A novel diterpene suppresses CWR22Rv1 tumor growth in vivo through antiproliferation and proapoptosis.

Abstract

Androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers (PCa). As recurrent tumors restore AR activity independent of hormones, new therapies that abolish AR activity have been sought to prevent or delay the emergence of ablation-resistant disease. Here, we report that a novel abietane diterpene, 6-hydroxy-5,6-dehydrosugiol (HDHS), isolated from the stem bark of Cryptomeria japonica, was a potent AR antagonist in PCa cells. HDHS treatment of androgen-dependent LNCaP and androgen-responsive 22Rv1 cells induced apoptosis as shown by nucleosome release, activation of caspase-3 and caspase-7, and cleavage of poly(ADP-ribose) polymerase accompanied with concomitant up-regulation of tumor suppressor p53. HDHS also decreased the protein expression of cyclins (D1 and E), cyclin-dependent kinases (CDK2, CDK4, and CDK6), and retinoblastoma phosphorylation in PCa cells, which suggest cell cycle arrest in the G(1) phase. Oral administration of HDHS at 0.5 and 2.5 mg/kg once daily for 24 days to 22Rv1 PCa xenografted mice suppressed tumor growth by 22% and 39%, respectively, in association with decreased proliferation and increased apoptosis in tumor cells, which further correlated with increased levels of HDHS in plasma and tumors. Overall, our data suggest that HDHS has potential for use in chemoprevention and chemotherapy of PCa.

• Authors: Feng-Min Lin, Chin-Hsien Tsai, Yu-Chih Yang, Wei-Chun Tu, Li-Ru Chen, Yun-Sa Liang, Sheng-Yang Wang, Lie-Fen Shyur, Shih-Chang Chien, Tai-Lung Cha, Pei-Wen Hsiao
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 16 Pg. 6634-42 (Aug 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18701487 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6-hydroxy-5,6-dehydrosugiol
• AR protein, human
• Abietanes
• Androgen Receptor Antagonists
• Cyclins
• Receptors, Androgen
• Cyclin-Dependent Kinases

Topics

• Abietanes (therapeutic use)
• Administration, Oral
• Androgen Receptor Antagonists
• Animals
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Cryptomeria (chemistry)
• Cyclin-Dependent Kinases (metabolism)
• Cyclins (metabolism)
• G1 Phase (drug effects)
• Humans
• Male
• Mice
• Mice, Nude
• Phytotherapy
• Plant Bark (chemistry)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Receptors, Androgen (genetics)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays