Date Published: September 20, 2018
Publisher: Public Library of Science
Author(s): Katarzyna Zabłocka-Słowińska, Sylwia Płaczkowska, Anna Prescha, Konrad Pawełczyk, Monika Kosacka, Irena Porębska, Halina Grajeta, Aamir Ahmad.
Altered systemic redox status is often observed in lung cancer. However, detailed information on factors other, than smoking, which influence this perturbation is rather scarce. Elevated oxidative stress has been linked with disturbances in glucose metabolism before, but such associations have not been investigated in lung cancer. The aim of this study was to evaluate the relationship between systemic parameters of glucose metabolism and redox status in lung cancer patients (LC). Biochemical variables related to circulating glucose, i.e. glucose, insulin, c-peptide, fructosamine (FA), and glucose metabolism, i.e. β-hydroxybutyrate (BHB), lactate (LACT), non-esterified fatty acids (NEFAs), as well as redox status i.e. total antioxidant status (TAS) and total oxidant status (TOS) were determined for LC (n = 122) and control subjects (CS) (n = 84). HOMA-IR and the oxidative stress index (OSI) were calculated. LC patients had an altered redox status and glucose metabolism compared to CS. Positive correlations in LC were observed between TOS, OSI and circulating glucose as well as FA, while TAS positively correlated with BHB and NEFAs. In contrast, in metastatic LC, NEFAs and BHB positively correlated with OSI. Smoking status additionally stratified the observed relationships. In conclusion, we found that parameters related to circulating glucose or non-enzymatic glycation were correlated with oxidative stress (TOS and OSI), while metabolites such as BHB and NEFAs were correlated with antioxidant capacity (TAS). Metastasis prevalence and smoking seem to influence these correlations. However, the detailed mechanism of this relationship requires further research, in particular as regards the surprising positive correlation between NEFAs and TAS.
In lung cancer, as well as in many other site-specific cancers, the redox status is altered and depletion of antioxidant capacity is observed along with tumor progression [1–5]. Several mechanisms may induce this perturbation, e.g. smoking, increasing cancer-related chronic inflammation, decrease in dietary antioxidant intake, and cancer-related malnutrition with depletion of antioxidant proteins, as well as metabolic alterations [4–6]. During the past decade, a vast body of investigation has remodeled our understanding of human redox status and alterations regarding this phenomenon, including during chronic disease. However, still little is known about the associations between metabolic perturbations and redox status, especially among cancer patients [7,8].
Results concerning baseline characteristics and nutritional status of lung cancer and control participants are summarized in Table 1. Lung cancer patients with GLC ≤ 99 mg/dL had significantly lower weight and BFP while lung cancer subjects with GLC > 99 mg/dL had a significantly higher WHR compared to control subjects. All lung cancer patients, regardless of glucose concentration, had significantly lower serum ALB in comparison with CS. Lung cancer patients with GLC > 99 mg/dL provided significantly higher amounts of energy in their diets compared to patients with GLC ≤ 99 mg/dL as well as to control subjects, and provided significantly less fiber in their diet compared with control subjects. Patients, regardless of glucose concentration, were sex- and age-matched, and were not differentiated by clinical stage of disease or type of lung cancer.
Large studies confirmed that systemic oxidative stress is associated with pathogenesis of many site-specific cancers, including lung cancer [3,25–27]. However there has been no advanced research indicating that metabolic alterations may influence the depletion of systemic antioxidant activity during cancerogenesis, and therefore contribute at least partially to oxidative stress, regardless of the tumor process itself. In light of previous papers reporting that systemic redox balance is disrupted during oncological treatment [28,29,30] the knowledge of the influence of metabolic disorders on redox status appears to be important also for the effectiveness of oncological treatment. Among metabolic disorders, alterations in glucose metabolism seem to be key in terms of tumorigenic properties as well as control of redox status in the tumor milieu, and much research has been devoted to investigating particular metabolic pathways that explain this phenomenon [31,32]. However, little is known about systemic changes in the context of glucose metabolism and oxidative stress in cancer patients. In lung cancer, the prevalence of alterations in glucose metabolism is high in general and is a consequence of cancerogenesis rather than an independent metabolic disorder that increases the risk of lung cancer [33,34,35]. Indeed, recent experimental research has revealed that lung cancer patients are characterized by orchestrated activation of glucose absorption and metabolism towards the anaerobic pathways . Based on above-mentioned data, we attempted to find a link between systemic glucose metabolic alterations and redox status in lung cancer patients.
Based on the presented results, we demonstrated that parameters related to circulating glucose or non-enzymatic glycation are correlated with oxidative stress (TOS and OSI), while metabolites such as β-hydroxybutyrate and NEFAs are linked with TAS in lung cancer patients. Metastasis prevalence and smoking seem to influence these correlations. However, detailed mechanisms of these relationships require further research, particularly considering the surprising positive correlation between NEFAs and TAS (Fig 1). The correlations and proposed mechanisms presented in this study may serve as a basis for future studies which could include lowering glucose levels or improving redox activity in lung cancer patients to support the positive outcome of them.