Antioxidants Promote Intestinal Tumor Progression in Mice

Abstract

Dietary antioxidants and supplements are widely used to protect against cancer, even though it is now clear that antioxidants can promote tumor progression by helping cancer cells to overcome barriers of oxidative stress. Although recent studies have, in great detail, explored the role of antioxidants in lung and skin tumors driven by RAS and RAF mutations, little is known about the impact of antioxidant supplementation on other cancers, including Wnt-driven tumors originating from the gut. Here, we show that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E promotes intestinal tumor progression in the ApcMin mouse model for familial adenomatous polyposis, a hereditary form of colorectal cancer, driven by Wnt signaling. Both antioxidants increased tumor size in early neoplasias and tumor grades in more advanced lesions without any impact on tumor initiation. Importantly, NAC treatment accelerated tumor progression at plasma concentrations comparable to those obtained in human subjects after prescription doses of the drug. These results demonstrate that antioxidants play an important role in the progression of intestinal tumors, which may have implications for patients with or predisposed to colorectal cancer.

Targeting oxidative stress in disease: promise and limitations of antioxidant therapy

“…It was assumed that both vitamin C and vitamin E have low toxicity and were not believed to cause serious adverse effects at much higher intake than needed for their function as vitamins. However, several non-human animal studies showed that antioxidant supplements, including NAC, vitamin E and the soluble vitamin E analogue Trolox, promoted cancer development and metastasis, for example, lung, melanoma and intestinal tumours in mouse models 228 – 230 . The potential effect of antioxidants on cancer promotion, including the aforementioned NRF2 activators, raises significant concerns regarding the use of antioxidant supplements, and novel strategies are needed to resolve the double-edged effect of antioxidants.…”

Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells

“…This is observed in both patient-derived xenografts growing in immunocompromised mice, as well as mouse melanomas growing in syngeneic, immunocompetent mice. Oxidative stress limits the metastasis of other cancers as well (42)(43)(44)(45)(46)(47)(48)(49)(50)(51), though oxidative stress may promote metastasis under certain circumstances (52,53). Large clinical trials found that antioxidant supplementation in humans increases cancer incidence and mortality (54)(55)(56)(57)(58).…”

G6PD deficiency sensitizes metastasizing melanoma cells to oxidative stress and glutaminolysis

“…This is observed in both patient-derived xenografts growing in immunocompromised mice as well as mouse melanomas growing in syngeneic, immunocompetent mice. Oxidative stress limits the metastasis of other cancers as well (41)(42)(43)(44)(45)(46)(47)(48)(49)(50), though oxidative stress may promote metastasis under certain circumstances (51,52). Large clinical trials found that antioxidant supplementation in humans increases cancer incidence and mortality (53)(54)(55)(56)(57).…”