Ketogenic diets are low in carbohydrates and high in fat, which forces cells to rely more heavily upon mitochondrial oxidation of fatty acids for energy. Relative to normal cells, cancer cells are ...believed to exist under a condition of chronic mitochondrial oxidative stress that is compensated for by increases in glucose metabolism to generate reducing equivalents. In this study we tested the hypothesis that a ketogenic diet concurrent with radiation and chemotherapy would be clinically tolerable in locally advanced non-small cell lung cancer (NSCLC) and pancreatic cancer and could potentially exploit cancer cell oxidative metabolism to improve therapeutic outcomes. Mice bearing MIA PaCa-2 pancreatic cancer xenografts were fed either a ketogenic diet or standard rodent chow, treated with conventionally fractionated radiation (2 Gy/fraction), and tumor growth rates were assessed daily. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modfied proteins as a marker of oxidative stress. Based on this and another previously published preclinical study, phase 1 clinical trials in locally advanced NSCLC and pancreatic cancer were initiated, combining standard radiation and chemotherapy with a ketogenic diet for six weeks (NSCLC) or five weeks (pancreatic cancer). The xenograft experiments demonstrated prolonged survival and increased 4HNE-modfied proteins in animals consuming a ketogenic diet combined with radiation compared to radiation alone. In the phase 1 clinical trial, over a period of three years, seven NSCLC patients enrolled in the study. Of these, four were unable to comply with the diet and withdrew, two completed the study and one was withdrawn due to a dose-limiting toxicity. Over the same time period, two pancreatic cancer patients enrolled in the trial. Of these, one completed the study and the other was withdrawn due to a dose-limiting toxicity. The preclinical experiments demonstrate that a ketogenic diet increases radiation sensitivity in a pancreatic cancer xenograft model. However, patients with locally advanced NSCLC and pancreatic cancer receiving concurrent radiotherapy and chemotherapy had suboptimal compliance to the oral ketogenic diet and thus, poor tolerance.
Exposure of eukaryotic cells to ionizing radiation (IR) results in the immediate formation of free radicals that last a matter of milliseconds. It has been assumed that the subsequent alterations in ...multiple intracellular processes following irradiation is due to the initial oxidative damage caused by these free radicals. However, it is becoming increasingly clear that intracellular metabolic oxidation/reduction (redox) reactions can be affected by this initial IR-induced free radical insult and may remain perturbed for minutes, hours, or days. It would seem logical that these cellular redox reactions might contribute to the activation of protective or damaging processes that could impact upon the damaging effects of IR. These processes include redox sensitive signaling pathways, transcription factor activation, gene expression, and metabolic activities that govern the formation of intracellular oxidants and reductants. The physiological manifestations of these radiation-induced alterations in redox sensitive processes have been suggested to contribute to adaptive responses, bystander effects, cell cycle perturbations, cytotoxicity, heat-induced radiosensitization, genomic instability, inflammation, and fibrosis. While a great deal is known about the molecular changes associated with the initial production of free radicals at the time of irradiation, the contribution of perturbations in redox sensitive metabolic processes to biological outcomes following exposure to IR is only recently becoming established. This review will focus on evidence supporting the concept that perturbations in intracellular metabolic oxidation/reduction reactions contribute to the biological effects of radiation exposure as well as new concepts emerging from the field of free radical biology that may be relevant to future studies in radiobiology.
Hepatocellular carcinoma (HCC) is a devastating cancer increasingly caused by non-alcoholic fatty liver disease (NAFLD). Disrupting the liver Mitochondrial Pyruvate Carrier (MPC) in mice attenuates ...NAFLD. Thus, we considered whether liver MPC disruption also prevents HCC. Here, we use the N-nitrosodiethylamine plus carbon tetrachloride model of HCC development to test how liver-specific MPC knock out affects hepatocellular tumorigenesis. Our data show that liver MPC ablation markedly decreases tumorigenesis and that MPC-deficient tumors transcriptomically downregulate glutathione metabolism. We observe that MPC disruption and glutathione depletion in cultured hepatomas are synthetically lethal. Stable isotope tracing shows that hepatocyte MPC disruption reroutes glutamine from glutathione synthesis into the tricarboxylic acid (TCA) cycle. These results support a model where inducing metabolic competition for glutamine by MPC disruption impairs hepatocellular tumorigenesis by limiting glutathione synthesis. These findings raise the possibility that combining MPC disruption and glutathione stress may be therapeutically useful in HCC and additional cancers.
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•The MPC is retained in HCC, supporting TCA cycle pyruvate metabolism•MPC disruption directs glutamine to the TCA cycle away from glutathione synthesis•Glutathione synthesis is diminished, impairing hepatocellular tumorigenesis
Tompkins et al. utilize stable glutamine isotope tracers in vivo and ex vivo to demonstrate hepatocyte MPC disruption increases TCA cycle glutamine utilization at the expense of glutathione synthesis and decreases hepatocellular tumorigenesis.
The goal of this study was to determine if depletion of glutathione (GSH) and inhibition of thioredoxin (Trx) reductase (TrxR) activity could enhance radiation responses in human breast cancer stem ...cells by a mechanism involving thiol-dependent oxidative stress. The following were used to inhibit GSH and Trx metabolism: buthionine sulfoximine (BSO), a GSH synthesis inhibitor; sulfasalazine (SSZ), an inhibitor of xc– cysteine/glutamate antiporter; auranofin (Au), a thioredoxin reductase inhibitor; or 2-AAPA, a GSH-reductase inhibitor. Clonogenic survival, Matrigel assays, flow cytometry cancer stem cell assays (CD44+CD24–ESA+ or ALDH1) and human tumor xenograft models were used to determine the antitumor activity of drug and radiation combinations. Combined inhibition of GSH and Trx metabolism enhanced cancer cell clonogenic killing and radiation responses in human breast and pancreatic cancer cells via a mechanism that could be inhibited by N-acetylcysteine (NAC). Au, BSO and radiation also significantly decreased breast cancer cell migration and invasion in a thiol-dependent manner that could be inhibited by NAC. In addition, pretreating cells with Au sensitized breast cancer stem cell populations to radiation in vitro as determined by CD44+CD24–ESA+ or ALDH1. Combined administration of Au and BSO, given prior to irradiation, significantly increased the survival of mice with human breast cancer xenografts, and decreased the number of ALDH1+ cancer stem cells. These results indicate that combined inhibition of GSH- and Trx-dependent thiol metabolism using pharmacologically relevant agents can enhance responses of human breast cancer stem cells to radiation both in vitro and in vivo.
Cancer cells (relative to normal cells) show increased steady-state levels of hydroperoxides that are compensated by increased glucose and hydroperoxide metabolism. The current study determined ...whether inhibitors of glucose and hydroperoxide metabolism could induce chemoradiosensitization by enhancing oxidative stress in lung cancer cells.
A549 and NCI-H292 human lung carcinoma cells were treated with 2-deoxy-d-glucose (2DG) combined with carboplatin + ionizing radiation (IR). Lung cancer cells were further sensitized with inhibitors of glutathione (GSH)- and thioredoxin (Trx)-dependent metabolism buthionine sulfoximine (BSO) and auranofin, respectively in vitro and in vivo.
When 2DG was combined with carboplatin + IR, clonogenic cell killing was enhanced in A549 and NCI-H292 cells, and this combination was more effective than paclitaxel + carboplatin + IR. The thiol antioxidant (N-acetylcysteine, NAC) was capable of protecting cancer cells from 2DG + carboplatin -induced cell killing. Simultaneous treatment of cancer cells with BSO and auranofin, at doses that were not toxic as single agents, also enhanced lung cancer cell killing and sensitivity to 2DG + carboplatin. This treatment combination also increased oxidation of both GSH and Trx, which were inhibited by NAC. Mice treated with auranofin + BSO showed no alterations in circulating leukocytes or red blood cells. Xenograft lung tumor growth in mice was more effectively inhibited by treatment with auranofin + BSO + carboplatin than animals treated with carboplatin or auranofin + BSO alone.
These results show in vitro and in vivo that simultaneous inhibition of GSH and Trx metabolism can effectively inhibit lung cancer cell growth and induce chemosensitization by a mechanism that involves thiol-mediated oxidative stress.
To apply a deep learning algorithm for automated, objective, and comprehensive quantification of OCT scans to a large real-world dataset of eyes with neovascular age-related macular degeneration ...(AMD) and make the raw segmentation output data openly available for further research.
Retrospective analysis of OCT images from the Moorfields Eye Hospital AMD Database.
A total of 2473 first-treated eyes and 493 second-treated eyes that commenced therapy for neovascular AMD between June 2012 and June 2017.
A deep learning algorithm was used to segment all baseline OCT scans. Volumes were calculated for segmented features such as neurosensory retina (NSR), drusen, intraretinal fluid (IRF), subretinal fluid (SRF), subretinal hyperreflective material (SHRM), retinal pigment epithelium (RPE), hyperreflective foci (HRF), fibrovascular pigment epithelium detachment (fvPED), and serous PED (sPED). Analyses included comparisons between first- and second-treated eyes by visual acuity (VA) and race/ethnicity and correlations between volumes.
Volumes of segmented features (mm3) and central subfield thickness (CST) (μm).
In first-treated eyes, the majority had both IRF and SRF (54.7%). First-treated eyes had greater volumes for all segmented tissues, with the exception of drusen, which was greater in second-treated eyes. In first-treated eyes, older age was associated with lower volumes for RPE, SRF, NSR, and sPED; in second-treated eyes, older age was associated with lower volumes of NSR, RPE, sPED, fvPED, and SRF. Eyes from Black individuals had higher SRF, RPE, and serous PED volumes compared with other ethnic groups. Greater volumes of the majority of features were associated with worse VA.
We report the results of large-scale automated quantification of a novel range of baseline features in neovascular AMD. Major differences between first- and second-treated eyes, with increasing age, and between ethnicities are highlighted. In the coming years, enhanced, automated OCT segmentation may assist personalization of real-world care and the detection of novel structure–function correlations. These data will be made publicly available for replication and future investigation by the AMD research community.
There is a rapidly growing body of literature supporting the notion that differential oxidative metabolism in cancer versus normal cells represents a metabolic frailty that can be exploited to open a ...therapeutic window into cancer therapy. These cancer cell-specific metabolic frailties may be amenable to manipulation with non-toxic small molecule redox active compounds traditionally thought to be antioxidants. In this review we describe the potential mechanisms and clinical applicability in cancer therapy of four small molecule redox active agents: melatonin, vitamin E, selenium, and vitamin C. Each has shown the potential to have pro-oxidant effects in cancer cells while retaining antioxidant activity in normal cells. This dichotomy can be exploited to improve responses to radiation and chemotherapy by opening a therapeutic window based on a testable biochemical rationale amenable to confirmation with biomarker studies during clinical trials. Thus, the unique pro-oxidant/antioxidant properties of melatonin, vitamin E, selenium, and vitamin C have the potential to act as effective adjuvants to traditional cancer therapies, thereby improving cancer patient outcomes.
Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non-small cell lung cancer (NSCLC).
To identify ...genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307,260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.
SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio HR of death = 1.59, 95% confidence interval CI = 1.32 to 1.92, P = 1.42 × 10(-6)), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10(-7)). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10(-6)) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).
These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.
A Risk Model for Prediction of Lung Cancer Spitz, Margaret R.; Hong, Waun Ki; Amos, Christopher I. ...
JNCI : Journal of the National Cancer Institute,
05/2007, Letnik:
99, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Background Reliable risk prediction tools for estimating individual probability of lung cancer have important public health implications. We constructed and validated a comprehensive clinical tool ...for lung cancer risk prediction by smoking status. Methods Epidemiologic data from 1851 lung cancer patients and 2001 matched control subjects were randomly divided into separate training (75% of the data) and validation (25% of the data) sets for never, former, and current smokers, and multivariable models were constructed from the training sets. The discriminatory ability of the models was assessed in the validation sets by examining the areas under the receiver operating characteristic curves and with concordance statistics. Absolute 1-year risks of lung cancer were computed using national incidence and mortality data. An ordinal risk index was constructed for each smoking status category by summing the odds ratios from the multivariable regression analyses for each risk factor. Results All variables that had a statistically significant association with lung cancer (environmental tobacco smoke, family history of cancer, dust exposure, prior respiratory disease, and smoking history variables) have strong biologically plausible etiologic roles in the disease. The concordance statistics in the validation sets for the never, former, and current smoker models were 0.57, 0.63, and 0.58, respectively. The computed 1-year absolute risk of lung cancer for a hypothetical male current smoker with an estimated relative risk close to 9 was 8.68%. The ordinal risk index performed well in that true-positive rates in the designated high-risk categories were 69% and 70% for current and former smokers, respectively. Conclusions If confirmed in other studies, this risk assessment procedure could use easily obtained clinical information to identify individuals who may benefit from increased screening surveillance for lung cancer. Although the concordance statistics were modest, they are consistent with those from other risk prediction models.
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