Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols
Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols
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DOI：
10.1073/pnas.171326098
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发表时间：
2001-08-28
影响因子：
11.1
通讯作者：
Mukhtar, H
中科院分区：
文献类型：
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作者：
Gupta, S;Hastak, K;Mukhtar, H
针对人类前列腺癌(CAP)的有效化学预防药物的开发需要在接近模拟人类疾病的动物模型中提供确凿证据证明其有效性。自发形成转移帽的自体转基因小鼠前列腺癌(TRAMP)模型就是这样一种模仿人类疾病进展形式的模型。使用雄性流浪鼠，我们发现以人类可达到的剂量(相当于每天六杯绿茶)口服从绿茶中分离出来的多酚部分(GTP)显著抑制帽子的发育并提高这些小鼠的存活率。在两个单独的实验中，20只未治疗的小鼠在32周龄时可触及的肿瘤累积发生率为100%(20/20)。在这些小鼠中，95%(19/20)、65%(13/20)、40%(8/20)和25%(5/20)的动物分别表现出远处淋巴结、肺、肝脏和骨骼的转移。然而，作为8-32周龄流浪鼠唯一饮用水来源的0.1%GTP(wt/VOL)导致(I)原发肿瘤发生率和肿瘤负担显著延迟，(Ii)前列腺(%)和泌尿生殖道(GU)重量显著下降(72%)，(Iii)血清胰岛素样生长因子-I显著抑制和胰岛素样生长因子结合蛋白-3水平恢复，(Iv)与水喂养流浪鼠相比，前列腺增殖细胞核抗原(PCNA)的蛋白表达显著降低。这项研究的显著观察结果是，GTP输注几乎完全抑制了远处转移。此外，GTP的摄入导致CAP细胞的显著凋亡，这可能导致癌细胞扩散减少，从而抑制前列腺癌的发展、进展和CAP向远处器官部位的转移。
Development of effective chemopreventive agents against prostate cancer (CaP) for humans requires conclusive evidence of their efficacy in animal models that closely emulates human disease. The autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which spontaneously develops metastatic CaP, is one such model that mimics progressive forms of human disease. Employing male TRAMP mice, we show that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a human achievable dose (equivalent to six cups of green tea per day) significantly inhibits CaP development and increases survival in these mice. In two separate experiments, the cumulative incidence of palpable tumors at 32 weeks of age in 20 untreated mice was 100% (20 of 20). In these mice, 95% (19 of 20),65% (13 of 20),40% (8 of 20), and 25% (5 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, liver, and bone, respectively. However, 0.1% GTP (wt/vol) provided as the sole source of drinking fluid to TRAMP mice from 8 to 32 weeks of age resulted in (i) significant delay in primary tumor incidence and tumor burden as assessed sequentially by MRI, (ii) significant decrease in prostate (64%) and genitourinary (GU) (72%) weight, (iii) significant inhibition in serum insulin-like growth factor-I and restoration of insulin-like growth factor binding protein-3 levels, and (iv) marked reduction in the protein expression of proliferating cell nuclear antigen (PCNA) in the prostate compared with water-fed TRAMP mice. The striking observation of this study was that GTP infusion resulted in almost complete inhibition of distant site metastases. Furthermore, GTP consumption caused significant apoptosis of CaP cells, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of prostate cancer development, progression, and metastasis of CaP to distant organ sites.