A novel antiandrogen, compound 30, suppresses castration-resistant and MDV3100-resistant prostate cancer growth In Vitro and In Vivo

Hidetoshi Kuruma, Hiroaki Matsumoto, Masaki Shiota, Jennifer Bishop, Francois Lamoureux, Christian Thomas, David Briere, Gerrit Los, Martin Gleave, Andrea Fanjul, Amina Zoubeidi

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Resistance to antiandrogen drugs, like MDV3100, occurs in patients with castration-resistant prostate cancer (CRPC). Thus, preventing or treating antiandrogen resistance is a major clinical challenge. We identified a novel antiandrogen, Compound 30, and compared its efficacy with MDV3100. We found that Compound 30 inhibits androgen receptor (AR) activity in LNCaP cells, C4-2 cells, as well as MDV3100-resistant cell lines. Compared with MDV3100, Compound 30 treatment induces greater reduction in AR, prostate-specific antigen (PSA), and AR transcriptional activity, and prevents AR nuclear translocation in AR-sensitive LNCaP cells. Compound 30 has antiproliferative effects in LNCaP cells, in castrate-resistant C4-2 cells, and those resistant to MDV3100. Compound 30 was equally as effective as MDV3100 in reducing tumor volume and PSA in vivo. More importantly, Compound 30 is effective at inhibiting AR activity in MDV3100-resistant cell lines and significantly prevented tumor growth and PSA increases in mice bearing MDV3100-resistant xenografts. Together, our data show that Compound 30 strongly inhibited AR activity and suppressed castration-resistant LNCaP growth as well as MDV3100-resistant cell growth in vitro and in vivo. These data provide a preclinical proof-of-principle that Compound 30 could be a promising next generation anti-AR agent, especially in the context of antiandrogen-resistant tumors.

Original languageEnglish
Pages (from-to)567-576
Number of pages10
JournalMolecular Cancer Therapeutics
Volume12
Issue number5
DOIs
Publication statusPublished - May 1 2013
Externally publishedYes

Fingerprint

Androgen Antagonists
Castration
Androgen Receptors
Prostatic Neoplasms
Growth
Prostate-Specific Antigen
compound 30
In Vitro Techniques
MDV 3100
Cell Line
Antigen Receptors
Tumor Burden
Heterografts
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

A novel antiandrogen, compound 30, suppresses castration-resistant and MDV3100-resistant prostate cancer growth In Vitro and In Vivo. / Kuruma, Hidetoshi; Matsumoto, Hiroaki; Shiota, Masaki; Bishop, Jennifer; Lamoureux, Francois; Thomas, Christian; Briere, David; Los, Gerrit; Gleave, Martin; Fanjul, Andrea; Zoubeidi, Amina.

In: Molecular Cancer Therapeutics, Vol. 12, No. 5, 01.05.2013, p. 567-576.

Research output: Contribution to journalArticle

Kuruma, H, Matsumoto, H, Shiota, M, Bishop, J, Lamoureux, F, Thomas, C, Briere, D, Los, G, Gleave, M, Fanjul, A & Zoubeidi, A 2013, 'A novel antiandrogen, compound 30, suppresses castration-resistant and MDV3100-resistant prostate cancer growth In Vitro and In Vivo', Molecular Cancer Therapeutics, vol. 12, no. 5, pp. 567-576. https://doi.org/10.1158/1535-7163.MCT-12-0798
Kuruma, Hidetoshi ; Matsumoto, Hiroaki ; Shiota, Masaki ; Bishop, Jennifer ; Lamoureux, Francois ; Thomas, Christian ; Briere, David ; Los, Gerrit ; Gleave, Martin ; Fanjul, Andrea ; Zoubeidi, Amina. / A novel antiandrogen, compound 30, suppresses castration-resistant and MDV3100-resistant prostate cancer growth In Vitro and In Vivo. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 5. pp. 567-576.
@article{f58ea1e1f283493597c0ce38dc7cb6ec,
title = "A novel antiandrogen, compound 30, suppresses castration-resistant and MDV3100-resistant prostate cancer growth In Vitro and In Vivo",
abstract = "Resistance to antiandrogen drugs, like MDV3100, occurs in patients with castration-resistant prostate cancer (CRPC). Thus, preventing or treating antiandrogen resistance is a major clinical challenge. We identified a novel antiandrogen, Compound 30, and compared its efficacy with MDV3100. We found that Compound 30 inhibits androgen receptor (AR) activity in LNCaP cells, C4-2 cells, as well as MDV3100-resistant cell lines. Compared with MDV3100, Compound 30 treatment induces greater reduction in AR, prostate-specific antigen (PSA), and AR transcriptional activity, and prevents AR nuclear translocation in AR-sensitive LNCaP cells. Compound 30 has antiproliferative effects in LNCaP cells, in castrate-resistant C4-2 cells, and those resistant to MDV3100. Compound 30 was equally as effective as MDV3100 in reducing tumor volume and PSA in vivo. More importantly, Compound 30 is effective at inhibiting AR activity in MDV3100-resistant cell lines and significantly prevented tumor growth and PSA increases in mice bearing MDV3100-resistant xenografts. Together, our data show that Compound 30 strongly inhibited AR activity and suppressed castration-resistant LNCaP growth as well as MDV3100-resistant cell growth in vitro and in vivo. These data provide a preclinical proof-of-principle that Compound 30 could be a promising next generation anti-AR agent, especially in the context of antiandrogen-resistant tumors.",
author = "Hidetoshi Kuruma and Hiroaki Matsumoto and Masaki Shiota and Jennifer Bishop and Francois Lamoureux and Christian Thomas and David Briere and Gerrit Los and Martin Gleave and Andrea Fanjul and Amina Zoubeidi",
year = "2013",
month = "5",
day = "1",
doi = "10.1158/1535-7163.MCT-12-0798",
language = "English",
volume = "12",
pages = "567--576",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

TY - JOUR

T1 - A novel antiandrogen, compound 30, suppresses castration-resistant and MDV3100-resistant prostate cancer growth In Vitro and In Vivo

AU - Kuruma, Hidetoshi

AU - Matsumoto, Hiroaki

AU - Shiota, Masaki

AU - Bishop, Jennifer

AU - Lamoureux, Francois

AU - Thomas, Christian

AU - Briere, David

AU - Los, Gerrit

AU - Gleave, Martin

AU - Fanjul, Andrea

AU - Zoubeidi, Amina

PY - 2013/5/1

Y1 - 2013/5/1

N2 - Resistance to antiandrogen drugs, like MDV3100, occurs in patients with castration-resistant prostate cancer (CRPC). Thus, preventing or treating antiandrogen resistance is a major clinical challenge. We identified a novel antiandrogen, Compound 30, and compared its efficacy with MDV3100. We found that Compound 30 inhibits androgen receptor (AR) activity in LNCaP cells, C4-2 cells, as well as MDV3100-resistant cell lines. Compared with MDV3100, Compound 30 treatment induces greater reduction in AR, prostate-specific antigen (PSA), and AR transcriptional activity, and prevents AR nuclear translocation in AR-sensitive LNCaP cells. Compound 30 has antiproliferative effects in LNCaP cells, in castrate-resistant C4-2 cells, and those resistant to MDV3100. Compound 30 was equally as effective as MDV3100 in reducing tumor volume and PSA in vivo. More importantly, Compound 30 is effective at inhibiting AR activity in MDV3100-resistant cell lines and significantly prevented tumor growth and PSA increases in mice bearing MDV3100-resistant xenografts. Together, our data show that Compound 30 strongly inhibited AR activity and suppressed castration-resistant LNCaP growth as well as MDV3100-resistant cell growth in vitro and in vivo. These data provide a preclinical proof-of-principle that Compound 30 could be a promising next generation anti-AR agent, especially in the context of antiandrogen-resistant tumors.

AB - Resistance to antiandrogen drugs, like MDV3100, occurs in patients with castration-resistant prostate cancer (CRPC). Thus, preventing or treating antiandrogen resistance is a major clinical challenge. We identified a novel antiandrogen, Compound 30, and compared its efficacy with MDV3100. We found that Compound 30 inhibits androgen receptor (AR) activity in LNCaP cells, C4-2 cells, as well as MDV3100-resistant cell lines. Compared with MDV3100, Compound 30 treatment induces greater reduction in AR, prostate-specific antigen (PSA), and AR transcriptional activity, and prevents AR nuclear translocation in AR-sensitive LNCaP cells. Compound 30 has antiproliferative effects in LNCaP cells, in castrate-resistant C4-2 cells, and those resistant to MDV3100. Compound 30 was equally as effective as MDV3100 in reducing tumor volume and PSA in vivo. More importantly, Compound 30 is effective at inhibiting AR activity in MDV3100-resistant cell lines and significantly prevented tumor growth and PSA increases in mice bearing MDV3100-resistant xenografts. Together, our data show that Compound 30 strongly inhibited AR activity and suppressed castration-resistant LNCaP growth as well as MDV3100-resistant cell growth in vitro and in vivo. These data provide a preclinical proof-of-principle that Compound 30 could be a promising next generation anti-AR agent, especially in the context of antiandrogen-resistant tumors.

UR - http://www.scopus.com/inward/record.url?scp=84877686260&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84877686260&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-12-0798

DO - 10.1158/1535-7163.MCT-12-0798

M3 - Article

C2 - 23493310

AN - SCOPUS:84877686260

VL - 12

SP - 567

EP - 576

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 5

ER -