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


METHODS
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.
Cotter
Murray A
MA
Department of Dermatology, Huntsman Cancer Institute, Salt Lake City, Utah 84112, USA.
Thomas
Joshua
J
Cassidy
Pamela
P
Robinette
Kyle
K
Jenkins
Noah
N
Florell
Scott R
SR
Leachman
Sancy
S
Samlowski
Wolfram E
WE
Grossman
Douglas
D
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000378:metabolism* / Q000528:radiation effects*; D008545:Melanoma / Q000188:drug therapy* / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy*; D018384:Oxidative Stress; D011740:Pyrimidine Dimers / Q000737:chemistry; D017382:Reactive Oxygen Species; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D014466:Ultraviolet Rays
D016588:Anticarcinogenic Agents; D011740:Pyrimidine Dimers; D017382:Reactive Oxygen Species; D000111:Acetylcysteine