In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 16 ( 2008-08-15), p. 6634-6642
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 G1 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. [Cancer Res 2008;68(16):6634–42]
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/0008-5472.CAN-08-0635
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2008
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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