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N-Acetylcysteine Protects Melanocytes against Oxidative Stress/Damage and Delays Onset of Ultraviolet-Induced Melanoma in Mice

Authors' Affiliations: Departments of ¹ Dermatology, ² Oncological Sciences, ³ Medicinal Chemistry, ⁴ Medicine, and ⁵ Melanoma Program, Huntsman Cancer Institute, University of Utah Health Science Center, Salt Lake City, Utah

Requests for reprints: Doug Grossman, Huntsman Cancer Institute, Suite 5243, 2000 Circle of Hope, Salt Lake City, UT 84112. Phone: 801-581-4682; Fax: 801-585-0900; E-mail: doug.grossman{at}hci.utah.edu.

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.