N-Acetylcysteine Promotes Metastatic Spread of Melanoma in Mice

Simple Summary Malignant melanoma is a cancer derived from melanocytes, the cells that produce pigment (melanin) in the skin. It develops on the skin, but can also appear on the mucous membranes and in other locations. Melanomas are responsible for 80% of deaths related to skin cancers. In recent years, the number of cases has increased alarmingly, likely in relation to sun exposure habits. Once melanoma spreads to distant parts of the body, the 5-year survival rate is about 10%. N-acetylcysteine (NAC) is a drug with antioxidant properties, and thereby could play a role in preventing cancer. NAC is commonly used as a mucolytic in different respiratory diseases, to treat acetaminophen (Tylenol) poisoning, and is also present in different nutritional supplements. Nevertheless, the use of NAC and other antioxidants in cancer has been questioned. Here, we show that high therapeutic doses of NAC may cause metastatic spread of a malignant melanoma. N-acetylcysteine (NAC) is a direct Cys donor and a promoter of glutathione (GSH) synthesis. GSH regulates melanoma growth and NAC has been suggested to increase melanoma metastases in mice. We found that high therapeutic doses of NAC do not increase the growth of melanoma xenografts, but can cause metastatic spread and distant metastases. Nevertheless, this is not due to an antioxidant effect since NAC, in fact, increases the generation of reactive oxygen species in the growing metastatic melanoma. Trolox, an antioxidant vitamin E derivative, administered in vivo, decreased metastatic growth. Metastatic cells isolated from NAC-treated mice showed an increase in the nuclear translocation of Nrf2, as compared to controls. Nrf2, a master regulator of the antioxidant response, controls the expression of different antioxidant enzymes and of the gamma-glutamylcysteine ligase (the rate-limiting step in GSH synthesis). Cystine uptake through the xCT cystine-glutamate antiporter (generating intracellular Cys) and the gamma-glutamylcysteine ligase activity are key to control metastatic growth. This is associated to an increase in the utilization of L-Gln by the metastatic cells, another metastases promoter. Our results demonstrate the potential of NAC as an inducer of melanoma metastases spread, and suggest that caution should be taken when administering GSH promoters to cancer patients.