Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Carcinogenesis. 2012 Dec;33(12):2457-66. doi: 10.1093/carcin/bgs293. Epub 2012 Sep 15.
Long-term treatment with thiopurines, such as the widely used anticancer, immunosuppressive and anti-inflammatory agent azathioprine, combined with exposure to ultraviolet (UV) radiation is associated with increased oxidative stress, hyperphotosensitivity and high risk for development of aggressive squamous cell carcinomas of the skin. Sulforaphane, an isothiocyanate derived from broccoli, is a potent inducer of endogenous cellular defenses regulated by transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), including cytoprotective enzymes and glutathione, which in turn act as efficient indirect and direct antioxidants that have long-lasting effects. Treatment with 6-thioguanine, a surrogate for azathioprine, leads to profound sensitization to oxidative stress and glutathione depletion upon exposure to UVA radiation, the damaging effects of which are primarily mediated by generation of reactive oxygen species. The degree of sensitization is greater for irradiation exposures spanning the absorption spectrum of 6-thioguanine, and is dependent on the length of treatment and the level of guanine substitution with 6-thioguanine, suggesting that the 6-thioguanine that is incorporated in genomic DNA is largely responsible for this sensitization. Sulforaphane provides protection against UVA, but not UVB, radiation without affecting the levels of 6-thioguanine incorporation into DNA. The protective effect is lost under conditions of Nrf2 deficiency, implying that it is due to induction of Nrf2-dependent cytoprotective proteins, and that this strategy could provide protection against any potentially photosensitizing drugs that generate electrophilic or reactive oxygen species. Thus, our findings support the development of Nrf2 activators as protectors against drug-mediated photooxidative stress and encourage future clinical trials in populations at high risk for cutaneous photodamage and photocarcinogenesis.
长期使用硫嘌呤类药物（如广泛应用于抗癌、免疫抑制和抗炎的药物硫唑嘌呤）与暴露于紫外线（UV）辐射相结合，会导致氧化应激增加、超敏反应和皮肤侵袭性鳞状细胞癌的高风险。萝卜硫素是一种源自西兰花的异硫氰酸盐，是转录因子核因子红细胞 2 相关因子 2（Nrf2）调节的内源性细胞防御的有效诱导剂，包括细胞保护酶和谷胱甘肽，它们反过来作为有效的间接和直接抗氧化剂发挥作用，具有持久的效果。用硫代鸟嘌呤（硫唑嘌呤的替代物）治疗会导致在暴露于 UVA 辐射时对氧化应激和谷胱甘肽耗竭产生深刻的敏感化，其损伤作用主要是通过产生活性氧来介导的。对于跨越硫代鸟嘌呤吸收光谱的照射暴露，敏化程度更大，并且取决于治疗时间的长度和硫代鸟嘌呤与鸟嘌呤的取代水平，这表明掺入基因组 DNA 中的硫代鸟嘌呤在很大程度上是这种敏化的原因。萝卜硫素可提供针对 UVA 但不针对 UVB 辐射的保护，而不会影响硫代鸟嘌呤掺入 DNA 的水平。在 Nrf2 缺乏的情况下，保护作用丧失，这意味着它是由于诱导 Nrf2 依赖性细胞保护蛋白所致，并且该策略可针对任何可能产生亲电或活性氧的光敏药物提供保护。因此，我们的发现支持开发 Nrf2 激活剂作为药物介导的光氧化应激的保护剂，并鼓励在皮肤光损伤和光致癌风险高的人群中进行未来的临床试验。
