Prognostic value of xanthine oxidoreductase expression in patients with non-small cell lung cancer

Kim, Anthony W.; Batus, Marta; Myint, Ronald; Fidler, Mary J.; Basu, Sanjib; Bonomi, Philip; Faber, L. Penfield; Wightman, Sean C.; Warren, William H.; McIntire, Maria; Arvanitis, Leonidas; Gattuso, Paolo; Xu, Xiulong; Liptay, Michael J.

doi:10.1016/j.lungcan.2010.05.006

Cited by 20 publications

(16 citation statements)

References 26 publications

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“…XOR, a key enzyme in the metabolism of purine nucleotides, has also been linked to the production of reactive oxygen species (ROS) (30, 31). Assessment of XOR activity has been suggested as a diagnostic for NSCLC (32). In particular, reduced XOR expression was associated with shortened survival times (30, 32), while XOR-induced ROS products have been linked with an increased risk for developing various forms of cancer, including NSCLC (30, 33–35).…”

Section: Discussionmentioning

confidence: 99%

“…Assessment of XOR activity has been suggested as a diagnostic for NSCLC (32). In particular, reduced XOR expression was associated with shortened survival times (30, 32), while XOR-induced ROS products have been linked with an increased risk for developing various forms of cancer, including NSCLC (30, 33–35). Given this evidence, assessment of xanthine and uric acid levels may provide novel indicators of XOR activity and serve as diagnostic marker of tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

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Metabolomic Markers of Altered Nucleotide Metabolism in Early Stage Adenocarcinoma

Wikoff

Grapov

Fahrmann

et al. 2015

Cancer Prevention Research

109

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Adenocarcinoma, a type of non-small-cell lung cancer (NSCLC), is the most frequently diagnosed lung cancer and the leading cause of lung cancer mortality in the United States. It is well documented that biochemical changes occur early in the transition from normal to cancer cells, but the extent to which these alterations affect tumorigenesis in adenocarcinoma remains largely unknown. Herein we describe the application of mass spectrometry and multivariate statistical analysis in one of the largest biomarker research studies to date aimed at distinguishing metabolic differences between malignant and non-malignant lung tissue. Gas chromatography time-of-flight mass spectrometry was used to measure 462 metabolites in 39 malignant and non-malignant lung tissue pairs from current or former smokers with early stage (Stage IA–IB) adenocarcinoma. Statistical mixed effects models, orthogonal partial least squares discriminant analysis and network integration, were used to identify key cancer-associated metabolic perturbations in adenocarcinoma compared to non-malignant tissue. Cancer-associated biochemical alterations were characterized by: 1) decreased glucose levels, consistent with the Warburg effect, 2) changes in cellular redox status highlighted by elevations in cysteine and antioxidants, alpha- and gamma-tocopherol, 3) elevations in nucleotide metabolites 5,6-dihydrouracil and xanthine suggestive of increased dihydropyrimidine dehydrogenase and xanthine oxidoreductase activity, 4) increased 5'-deoxy-5'-methylthioadenosine levels indicative of reduced purine salvage and increased de novo purine synthesis and 5) coordinated elevations in glutamate and UDP-N-acetylglucosamine suggesting increased protein glycosylation. The present study revealed distinct metabolic perturbations associated with early stage lung adenocarcinoma which may provide candidate molecular targets for personalizing therapeutic interventions and treatment efficacy monitoring.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Metabolomic Markers of Altered Nucleotide Metabolism in Early Stage Adenocarcinoma

Wikoff

Grapov

Fahrmann

et al. 2015

Cancer Prevention Research

109

View full text Add to dashboard Cite

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“…While there is some support for this hypothesis among epidemiological studies, this idea has been strongly supported by molecular investigations, suggesting that an indirect pharmacological reduction in SUA levels, by inhibiting the XOR receptor, provokes tumorigenesis [19, 20]. Another example that supports the antioxidant capacity of SUA is a recent study on the link between a broad range of oxidative stress parameters and colon cancer survival [21].…”

Section: Discussionmentioning

confidence: 99%

Serum uric acid levels and cancer mortality risk among males in a large general population-based cohort study

Taghizadeh

Vonk

Boezen

2014

Cancer Causes Control

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PurposeSerum uric acid (SUA) has antioxidant capacities and therefore may protect against the development of cancer. Few epidemiological studies have tested this hypothesis, and findings were inconsistent.MethodsWe studied the association between SUA levels and mortality due to any type of cancer, and three common types of cancer among males (lung, colorectal, and prostate cancer) in the general population-based Vlagtwedde–Vlaardingen cohort with 38 years of follow-up and 8 surveys (total number of males = 4,350). Of 1,823 males with data available on SUA, 254 (13.9 %) died due to any cancer (lung n = 75 (4.1 %), colorectal n = 27 (1.5 %), and prostate cancer n = 23 (1.3 %), assessed on 31 December 2008). SUA, cholesterol, and triglyceride were measured in males during the surveys in 1970, 1972, and 1973. We analyzed the association between cancer mortality risk and SUA level both as continuous variable and as tertiles: lowest <5 mg/dl (reference), middle 5–5.8 mg/dl, and highest >5.8 mg/dl, using multivariate Cox regression with adjustment for age, smoking (pack years), and body mass index.ResultsHigher levels of SUA were associated with a lower risk of mortality from any cancer [HR (95 % CI) = 0.85 (0.73–0.97)]. SUA levels in the highest tertile (>5.8 mg/dl) were associated with a lower risk of mortality from any cancer [0.68 (0.48–0.97)]. Additional adjustment for serum total cholesterol and triglyceride levels did not change the results.ConclusionsOur study indicates that elevated SUA levels may protect against cancer mortality.

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“…Patients with a high percentage of cells expressing XOR protein had a longer median survival than patients with a lower expression frequency. Additionally, a low intensity of XOR expression was associated with a worse prognosis for patients who received adjuvant chemotherapy, suggesting a role for XOR‐produced ROS in contributing to the tumoricidal effect of chemotherapy . While the lack of XOR expression was confirmed in human lung tissue, the acquisition of such expression was associated with a shortened survival in patients with resected lung adenocarcinoma.…”

Section: Level Of Xanthine Oxidoreductase In Cancer Tissuementioning

confidence: 99%

Xanthine oxidoreductase in cancer: more than a differentiation marker

et al. 2015

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Human xanthine oxidoreductase (XOR) catalyzes the last two steps of purine catabolism and is present in two interconvertible forms, which may utilize O2 or NAD + as electron acceptors. In addition to uric acid, XOR products may comprise reactive oxygen and nitrogen species that have many biologic effects, including inflammation, endothelial dysfunction, and cytotoxicity, as well as mutagenesis and induction of proliferation. XOR is strictly modulated at the transcriptional and post‐translational levels, and its expression and activity are highly variable in cancer. Xanthine oxidoreductase (XOR) expression has been negatively associated with a high malignity grade and a worse prognosis in neoplasms of the breast, liver, gastrointestinal tract, and kidney, which normally express a high level of XOR protein. However, the level of XOR expression may be associated with a worse outcome in cancer of low XOR‐expressing cells, in relation to the inflammatory response elicited through the tissue damage induced by tumor growth. Xanthine oxidoreductase (XOR) has been implicated in the process of oncogenesis either directly because it is able to catalyze the metabolic activation of carcinogenic substances or indirectly through the action of XOR‐derived reactive oxygen and nitrogen species. The role of uric acid is characterized by both oxidant and antioxidant action; thus, it is still debatable whether control of uricemia may be helpful to improve the outcomes of tumor illness.

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Prognostic value of xanthine oxidoreductase expression in patients with non-small cell lung cancer

Cited by 20 publications

References 26 publications

Metabolomic Markers of Altered Nucleotide Metabolism in Early Stage Adenocarcinoma

Metabolomic Markers of Altered Nucleotide Metabolism in Early Stage Adenocarcinoma

Serum uric acid levels and cancer mortality risk among males in a large general population-based cohort study

Xanthine oxidoreductase in cancer: more than a differentiation marker

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