Cotter Murray A, Thomas Joshua, Cassidy Pamela, Robinette Kyle, Jenkins Noah, Florell Scott R, Leachman Sancy, Samlowski Wolfram E, Grossman Douglas
Department of Dermatology, Huntsman Cancer Institute, Salt Lake City, Utah 84112, USA.
Clin Cancer Res. 2007 Oct 1;13(19):5952-8. doi: 10.1158/1078-0432.CCR-07-1187.
UV radiation is the major environmental risk factor for melanoma and a potent inducer of oxidative stress, which is implicated in the pathogenesis of several malignancies. We evaluated whether the thiol antioxidant N-acetylcysteine (NAC) could protect melanocytes from UV-induced oxidative stress/damage in vitro and from UV-induced melanoma in vivo.
In vitro experiments used the mouse melanocyte line melan-a. For in vivo experiments, mice transgenic for hepatocyte growth factor and survivin, shown previously to develop melanoma following a single neonatal dose of UV irradiation, were given NAC (7 mg/mL; mother's drinking water) transplacentally and through nursing until 2 weeks after birth.
NAC (1-10 mmol/L) protected melan-a cells from several UV-induced oxidative sequelae, including production of intracellular peroxide, formation of the signature oxidative DNA lesion 8-oxoguanine, and depletion of free reduced thiols (primarily glutathione). Delivery of NAC reduced thiol depletion and blocked formation of 8-oxoguanine in mouse skin following neonatal UV treatment. Mean onset of UV-induced melanocytic tumors was significantly delayed in NAC-treated compared with control mice (21 versus 14 weeks; P = 0.0003).
Our data highlight the potential importance of oxidative stress in the pathogenesis of melanoma and suggest that NAC may be useful as a chemopreventive agent.
紫外线辐射是黑色素瘤的主要环境风险因素，也是氧化应激的强效诱导剂，氧化应激与多种恶性肿瘤的发病机制有关。我们评估了硫醇抗氧化剂N-乙酰半胱氨酸（NAC）是否能在体外保护黑素细胞免受紫外线诱导的氧化应激/损伤，并在体内保护其免受紫外线诱导的黑色素瘤的侵害。
体外实验使用小鼠黑素细胞系melan-a。对于体内实验，先前已证明在新生期单次接受紫外线照射后会发生黑色素瘤的肝细胞生长因子和生存素转基因小鼠，在出生前通过胎盘并在出生后通过哺乳给予NAC（7 mg/mL；母亲的饮用水），直至出生后2周。
NAC（1-10 mmol/L）保护melan-a细胞免受多种紫外线诱导的氧化后遗症，包括细胞内过氧化物的产生、标志性氧化DNA损伤8-氧代鸟嘌呤的形成以及游离还原硫醇（主要是谷胱甘肽）的消耗。给予NAC可减少新生小鼠紫外线处理后小鼠皮肤中的硫醇消耗并阻止8-氧代鸟嘌呤的形成。与对照小鼠相比，NAC处理的小鼠中紫外线诱导的黑素细胞肿瘤的平均发病时间显著延迟（21周对14周；P = 0.0003）。
我们的数据突出了氧化应激在黑色素瘤发病机制中的潜在重要性，并表明NAC可能作为一种化学预防剂有用。
