProstate
Volume64
Issue number1
DOIs
StatePublished - Jun 15 2005
Externally publishedYes

Fingerprint

Retinoic Acid Receptors
Histone Deacetylase Inhibitors
Retinoids
Transcriptional Activation
Prostatic Neoplasms
NSC 153174
Tretinoin
Luciferases
Reporter Genes
Prostate
Neoplasms
entinostat
Carcinoma
Cell Line
Isotretinoin
Chromatin Assembly and Disassembly
Drug Combinations
Acetylation
Epigenomics
Antineoplastic Agents

Keywords

  • HDAC inhibitor
  • MS-275
  • Prostate cancer
  • Retinoic acid receptor
  • Retinoid resistance

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Urology

Cite this

In vivo imaging of retinoic acid receptor β2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells. / Qian, David Z.; Ren, Mingqiang; Wei, Yongfeng; Wang, Xiaofei; Van De Geijn, Fleur; Rasmussen, Camilla; Nakanishi, Osamu; Sacchi, Nicoletta; Pili, Roberto.

In: Prostate, Vol. 64, No. 1, 15.06.2005, p. 20-28.

Research output: Contribution to journalArticle

Qian, David Z. ; Ren, Mingqiang ; Wei, Yongfeng ; Wang, Xiaofei ; Van De Geijn, Fleur ; Rasmussen, Camilla ; Nakanishi, Osamu ; Sacchi, Nicoletta ; Pili, Roberto. / In vivo imaging of retinoic acid receptor β2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells. In: Prostate. 2005 ; Vol. 64, No. 1. pp. 20-28.
@article{674667597a024cc48d450dddd7fade6d,
title = "In vivo imaging of retinoic acid receptor β2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells",
abstract = "BACKGROUND. In retinoid resistant epithelial tumors, the lack of retinoic acid receptor β2 (RARβ2) expression due to epigenetic silencing impairs the activation of retinoid target genes including RARβ2, and has been associated with the development of cancer. In this study we developed a strategy to monitor the re-activation of RARβ2 by chromatin remodeling agents combined with retinoids in real time, and to correlate the RARβ2 re-activation with anti-tumor activity. METHODS. We selected the RARβ2-negative retinoid resistant human prostate carcinoma cell line PC3 and stably transfected it with a luciferase expression vector under the control of a functional segment of RARβ2 promoter (pGL2-RARβ2-PC3). Then, we used the bioluminescence technology to monitor the reporter gene expression in real time both in vitro and in vivo following combination treatment with the histone deacetylase inhibitor MS-275 and 13-cis retinoic acid (CRA). Based on the effective dose for the RARβ2 re-activation, we tested the antitumor activity of this drug combination. RESULTS. Following combination treatment with MS-275 and CRA, we observed endogenous RARβ2 re-expression, acetylation at the RARβ2 promoter level, and synergistic activation of the luciferase reporter gene by real time imaging both in vitro and in vivo. Combination treatment with MS-275 and CRA restored retinoid sensitivity in human prostate carcinoma cell lines, and had a greater inhibitory effect on tumor cell growth than single agents in vitro and in vivo. CONCLUSIONS. This study provides evidence that HDAC inhibitors restore retinoid sensitivity in prostate cancer cells, and in vivo real time imaging of RARβ2 activation may represent a useful tool to study the pharmacodynamics of combination therapy with HDAC inhibitors and retinoids.",
keywords = "HDAC inhibitor, MS-275, Prostate cancer, Retinoic acid receptor, Retinoid resistance",
author = "Qian, {David Z.} and Mingqiang Ren and Yongfeng Wei and Xiaofei Wang and {Van De Geijn}, Fleur and Camilla Rasmussen and Osamu Nakanishi and Nicoletta Sacchi and Roberto Pili",
year = "2005",
month = "6",
day = "15",
doi = "10.1002/pros.20209",
language = "English (US)",
volume = "64",
pages = "20--28",
journal = "Prostate",
issn = "0270-4137",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - In vivo imaging of retinoic acid receptor β2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells

AU - Qian, David Z.

AU - Ren, Mingqiang

AU - Wei, Yongfeng

AU - Wang, Xiaofei

AU - Van De Geijn, Fleur

AU - Rasmussen, Camilla

AU - Nakanishi, Osamu

AU - Sacchi, Nicoletta

AU - Pili, Roberto

PY - 2005/6/15

Y1 - 2005/6/15

N2 - BACKGROUND. In retinoid resistant epithelial tumors, the lack of retinoic acid receptor β2 (RARβ2) expression due to epigenetic silencing impairs the activation of retinoid target genes including RARβ2, and has been associated with the development of cancer. In this study we developed a strategy to monitor the re-activation of RARβ2 by chromatin remodeling agents combined with retinoids in real time, and to correlate the RARβ2 re-activation with anti-tumor activity. METHODS. We selected the RARβ2-negative retinoid resistant human prostate carcinoma cell line PC3 and stably transfected it with a luciferase expression vector under the control of a functional segment of RARβ2 promoter (pGL2-RARβ2-PC3). Then, we used the bioluminescence technology to monitor the reporter gene expression in real time both in vitro and in vivo following combination treatment with the histone deacetylase inhibitor MS-275 and 13-cis retinoic acid (CRA). Based on the effective dose for the RARβ2 re-activation, we tested the antitumor activity of this drug combination. RESULTS. Following combination treatment with MS-275 and CRA, we observed endogenous RARβ2 re-expression, acetylation at the RARβ2 promoter level, and synergistic activation of the luciferase reporter gene by real time imaging both in vitro and in vivo. Combination treatment with MS-275 and CRA restored retinoid sensitivity in human prostate carcinoma cell lines, and had a greater inhibitory effect on tumor cell growth than single agents in vitro and in vivo. CONCLUSIONS. This study provides evidence that HDAC inhibitors restore retinoid sensitivity in prostate cancer cells, and in vivo real time imaging of RARβ2 activation may represent a useful tool to study the pharmacodynamics of combination therapy with HDAC inhibitors and retinoids.

AB - BACKGROUND. In retinoid resistant epithelial tumors, the lack of retinoic acid receptor β2 (RARβ2) expression due to epigenetic silencing impairs the activation of retinoid target genes including RARβ2, and has been associated with the development of cancer. In this study we developed a strategy to monitor the re-activation of RARβ2 by chromatin remodeling agents combined with retinoids in real time, and to correlate the RARβ2 re-activation with anti-tumor activity. METHODS. We selected the RARβ2-negative retinoid resistant human prostate carcinoma cell line PC3 and stably transfected it with a luciferase expression vector under the control of a functional segment of RARβ2 promoter (pGL2-RARβ2-PC3). Then, we used the bioluminescence technology to monitor the reporter gene expression in real time both in vitro and in vivo following combination treatment with the histone deacetylase inhibitor MS-275 and 13-cis retinoic acid (CRA). Based on the effective dose for the RARβ2 re-activation, we tested the antitumor activity of this drug combination. RESULTS. Following combination treatment with MS-275 and CRA, we observed endogenous RARβ2 re-expression, acetylation at the RARβ2 promoter level, and synergistic activation of the luciferase reporter gene by real time imaging both in vitro and in vivo. Combination treatment with MS-275 and CRA restored retinoid sensitivity in human prostate carcinoma cell lines, and had a greater inhibitory effect on tumor cell growth than single agents in vitro and in vivo. CONCLUSIONS. This study provides evidence that HDAC inhibitors restore retinoid sensitivity in prostate cancer cells, and in vivo real time imaging of RARβ2 activation may represent a useful tool to study the pharmacodynamics of combination therapy with HDAC inhibitors and retinoids.

KW - HDAC inhibitor

KW - MS-275

KW - Prostate cancer

KW - Retinoic acid receptor

KW - Retinoid resistance

UR - http://www.scopus.com/inward/record.url?scp=19544386612&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=19544386612&partnerID=8YFLogxK

U2 - 10.1002/pros.20209

DO - 10.1002/pros.20209

M3 - Article

VL - 64

SP - 20

EP - 28

JO - Prostate

JF - Prostate

SN - 0270-4137

IS - 1

ER -