Antioxidants can increase melanoma metastasis in mice

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.

Metastatic colonization by circulating tumour cells

“…Melanoma cells show increased dependence on NADPH-generating enzymes in the folate pathway and inhibition of this pathway reduced overt metastasis 34 . In support of this finding, anti-oxidant supplementation increased lymph node metastases but had no effect on the growth of primary tumours 33,34 .…”

“…To protect themselves during transit, cancer cells associate with platelets 32 and undergo reversible metabolic changes to increase their ability to withstand oxidative stress 33 . Melanoma cells show increased dependence on NADPH-generating enzymes in the folate pathway and inhibition of this pathway reduced overt metastasis 34 .…”

Mitochondria and Cancer

“…In this system, antioxidants promoted distant metastasis, while folate pathway inhibition prevented metastasis due to decreased NADPH production, but had no effect on the primary tumor. Similarly, antioxidant treatment increased the number of metastasis in a mouse model of malignanat melanoma, causing increased invasiveness dependent on glutathione synthesis cells (Le Gal et al, 2015). Thus, successful tumors maintain ROS levels within a window that stimulates proliferation without causing cytotoxicity.…”

Pilot study demonstrating metabolic and anti-proliferative effects of in vivo anti-oxidant supplementation with N-Acetylcysteine in Breast Cancer

“…NAC also altered the metabolism marker MCT4 in the tumor stroma of subjects with breast cancer in this trial. These results are important because there is controversy as to whether NAC has anticancer properties since several studies have shown cancer progression 363738 . Also, there is controversy as to what dose of NAC should be used in oncology trials since some advocate using higher doses because of its pharmacokinetics 39 .…”