Antioxidants — On the Wrong Side of the Tracks?
Kenneth Y. Tsai, MD, PhD reviewing Piskounova E et al. Nature 2015 Oct 14. Le Gal K et al. Sci Transl Med 2015 Oct 7.
Two animal studies indicate that antioxidant exposure may have significant unintended consequences for the progression of melanoma.
Antioxidants, available in many over-the-counter forms (vitamins C, E), are commonly regarded as safe and possibly cancer-protective. However, regulation of reactive oxygen species in cancers is quite complex, and though cells have evolved multiple mechanisms to control potentially mutagenic and damaging reactive oxygen species (ROS), increasing evidence suggests that cancers tune ROS levels to a sweet spot that avoids catastrophic toxicity while preserving generation of new mutations and inhibiting immune control.
Two recent studies in mouse models directly addressed how antioxidants might affect melanoma progression. Le Gal and colleagues showed that antioxidants increased melanoma invasiveness and metastasis. Both N-acetylcysteine (NAC) and Trolox (a vitamin E analogue) affected RHOA kinase pathways that regulate invasiveness and migration. NAC administration in a Braf/Pten mouse model of melanoma doubled the number of lymph node metastases. Piskounova and colleagues made similar observations but took things further, determining that melanoma cells experience oxidative stress in circulation. They showed that melanomas passaged through subcutaneous tissue had a substantially different redox status than did melanomas moving through the circulation or implanted in the spleen. In their assays, NAC also increased the metastatic efficiency of melanoma cells by 10-fold. Having detected greater levels of reduced glutathione in efficiently metastatic cells, the authors reasoned that NADPH-generating enzymes allow these cells to withstand oxidative stress. Since folate metabolism is critical for this process, they tested whether methotrexate would suppress metastases, which it did.
CITATION(S):
Piskounova E et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 2015 Oct 14; [e-pub].
Le Gal K et al. Antioxidants can increase melanoma metastasis in mice. Sci Transl Med 2015 Oct 7; [e-pub].
