Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells

Vikas Verma, Vikas Sharma, Vishal Singh, Siddharth Sharma, Ajay Kumar Bishnoi, Vishal Chandra, J. P. Maikhuri, Anila Dwivedi, Atul Kumar, Gopal Gupta

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The predominant estrogen-receptor (ER)-β signaling in normal prostate is countered by increased ER-α signaling in prostate cancer (CaP), which in association with androgen-receptor (AR) signaling results in pathogenesis of the disease. However CaP treatments mostly target AR signaling which is initially effective but eventually leads to androgen resistance, hence simultaneous targeting of ERs has been proposed. A novel series of molecules were designed with multiple sex-steroid receptor modulating capabilities by coalescing the pharmacophores of known anti-CaP molecules that act via modulation of ER(α/β) and/or AR, viz. 3,3'diindolylmethane (DIM), mifepristone, toremifene, tamoxifen and raloxifene. N,N-diethyl-4-((2-(4-methoxyphenyl)-1. H-indol-3-yl)methyl) aniline (DIMA) was identified as the most promising structure of this new series. DIMA increased annexin-V labelling, cell-cycle arrest and caspase-3 activity, and decreased expression of AR and prostate specific antigen in LNCaP cells, in vitro. Concurrently, DIMA increased ER-β, p21 and p27 protein levels in LNCaP cells and exhibited ~. 5 times more selective binding for ER-β than ER-α, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-β agonism and ER-α antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0. μM (P. <. 0.05). DIMA also dose-dependently decreased telomerase enzyme activity in prostate cancer cells. It is thus concluded that DIMA acts as a multi-steroid receptor modulator and effectively inhibits proliferation of prostate cancer cells through ER-β mediated telomerase inhibition, by countering actions of ER-α and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP.

Original languageEnglish (US)
Pages (from-to)323-334
Number of pages12
JournalToxicology and Applied Pharmacology
Volume280
Issue number2
DOIs
StatePublished - Oct 5 2014

Fingerprint

Telomerase
Human Activities
Estrogen Receptors
Prostatic Neoplasms
Steroids
Cells
Modulation
Androgen Receptors
Steroid Receptors
Toremifene
Mifepristone
Molecules
Annexin A5
Enzyme activity
Tamoxifen
Prostate-Specific Antigen
Cell Cycle Checkpoints
Reporter Genes
Caspase 3
Labeling

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

Cite this

Verma, Vikas ; Sharma, Vikas ; Singh, Vishal ; Sharma, Siddharth ; Bishnoi, Ajay Kumar ; Chandra, Vishal ; Maikhuri, J. P. ; Dwivedi, Anila ; Kumar, Atul ; Gupta, Gopal. / Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells. In: Toxicology and Applied Pharmacology. 2014 ; Vol. 280, No. 2. pp. 323-334.
@article{8cd08d291dfe480ea4c1e69373e94124,
title = "Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells",
abstract = "The predominant estrogen-receptor (ER)-β signaling in normal prostate is countered by increased ER-α signaling in prostate cancer (CaP), which in association with androgen-receptor (AR) signaling results in pathogenesis of the disease. However CaP treatments mostly target AR signaling which is initially effective but eventually leads to androgen resistance, hence simultaneous targeting of ERs has been proposed. A novel series of molecules were designed with multiple sex-steroid receptor modulating capabilities by coalescing the pharmacophores of known anti-CaP molecules that act via modulation of ER(α/β) and/or AR, viz. 3,3'diindolylmethane (DIM), mifepristone, toremifene, tamoxifen and raloxifene. N,N-diethyl-4-((2-(4-methoxyphenyl)-1. H-indol-3-yl)methyl) aniline (DIMA) was identified as the most promising structure of this new series. DIMA increased annexin-V labelling, cell-cycle arrest and caspase-3 activity, and decreased expression of AR and prostate specific antigen in LNCaP cells, in vitro. Concurrently, DIMA increased ER-β, p21 and p27 protein levels in LNCaP cells and exhibited ~. 5 times more selective binding for ER-β than ER-α, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-β agonism and ER-α antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0. μM (P. <. 0.05). DIMA also dose-dependently decreased telomerase enzyme activity in prostate cancer cells. It is thus concluded that DIMA acts as a multi-steroid receptor modulator and effectively inhibits proliferation of prostate cancer cells through ER-β mediated telomerase inhibition, by countering actions of ER-α and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP.",
author = "Vikas Verma and Vikas Sharma and Vishal Singh and Siddharth Sharma and Bishnoi, {Ajay Kumar} and Vishal Chandra and Maikhuri, {J. P.} and Anila Dwivedi and Atul Kumar and Gopal Gupta",
year = "2014",
month = "10",
day = "5",
doi = "10.1016/j.taap.2014.08.002",
language = "English (US)",
volume = "280",
pages = "323--334",
journal = "Toxicology and Applied Pharmacology",
issn = "0041-008X",
publisher = "Academic Press Inc.",
number = "2",

}

Verma, V, Sharma, V, Singh, V, Sharma, S, Bishnoi, AK, Chandra, V, Maikhuri, JP, Dwivedi, A, Kumar, A & Gupta, G 2014, 'Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells', Toxicology and Applied Pharmacology, vol. 280, no. 2, pp. 323-334. https://doi.org/10.1016/j.taap.2014.08.002

Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells. / Verma, Vikas; Sharma, Vikas; Singh, Vishal; Sharma, Siddharth; Bishnoi, Ajay Kumar; Chandra, Vishal; Maikhuri, J. P.; Dwivedi, Anila; Kumar, Atul; Gupta, Gopal.

In: Toxicology and Applied Pharmacology, Vol. 280, No. 2, 05.10.2014, p. 323-334.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells

AU - Verma, Vikas

AU - Sharma, Vikas

AU - Singh, Vishal

AU - Sharma, Siddharth

AU - Bishnoi, Ajay Kumar

AU - Chandra, Vishal

AU - Maikhuri, J. P.

AU - Dwivedi, Anila

AU - Kumar, Atul

AU - Gupta, Gopal

PY - 2014/10/5

Y1 - 2014/10/5

N2 - The predominant estrogen-receptor (ER)-β signaling in normal prostate is countered by increased ER-α signaling in prostate cancer (CaP), which in association with androgen-receptor (AR) signaling results in pathogenesis of the disease. However CaP treatments mostly target AR signaling which is initially effective but eventually leads to androgen resistance, hence simultaneous targeting of ERs has been proposed. A novel series of molecules were designed with multiple sex-steroid receptor modulating capabilities by coalescing the pharmacophores of known anti-CaP molecules that act via modulation of ER(α/β) and/or AR, viz. 3,3'diindolylmethane (DIM), mifepristone, toremifene, tamoxifen and raloxifene. N,N-diethyl-4-((2-(4-methoxyphenyl)-1. H-indol-3-yl)methyl) aniline (DIMA) was identified as the most promising structure of this new series. DIMA increased annexin-V labelling, cell-cycle arrest and caspase-3 activity, and decreased expression of AR and prostate specific antigen in LNCaP cells, in vitro. Concurrently, DIMA increased ER-β, p21 and p27 protein levels in LNCaP cells and exhibited ~. 5 times more selective binding for ER-β than ER-α, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-β agonism and ER-α antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0. μM (P. <. 0.05). DIMA also dose-dependently decreased telomerase enzyme activity in prostate cancer cells. It is thus concluded that DIMA acts as a multi-steroid receptor modulator and effectively inhibits proliferation of prostate cancer cells through ER-β mediated telomerase inhibition, by countering actions of ER-α and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP.

AB - The predominant estrogen-receptor (ER)-β signaling in normal prostate is countered by increased ER-α signaling in prostate cancer (CaP), which in association with androgen-receptor (AR) signaling results in pathogenesis of the disease. However CaP treatments mostly target AR signaling which is initially effective but eventually leads to androgen resistance, hence simultaneous targeting of ERs has been proposed. A novel series of molecules were designed with multiple sex-steroid receptor modulating capabilities by coalescing the pharmacophores of known anti-CaP molecules that act via modulation of ER(α/β) and/or AR, viz. 3,3'diindolylmethane (DIM), mifepristone, toremifene, tamoxifen and raloxifene. N,N-diethyl-4-((2-(4-methoxyphenyl)-1. H-indol-3-yl)methyl) aniline (DIMA) was identified as the most promising structure of this new series. DIMA increased annexin-V labelling, cell-cycle arrest and caspase-3 activity, and decreased expression of AR and prostate specific antigen in LNCaP cells, in vitro. Concurrently, DIMA increased ER-β, p21 and p27 protein levels in LNCaP cells and exhibited ~. 5 times more selective binding for ER-β than ER-α, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-β agonism and ER-α antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0. μM (P. <. 0.05). DIMA also dose-dependently decreased telomerase enzyme activity in prostate cancer cells. It is thus concluded that DIMA acts as a multi-steroid receptor modulator and effectively inhibits proliferation of prostate cancer cells through ER-β mediated telomerase inhibition, by countering actions of ER-α and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP.

UR - http://www.scopus.com/inward/record.url?scp=84908054805&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908054805&partnerID=8YFLogxK

U2 - 10.1016/j.taap.2014.08.002

DO - 10.1016/j.taap.2014.08.002

M3 - Article

C2 - 25123791

AN - SCOPUS:84908054805

VL - 280

SP - 323

EP - 334

JO - Toxicology and Applied Pharmacology

JF - Toxicology and Applied Pharmacology

SN - 0041-008X

IS - 2

ER -