This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Guo, J. Articles by Lu, J. Search for Related Content PubMed PubMed Citation Articles by Guo, J. Articles by Lu, J.

Research Articles: Therapeutics, Targets, and Development

A novel class of pyranocoumarin anti–androgen receptor signaling compounds

¹ Hormel Institute, University of Minnesota, Austin, Minnesota; ² College of Oriental Medicine, Kyunghee University; ³ Seoul National University, Seoul, Republic of Korea; ⁴ Kyunghee University, Yongin, Republic of Korea; and ⁵ Wouseok University, Chunju, Republic of Korea

Requests for reprints: Junxuan Lu, Hormel Institute, University of Minnesota, 801 16th Avenue Northeast, Austin, MN 55912. Phone: 507-437-9680; Fax: 507-437-9606. E-mail: jlu{at}hi.umn.edu or Sung-Hoon Kim, College of Oriental Medicine, Kyunghee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 131-701, Republic of Korea. Phone: 82-2-961-9233; Fax: 82-2-964-1074. E-mail: sungkim7{at}khu.ac.kr

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 IC₅₀ 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. [Mol Cancer Ther 2007;6(3):907–17]

Grant support: The Hormel Foundation, the Prostate Cancer Foundation, and National Cancer Institute grant CA95642 (J. Lu) and Korea Science Engineering Foundation grants BRP;R01-2-005-000-10993-0 and MRC, Korea Ministry of Health and Welfare grant B050007, Korea Biogreen 21 Project, and Korea Agricultural R&D Promotion Center grants (S-H. Kim).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: J. Guo and C. Jiang contributed equally to this work and should be considered co-first authors.

J. Lu and S-H. Kim are senior corresponding authors.

Current address for J. Guo: Ningbo University Medical School, Ningbo, Zhejiang Province, The People's Republic of China.

The University of Minnesota is an equal opportunity educator and employer.

⁶ M. Grossmann and J. Lu, unpublished data.

Received 5/ 1/06; revised 10/ 9/06; accepted 1/11/07.

This article has been cited by other articles:

				G.-Y. Song, J.-H. Lee, M. Cho, B.-S. Park, D.-E. Kim, and S. Oh Decursin Suppresses Human Androgen-Independent PC3 Prostate Cancer Cell Proliferation by Promoting the Degradation of beta-Catenin Mol. Pharmacol., December 1, 2007; 72(6): 1599 - 1606. [Abstract] [Full Text] [PDF]