A novel diterpene suppresses CWR22Rv1 tumor growth in vivo through anti proliferation and proapoptosis
A novel diterpene suppresses CWR22Rv1 tumor growth in vivo through anti proliferation and proapoptosis
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DOI：
10.1158/0008-5472.can-08-0635
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发表时间：
2008-08-15
期刊：
影响因子：
11.2
通讯作者：
Hsiao, Pei-Wen
中科院分区：
文献类型：
--
作者：
Lin, Feng-Min;Tsai, Chin-Hsien;Hsiao, Pei-Wen
雄激素受体（AR）是治疗转移性前列腺癌（PCa）的主要治疗靶点。由于复发性肿瘤恢复AR活性不依赖于激素，因此已经寻求消除AR活性的新疗法来预防或延迟消融抗性疾病的出现。在这里，我们报告了一种新的松香烷二萜，6-羟基-5，6-脱氢糖醇（HDHS），从日本柳杉干树皮分离，是一个有效的AR拮抗剂在PCa细胞。HDHS处理雄激素依赖性LNCaP和雄激素响应性22 Rv 1细胞诱导凋亡，如核小体释放，半胱天冬酶-3和半胱天冬酶-7的激活，以及聚（ADP-核糖）聚合酶的裂解伴随着肿瘤抑制因子p53的上调所示。HDHS还降低了PCa细胞中细胞周期蛋白（D1和E）、细胞周期蛋白依赖性激酶（CDK 2、CDK 4和CDK 6）和视网膜母细胞瘤磷酸化的蛋白表达，这表明细胞周期停滞在G1期。以0.5和2.5 mg/kg每日一次口服给予22 Rv 1 PCa异种移植小鼠HDHS 24天，分别抑制肿瘤生长22%和39%，与肿瘤细胞增殖减少和凋亡增加相关，这进一步与血浆和肿瘤中HDHS水平增加相关。总的来说，我们的数据表明，HDHS有潜力用于PCa的化学预防和化疗。
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, 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.