A synthetic decursin analog with increased in vivo stability suppresses androgen receptor signaling in vitro and in vivo

Yong Zhang, Ahmad Ali Shaik, Chengguo Xing, Yubo Chai, Li Li, Jinhui Zhang, Wei Zhang, Sung Hoon Kim, Junxuan Lü, Cheng Jiang

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Summary: Targeting androgen receptor (AR) signaling with agents distinct from current antagonist drugs remains a rational approach to the prevention and treatment of prostate cancer (PCa). Our previous studies have shown that decursin and isomer decursinol angelate (DA), isolated from the Korean medicinal herb Angelica gigas Nakai, interrupt AR signaling and possess anti-PCa activities in vitro. In the LNCaP PCa cell model, these pyranoccoumarin compounds exhibit properties distinct from currently used antagonists (e.g., Casodex). However, both are rapidly de-esterified to decursinol, a partial AR agonist. We report here that a synthetic decursin analog, decursinol phenylthiocarbamate (DPTC), has greater in vivo stability than the parent compounds. DPTC-decursinol conversion was undetectable in mice. Furthermore, in LNCaP cells, DPTC decreased prostate specific antigen (PSA) expression, down-regulated AR abundance and mRNA and inhibited AR nuclear translocation. The effect of DPTC on AR and PSA mRNA and protein abundance was also observed in VCaP cells expressing wild type AR. DPTC inhibited growth of both PCa cell lines through G1 cell cycle arrest and apoptosis, as did decursin and DA. Furthermore, i.p. administration of DPTC for 3 weeks suppressed the expression of AR target genes probasin and Nkx3.1 in mouse prostate glands. Overall, our data suggest that DPTC represents a prototype lead compound for development of in vivo stable and active novel decursin analogs for the prevention or therapy of PCa.

Original languageEnglish (US)
Pages (from-to)1820-1829
Number of pages10
JournalInvestigational New Drugs
Volume30
Issue number5
DOIs
StatePublished - Oct 1 2012

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Androgen Receptors
Prostatic Neoplasms
In Vitro Techniques
decursin
Prostate-Specific Antigen
Angelica
G1 Phase Cell Cycle Checkpoints
Messenger RNA
Medicinal Plants
phenylthiocarbamate
Androgens
Prostate

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Zhang, Yong ; Shaik, Ahmad Ali ; Xing, Chengguo ; Chai, Yubo ; Li, Li ; Zhang, Jinhui ; Zhang, Wei ; Kim, Sung Hoon ; Lü, Junxuan ; Jiang, Cheng. / A synthetic decursin analog with increased in vivo stability suppresses androgen receptor signaling in vitro and in vivo. In: Investigational New Drugs. 2012 ; Vol. 30, No. 5. pp. 1820-1829.
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A synthetic decursin analog with increased in vivo stability suppresses androgen receptor signaling in vitro and in vivo. / Zhang, Yong; Shaik, Ahmad Ali; Xing, Chengguo; Chai, Yubo; Li, Li; Zhang, Jinhui; Zhang, Wei; Kim, Sung Hoon; Lü, Junxuan; Jiang, Cheng.

In: Investigational New Drugs, Vol. 30, No. 5, 01.10.2012, p. 1820-1829.

Research output: Contribution to journalArticle

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AU - Zhang, Yong

AU - Shaik, Ahmad Ali

AU - Xing, Chengguo

AU - Chai, Yubo

AU - Li, Li

AU - Zhang, Jinhui

AU - Zhang, Wei

AU - Kim, Sung Hoon

AU - Lü, Junxuan

AU - Jiang, Cheng

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N2 - Summary: Targeting androgen receptor (AR) signaling with agents distinct from current antagonist drugs remains a rational approach to the prevention and treatment of prostate cancer (PCa). Our previous studies have shown that decursin and isomer decursinol angelate (DA), isolated from the Korean medicinal herb Angelica gigas Nakai, interrupt AR signaling and possess anti-PCa activities in vitro. In the LNCaP PCa cell model, these pyranoccoumarin compounds exhibit properties distinct from currently used antagonists (e.g., Casodex). However, both are rapidly de-esterified to decursinol, a partial AR agonist. We report here that a synthetic decursin analog, decursinol phenylthiocarbamate (DPTC), has greater in vivo stability than the parent compounds. DPTC-decursinol conversion was undetectable in mice. Furthermore, in LNCaP cells, DPTC decreased prostate specific antigen (PSA) expression, down-regulated AR abundance and mRNA and inhibited AR nuclear translocation. The effect of DPTC on AR and PSA mRNA and protein abundance was also observed in VCaP cells expressing wild type AR. DPTC inhibited growth of both PCa cell lines through G1 cell cycle arrest and apoptosis, as did decursin and DA. Furthermore, i.p. administration of DPTC for 3 weeks suppressed the expression of AR target genes probasin and Nkx3.1 in mouse prostate glands. Overall, our data suggest that DPTC represents a prototype lead compound for development of in vivo stable and active novel decursin analogs for the prevention or therapy of PCa.

AB - Summary: Targeting androgen receptor (AR) signaling with agents distinct from current antagonist drugs remains a rational approach to the prevention and treatment of prostate cancer (PCa). Our previous studies have shown that decursin and isomer decursinol angelate (DA), isolated from the Korean medicinal herb Angelica gigas Nakai, interrupt AR signaling and possess anti-PCa activities in vitro. In the LNCaP PCa cell model, these pyranoccoumarin compounds exhibit properties distinct from currently used antagonists (e.g., Casodex). However, both are rapidly de-esterified to decursinol, a partial AR agonist. We report here that a synthetic decursin analog, decursinol phenylthiocarbamate (DPTC), has greater in vivo stability than the parent compounds. DPTC-decursinol conversion was undetectable in mice. Furthermore, in LNCaP cells, DPTC decreased prostate specific antigen (PSA) expression, down-regulated AR abundance and mRNA and inhibited AR nuclear translocation. The effect of DPTC on AR and PSA mRNA and protein abundance was also observed in VCaP cells expressing wild type AR. DPTC inhibited growth of both PCa cell lines through G1 cell cycle arrest and apoptosis, as did decursin and DA. Furthermore, i.p. administration of DPTC for 3 weeks suppressed the expression of AR target genes probasin and Nkx3.1 in mouse prostate glands. Overall, our data suggest that DPTC represents a prototype lead compound for development of in vivo stable and active novel decursin analogs for the prevention or therapy of PCa.

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