A novel diterpene suppresses CWR22Rv1 tumor growth in vivo through antiproliferation and proapoptosis.
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.
Lin
Feng-Min
FM
Agricultural Biotechnology Research Center, Academia Sinica, Nankang, Taipei, Taiwan.
Tsai
Chin-Hsien
CH
Yang
Yu-Chih
YC
Tu
Wei-Chun
WC
Chen
Li-Ru
LR
Liang
Yun-Sa
YS
Wang
Sheng-Yang
SY
Shyur
Lie-Fen
LF
Chien
Shih-Chang
SC
Cha
Tai-Lung
TL
Hsiao
Pei-Wen
PW
D045784:Abietanes / Q000627:therapeutic use*; D000284:Administration, Oral; D059002:Androgen Receptor Antagonists; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D032485:Cryptomeria / Q000737:chemistry; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008517:Phytotherapy; D024301:Plant Bark / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C531969:6-hydroxy-5,6-dehydrosugiol; C410798:AR protein, human; D045784:Abietanes; D059002:Androgen Receptor Antagonists; D016213:Cyclins; D011944:Receptors, Androgen; D018844:Cyclin-Dependent Kinases