Antioxidants Promote Intestinal Tumor Progression in Mice.

Zhiyuan V Zou,Martin O Bergo,Kristell Le Gal,Lara E Pehlivanoglu,Per-Olof Bergh,Volkan I Sayin,Levent M Akyürek,Clotilde Wiel,Marcus Henricsson,Mohamed X Ibrahim,Viktor Garellick,Nadia Gul,Per Lindahl,Ahmed E El Zowalaty

doi:10.3390/antiox10020241

Zhiyuan V Zou, Martin O Bergo + Show 12 more

Open Access

https://doi.org/10.3390/antiox10020241

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Journal: Antioxidants	Publication Date: Feb 4, 2021
Citations: 15	License type: CC BY 4.0

Affiliation: University of Gothenburg, Karolinska Institutet

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.

Highlights

Accumulating evidence shows that dietary antioxidants have adverse effects on certain cancers
Tumors in APCMin/+ mice are driven by the homozygous loss of the tumor suppressor APC: the first allele is inactivated by a truncating germline mutation, and the second allele, by a stochastic loss-of-heterozygosity in somatic cells, leading to constitutive WNT signaling and neoplastic transformation (Figure 1A)
Because similar APC mutations are found in the majority of spontaneous human colorectal cancers, APCMin/+ mice are used as a general model for the early stages of colorectal cancer

Summary

Introduction

Accumulating evidence shows that dietary antioxidants have adverse effects on certain cancers. Endogenous antioxidants appear to promote cancer development in a similar manner: lung cancer cells accumulate somatic mutations in KEAP1 and NFE2L2 that increase the production of endogenous antioxidants [9,10,11,12,13]. These and other studies stand in stark contrast to the decades-long notion of antioxidants having protective effects in cancer [14,15]. To identify the conditions under which dietary antioxidants pose a risk is vital given the widespread use of antioxidant supplements

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