Antioxidants Accelerate Lung Cancer Progression in Mice

Science translational medicine (Impact Factor: 15.84). 01/2014; 6(221):221ra15. DOI: 10.1126/scitranslmed.3007653
Source: PubMed


Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.

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Available from: Volkan I Sayin, Aug 25, 2014
    • "Next, we tested eIF4E dose requirements in the setting of in vivo tumorigenesis driven by endogenous expression of oncogenic KRas. Importantly, the ability to properly respond to and control ROS is critical for lung cancer driven by endogenous expression of oncogenic KRas (DeNicola et al., 2011; Sayin et al., 2014). Thus, we asked what effect genetically reducing the dose of eIF4E by 50% would have in the KRas LA2 model of lung cancer (Figure 7A) (Johnson et al., 2001). "
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    ABSTRACT: eIF4E, the major cap-binding protein, has long been considered limiting for translating the mammalian genome. However, the eIF4E dose requirement at an organismal level remains unexplored. By generating an Eif4e haploinsufficient mouse, we found that a 50% reduction in eIF4E expression, while compatible with normal development and global protein synthesis, significantly impeded cellular transformation. Genome-wide translational profiling uncovered a translational program induced by oncogenic transformation and revealed a critical role for the dose of eIF4E, specifically in translating a network of mRNAs enriched for a unique 5' UTR signature. In particular, we demonstrate that the dose of eIF4E is essential for translating mRNAs that regulate reactive oxygen species, fueling transformation and cancer cell survival in vivo. Our findings indicate eIF4E is maintained at levels in excess for normal development that are hijacked by cancer cells to drive a translational program supporting tumorigenesis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 06/2015; 162(1). DOI:10.1016/j.cell.2015.05.049 · 32.24 Impact Factor
    • "Although reports on the consumption of such supplements are scarce, it has been estimated that more than half of the adults just in the U.S., regularly consume some kind of supplements [2]. In past decades, several researches have documented the efficient activity of antioxidants, however recent studies suggest that antioxidants in addition to scavenging free radicals, may have the opposite effect and promote or even accelerate the development of tumors [3] [4]. On the other hand, pro-oxidants are referred as reactive oxygen species (ROS) and can be classified in two groups, (1) radicals, that include molecules that contain at least one unpaired electron, and (2) non-radicals, that include electronically excited species as singlet oxygen ( 1 O 2 ) [5]. 1 O 2 can be generated by photochemical reactions type II that involve a photosensitizer dye capable of absorbing UV–Vis light in the presence of molecular oxygen ( 3 O 2 ), and its detection is possible by either spectroscopic technics or its presence is inferred by the formation of specific products [6]. "
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    ABSTRACT: Consumption of antioxidant supplements is associated to prevention of several diseases. However, recent studies suggest that antioxidants, besides scavenge free radicals could lead development of tumors. Due to conflicting reports on the antioxidant benefits, the capacity to photosensitize the generation of singlet oxygen of seven natural antioxidants was evaluated through photo-oxidation of ergosterol which proved to be an efficient method of indirect detection of singlet oxygen. Our results showed that curcumin, resveratrol and quercetin have pro-oxidant activity due they act as photosensitizers in generation of singlet oxygen. In addition, we observed that genistein, naringenin, β-carotene and gallic acid besides their antioxidant activity against ROS radicals, are capable of quenching ROS non-radicals as singlet oxygen. Finally, our results allow us to propose a new approach in classification of natural antioxidants scavengers of free radicals, based on their activity as quenchers of singlet oxygen or as photosensitizers in singlet oxygen generation. Copyright © 2015. Published by Elsevier B.V.
    Journal of Photochemistry and Photobiology B Biology 02/2015; 145:30-34. DOI:10.1016/j.jphotobiol.2015.02.014 · 2.96 Impact Factor
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    • "However, we observed decreased ROS production in OTA treatment groups at 4 and 13 weeks. Reduced ROS can facilitate tumor cell proliferation (Sayin et al., 2014). In addition, increased PCNA of the kidneys in the highdose group suggested that the rat kidney is likely to be the target for OTA carcinogenicity. "
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    ABSTRACT: Ochratoxin A (OTA) has displayed nephrotoxicity and renal carcinogenicity in mammals, however, no clear mechanisms have been identified detailing the relationship between oxidative stress and these toxicities. This study was performed to clarify the relationship between oxidative stress and the renal carcinogenicity induced by OTA. Rats were treated with 70 or 210 μg/kg b.w. OTA for 4 or 13 weeks. In the rats administrated with OTA for 13 weeks, the kidney was damaged seriously. Cytoplasmic vacuolization was observed in the outer stripe of outer medulla. Karyomegaly was prominent in the tubular epithelium. Kidney injury molecule-1 (Kim-1) was detected in the outer stripe of the outer medulla in both low- and high-dose groups. OTA increased the mRNA levels of clusterin in rat kidneys. Interestingly, OTA did not significantly alter oxidative stress level in rat liver and kidney. Yet, some indications related to proliferation and carcinogenicity were observed. A dose-related increase in proliferating cell nuclear antigen (PCNA) was observed at 4 weeks in both liver and kidney, but at 13 weeks, only in the kidney. OTA down-regulated reactive oxygen species (ROS); and up-regulated vimentin and lipocalin 2 in rat kidney at 13 weeks. The p53 gene was decreased in both liver and kidney at 13 weeks. These results suggest that OTA caused apparent kidney damage within 13 weeks but exerted limited effect on oxidative stress parameters. It implies that cell proliferation is the proposed mode of action for OTA-induced renal carcinogenicity.
    Toxicology and Applied Pharmacology 09/2014; 280(3). DOI:10.1016/j.taap.2014.08.030 · 3.71 Impact Factor
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