Chemoprevention of skin cancer by grape constituent resveratrol: relevance to human disease?
Chemoprevention of skin cancer by grape constituent resveratrol: relevance to human disease?
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DOI：
10.1096/fj.04-3582fje
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发表时间：
2005-04-01
期刊：
影响因子：
4.8
通讯作者：
Ahmad, N
中科院分区：
文献类型：
--
作者：
Aziz, MH;Reagan-Shaw, S;Ahmad, N
根据《世界癌症报告》，皮肤癌约占世界上所有新诊断癌症的 30%，而太阳紫外线 (UV) 辐射（特别是其 UVB 成分；290-320 nm）是约 90% 皮肤癌的既定病因。事实证明，现有的选择不足以治疗皮肤癌。因此，迫切需要开发基于机制的皮肤癌预防/治疗新方法。在这项研究中，我们在 SKH-1 无毛小鼠模型中评估了白藜芦醇对 UVB 辐射介导的皮肤肿瘤发生的化学预防作用。在我们的研究中，我们使用了 UVB 启动-促进方案，其中对照小鼠接受慢性 UVB 暴露（180 mJ/cm(2)，每周两次，持续 28 周）。实验动物接受白藜芦醇（25或50微摩尔/0.2毫升丙酮/小鼠）的预处理（每次UVB前30分钟）或后处理（UVB后5分钟）。对小鼠进行皮肤肿瘤发生跟踪，并在最后一次 UVB 暴露后 24 小时处死，以进行进一步研究。皮肤局部应用白藜芦醇（治疗前和治疗后）可产生非常显着的效果：1）抑制肿瘤发生，2）延迟肿瘤发生。有趣的是，白藜芦醇的后处理被发现可以提供与预处理相同的保护作用。这表明白藜芦醇介导的反应可能不是防晒霜的效果。由于 Survivin 是细胞存活/死亡的关键调节因子，并且其过度表达与多种癌症有关，因此我们评估了其在白藜芦醇对 UVB 介导的皮肤癌的化学预防中的作用。我们的数据表明，皮肤肿瘤中存在显着的 1) Survivin 上调（蛋白质和 mRNA 水平），2) 磷酸化 Survivin 蛋白质上调，以及 3) 促凋亡 Smac/DIABLO 蛋白质下调；而白藜芦醇治疗会导致这些反应减弱。我们的研究还表明，白藜芦醇可增强 UVB 暴露介导的皮肤肿瘤的细胞凋亡。我们的研究首次证明：1) 白藜芦醇对 UVB 暴露介导的皮肤癌（与人类皮肤癌相关）具有强大的化学预防作用，2) 白藜芦醇的化学预防作用可能至少部分是通过调节生存素和其他相关事件来介导的。根据我们的工作，可以想象设计出含有白藜芦醇的润肤剂或贴剂，以及防晒霜和护肤品，以预防皮肤癌和其他被认为是由紫外线辐射引起的疾病。
According to the World Cancer Report, skin cancer constitutes similar to 30% of all newly diagnosed cancers in the world, and solar ultraviolet (UV) radiation (particularly, its UVB component; 290-320 nm) is an established cause of similar to 90% of skin cancers. The available options have proven to be inadequate for the management of skin cancers. Therefore, there is an urgent need to develop mechanism-based novel approaches for prevention/therapy of skin cancer. In this study, we evaluated the chemopreventive effects of resveratrol against UVB radiation-mediated skin tumorigenesis in the SKH-1 hairless mouse model. For our studies, we used a UVB initiation-promotion protocol in which the control mice were subjected to chronic UVB exposure (180 mJ/cm(2), twice weekly, for 28 weeks). The experimental animals received either a pretreatment (30 min before each UVB) or post-treatment (5 min after UVB) of resveratrol (25 or 50 micro mole/0.2 ml acetone/mouse). The mice were followed for skin tumorigenesis and were killed at 24 h after the last UVB exposure, for further studies. The topical application of skin with resveratrol (both pre- and post- treatment) resulted in a highly significant 1) inhibition in tumor incidence, and 2) delay in the onset of tumorigenesis. Interestingly, the post-treatment of resveratrol was found to impart equal protection than the pretreatment; suggesting that resveratrol-mediated responses may not be sunscreen effects. Because Survivin is a critical regulator of survival/death of cells, and its overexpression has been implicated in several cancers, we evaluated its involvement in chemoprevention of UVB-mediated skin carcinogenesis by resveratrol. Our data demonstrated a significant 1) up-regulation of Survivin (both at protein- and mRNA- levels), 2) up-regulation of phospho-Survivin protein, and 3) down-regulation of proapoptotic Smac/DIABLO protein in skin tumors; whereas treatment with resveratrol resulted in the attenuation of these responses. Our study also suggests that resveratrol enhanced apoptosis in UVB-exposure-mediated skin tumors. Our study, for the first time, demonstrated that 1) resveratrol imparts strong chemopreventive effects against UVB exposure-mediated skin carcinogenesis (relevant to human skin cancers), and 2) the chemopreventive effects of resveratrol may, at least in part, be mediated via modulations in Survivin and other associated events. On the basis of our work, it is conceivable to design resveratrol-containing emollient or patch, as well as sunscreen and skin-care products for prevention of skin cancer and other conditions, which are believed to be caused by UV radiation.