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Antioxidants can increase melanoma metastasis in mice

Science Translational Medicine  07 Oct 2015:
Vol. 7, Issue 308, pp. 308re8
DOI: 10.1126/scitranslmed.aad3740

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Another strike against antioxidants

Antioxidants are found in a variety of foods and dietary supplements and are frequently used with the goal of preventing cancer, but mounting evidence suggests that they may not be as beneficial as once thought. Clinical studies have shown mixed or no benefits, and other works demonstrated that antioxidants may accelerate the progression of lung cancer. Now, Le Gal et al. discovered that some common antioxidants increase the rate of melanoma cell migration and invasion and increase metastasis in a mouse model. These are early findings, and additional work will be required to confirm the generalizability of this observation. Nevertheless, the results suggest a need for caution in the use of antioxidants, especially for patients with existing cancer.

Abstract

Antioxidants in the diet and supplements are widely used to protect against cancer, but clinical trials with antioxidants do not support this concept. Some trials show that antioxidants actually increase cancer risk and a study in mice showed that antioxidants accelerate the progression of primary lung tumors. However, little is known about the impact of antioxidant supplementation on the progression of other types of cancer, including malignant melanoma. We show that administration of N-acetylcysteine (NAC) increases lymph node metastases in an endogenous mouse model of malignant melanoma but has no impact on the number and size of primary tumors. Similarly, NAC and the soluble vitamin E analog Trolox markedly increased the migration and invasive properties of human malignant melanoma cells but did not affect their proliferation. Both antioxidants increased the ratio between reduced and oxidized glutathione in melanoma cells and in lymph node metastases, and the increased migration depended on new glutathione synthesis. Furthermore, both NAC and Trolox increased the activation of the small guanosine triphosphatase (GTPase) RHOA, and blocking downstream RHOA signaling abolished antioxidant-induced migration. These results demonstrate that antioxidants and the glutathione system play a previously unappreciated role in malignant melanoma progression.

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