A novel class of pyranocoumarin anti-androgen receptor signaling compounds

Junming Guo, Cheng Jiang, Zhe Wang, Hyo Jeong Lee, Hongbo Hu, Barbara Malewicz, Hyo Jung Lee, Jae Ho Lee, Nam In Baek, Jin-Hyun Jeong, Dae Keun Kim, Kyung Sun Kang, Sung Hoon Kim, Junxuan Lu

Research output: Contribution to journalArticle

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Abstract

Androgen and the androgen receptor (AR)-mediated signaling are crucial for prostate cancer development. Novel agents that can inhibit AR signaling in ligand-dependent and ligand-independent manners are desirable for the chemoprevention of prostate carcinogenesis and for the treatment of advanced prostate cancer. We have shown recently that the pyranocoumarin compound decursin from the herb Angelica gigas possesses potent anti-AR activities distinct from the anti-androgen bicalutamide. Here, we compared the anti-AR activities and the cell cycle arrest and apoptotic effects of decursin and two natural analogues in the androgen-dependent LNCaP human prostate cancer cell culture model to identify structure-activity relationships and mechanisms. Decursin and its isomer decursinol angelate decreased prostate-specific antigen expression with IC 50 of ∼ 1 μmol/L. Both inhibited the androgen-stimulated AR nuclear translocation and transactivation, decreased AR protein abundance through proteasomal degradation, and induced G 0/1 arrest and morphologic differentiation. They also induced caspase-mediated apoptosis and reactive oxygen species at higher concentrations. Furthermore, they lacked the agonist activity of bicalutamide in the absence of androgen and were more potent than bicalutamide for suppressing androgen-stimulated cell growth. Decursinol, which does not contain a side chain, lacked the reactive oxygen species induction and apoptotic activities and exerted paradoxically an inhibitory and a stimulatory effect on AR signaling and cell growth. In conclusion, decursin and decursinol angelate are members of a novel class of nonsteroidal compounds that exert a long-lasting inhibition of both ligand-dependent and ligand-independent AR signaling. The side chain is critical for sustaining the anti-AR activities and the growth arrest and apoptotic effects.

Original languageEnglish
Pages (from-to)907-917
Number of pages11
JournalMolecular Cancer Therapeutics
Volume6
Issue number3
DOIs
Publication statusPublished - 2007 Mar 1

Fingerprint

Pyranocoumarins
Androgen Receptors
Androgens
Ligands
Prostatic Neoplasms
Reactive Oxygen Species
Growth
Testosterone Congeners
Angelica
Activity Cycles
Chemoprevention
Structure-Activity Relationship
Prostate-Specific Antigen
Caspases
Cell Cycle Checkpoints
decursin
Transcriptional Activation
Prostate
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Guo, J., Jiang, C., Wang, Z., Lee, H. J., Hu, H., Malewicz, B., ... Lu, J. (2007). A novel class of pyranocoumarin anti-androgen receptor signaling compounds. Molecular Cancer Therapeutics, 6(3), 907-917. https://doi.org/10.1158/1535-7163.MCT-06-0231
Guo, Junming ; Jiang, Cheng ; Wang, Zhe ; Lee, Hyo Jeong ; Hu, Hongbo ; Malewicz, Barbara ; Lee, Hyo Jung ; Lee, Jae Ho ; Baek, Nam In ; Jeong, Jin-Hyun ; Kim, Dae Keun ; Kang, Kyung Sun ; Kim, Sung Hoon ; Lu, Junxuan. / A novel class of pyranocoumarin anti-androgen receptor signaling compounds. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 3. pp. 907-917.
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Guo, J, Jiang, C, Wang, Z, Lee, HJ, Hu, H, Malewicz, B, Lee, HJ, Lee, JH, Baek, NI, Jeong, J-H, Kim, DK, Kang, KS, Kim, SH & Lu, J 2007, 'A novel class of pyranocoumarin anti-androgen receptor signaling compounds', Molecular Cancer Therapeutics, vol. 6, no. 3, pp. 907-917. https://doi.org/10.1158/1535-7163.MCT-06-0231

A novel class of pyranocoumarin anti-androgen receptor signaling compounds. / Guo, Junming; Jiang, Cheng; Wang, Zhe; Lee, Hyo Jeong; Hu, Hongbo; Malewicz, Barbara; Lee, Hyo Jung; Lee, Jae Ho; Baek, Nam In; Jeong, Jin-Hyun; Kim, Dae Keun; Kang, Kyung Sun; Kim, Sung Hoon; Lu, Junxuan.

In: Molecular Cancer Therapeutics, Vol. 6, No. 3, 01.03.2007, p. 907-917.

Research output: Contribution to journalArticle

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