N-acetylcysteine protects melanocytes against oxidative stress/damage and delays onset of ultraviolet induced melanoma in mice

被引:67
作者
Cotter, Murray A.
Thomas, Joshua
Cassidy, Pamela
Robinette, Kyle
Jenkins, Noah
Florell, Scott R.
Leachman, Sancy
Samlowski, Wolfram E.
Grossman, Douglas
机构
[1] Univ Utah, Hlth Sci Ctr, Huntsman Canc Inst, Melanoma Program, Salt Lake City, UT 84112 USA
[2] Univ Utah, Hlth Sci Ctr, Dept Dermatol, Salt Lake City, UT USA
[3] Univ Utah, Hlth Sci Ctr, Dept Oncol Sci, Salt Lake City, UT USA
[4] Univ Utah, Hlth Sci Ctr, Dept Med Chem, Salt Lake City, UT USA
[5] Univ Utah, Hlth Sci Ctr, Dept Med, Salt Lake City, UT USA
关键词
D O I
10.1158/1078-0432.CCR-07-1187
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: 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. Experimental Design: 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. Results: 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). Conclusions: 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.
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收藏
页码:5952 / 5958
页数:7
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