-
Oxidative Medicine and Cellular... 2022Ferroptosis is a type of regulated cell death that displays a promising therapeutic pathway for drug-resistant tumor cells. However, some pancreatic cancer (PC) cells...
Ferroptosis is a type of regulated cell death that displays a promising therapeutic pathway for drug-resistant tumor cells. However, some pancreatic cancer (PC) cells are less sensitive to erastin-induced ferroptosis, and normal pancreatic cells are susceptible to this newly discovered cell death. Therefore, there is an urgent need to find drugs to enhance the sensitivity of these PC cells to erastin while limiting side effects. Here, we found that the oxidized form of vitamin C-dehydroascorbic acid (DHA) can be transported into PC cells expressing high levels of GLUT1, resulting in ferroptosis. Moreover, pharmacological vitamin C combined with erastin can synergistically induce ferroptosis of PC cells involving glutathione (GSH) reduction and ferrous iron accumulation while inhibiting the cytotoxicity of normal cells. Mechanistically, as a direct system Xc inhibitor, erastin can directly suppress the synthesis of GSH, and the recycling of vitamin C and DHA is performed through GSH consumption, which is denoted as the classical mode. Furthermore, oxidative stress induced by erastin and vitamin C could enhance the expression of HMOX1 via the AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway to increase the labile iron level, which is named the nonclassical mode. In vivo experiments showed that erastin and vitamin C can significantly slow tumor growth in PC xenografts. In summary, the combination of erastin and vitamin C exerts a synergistic effect of classical and nonclassical modes to induce ferroptosis in PC cells, which may provide a promising therapeutic strategy for PC.
Topics: Humans; AMP-Activated Protein Kinases; Ascorbic Acid; Ferroptosis; Glutathione; Heme Oxygenase-1; Iron; NF-E2-Related Factor 2; Nuclear Respiratory Factor 1; Pancreatic Neoplasms; Piperazines
PubMed: 35915609
DOI: 10.1155/2022/5361241 -
Cell Death & Disease Sep 2023Since the discovery of ferroptosis, it has been postulated that this type of cell death could be utilized in treatments for cancer. Unfortunately, several highly...
Since the discovery of ferroptosis, it has been postulated that this type of cell death could be utilized in treatments for cancer. Unfortunately, several highly aggressive tumor models are resistant to the pharmacological induction of ferroptosis. However, with the use of combined therapies, it is possible to recover sensitivity to ferroptosis in certain cellular models. Here, we discovered that co-treatment with the metabolically stable ferroptosis inducer imidazole ketone erastin (IKE) and the oxidized form of vitamin C, dehydroascorbic acid (DHAA), is a powerful therapy that induces ferroptosis in tumor cells previously resistant to IKE-induced ferroptosis. We determined that DHAA and IKE + DHAA delocalize and deplete GPX4 in tumor cells, specifically inducing lipid droplet peroxidation, which leads to ferroptosis. Moreover, in vivo, IKE + DHAA has high efficacy with regard to the eradication of highly aggressive tumors such as glioblastomas. Thus, the use of IKE + DHAA could be an effective and safe therapy for the eradication of difficult-to-treat cancers.
Topics: Humans; Ferroptosis; Dehydroascorbic Acid; Lipid Droplets; Neoplasms; Cell Death; Lipid Peroxidation
PubMed: 37752118
DOI: 10.1038/s41419-023-06153-9 -
Antioxidants & Redox Signaling Jul 2021Vitamin C is a powerful antioxidant that has an intricate relationship with cancer and has been studied for more than 60 years. However, the specific mechanisms that... (Review)
Review
Vitamin C is a powerful antioxidant that has an intricate relationship with cancer and has been studied for more than 60 years. However, the specific mechanisms that allow malignant cells to uptake, metabolize, and compartmentalize vitamin C remain unclear. In normal human cells, two different transporter systems are responsible for its acquisition: glucose transporters (GLUTs) transport the oxidized form of vitamin C (dehydroascorbic acid) and sodium-coupled ascorbic acid transporters (SVCTs) transport the reduced form (ascorbic acid [AA]). In this study, we review the mechanisms described for vitamin C uptake and metabolization in cancer. Several studies performed recently and have provided the scientific community a better understanding of the differential capacities of cancer cells to acquire vitamin C: tumors from different origins do not express SVCTs in the plasma membrane and are only able to acquire vitamin C in its oxidized form. Interestingly, cancer cells differentially express a mitochondrial form of SVCT2. Why tumors have reduced AA uptake capacity at the plasma membrane, but develop the capacity of AA transport within mitochondria, remains a mystery. However, it shows that understanding vitamin C physiology in tumor survival might be key to decipher the controversies in its relationship with cancer. A comprehensive analysis of the mechanisms by which cancer cells acquire, compartmentalize, and use vitamin C will allow the design of new therapeutic approaches in human cancer. 35, 61-74.
Topics: Antioxidants; Ascorbic Acid; Dehydroascorbic Acid; Glucose Transport Proteins, Facilitative; Humans; Mitochondria; Neoplasms; Sodium-Coupled Vitamin C Transporters
PubMed: 33607936
DOI: 10.1089/ars.2020.8166 -
Journal of Cellular Physiology Nov 2019For a long time, the effect of vitamin C on cancer cells has been a controversial concept. From Linus Pauling's studies in 1976, it was proposed that ascorbic acid (AA)... (Review)
Review
For a long time, the effect of vitamin C on cancer cells has been a controversial concept. From Linus Pauling's studies in 1976, it was proposed that ascorbic acid (AA) could selectively kill tumor cells. However, further research suggested that vitamin C has no effect on tumor survival. In the last decade, new and emerging functions for vitamin C have been discovered using the reduced form, AA, and the oxidized form, dehydroascorbic acid (DHA), independently. In this review, we summarized the latest findings related to the effects of DHA on the survival and metabolism of tumor cells. At the same time, we put special emphasis on the bystander effect and the recycling capacity of vitamin C in various cellular models, and how these concepts can affect the experimentation with vitamin C and its therapeutic application in the treatment against cancer.
Topics: Ascorbic Acid; Biological Transport; Dehydroascorbic Acid; Humans; Neoplasms; Oxidation-Reduction
PubMed: 30963581
DOI: 10.1002/jcp.28637 -
Frontiers in Neuroscience 2023Different studies have established the fundamental role of vitamin C in proliferation, differentiation, and neurogenesis in embryonic and adult brains, as well as in... (Review)
Review
Different studies have established the fundamental role of vitamin C in proliferation, differentiation, and neurogenesis in embryonic and adult brains, as well as in cell models. To fulfill these functions, the cells of the nervous system regulate the expression and sorting of sodium-dependent vitamin C transporter 2 (SVCT2), as well as the recycling of vitamin C between ascorbic acid (AA) and dehydroascorbic acid (DHA) via a bystander effect. SVCT2 is a transporter preferentially expressed in neurons and in neural precursor cells. In developmental stages, it is concentrated in the apical region of the radial glia, and in adult life, it is expressed preferentially in motor neurons of the cerebral cortex, starting on postnatal day 1. In neurogenic niches, SVCT2 is preferentially expressed in precursors with intermediate proliferation, where a scorbutic condition reduces neuronal differentiation. Vitamin C is a potent epigenetic regulator in stem cells; thus, it can induce the demethylation of DNA and histone H3K27m3 in the promoter region of genes involved in neurogenesis and differentiation, an effect mediated by Tet1 and Jmjd3 demethylases, respectively. In parallel, it has been shown that vitamin C induces the expression of stem cell-specific microRNA, including the Dlk1-Dio3 imprinting region and miR-143, which promotes stem cell self-renewal and suppresses expression of the methyltransferase gene Dnmt3a. The epigenetic action of vitamin C has also been evaluated during gene reprogramming of human fibroblasts to induced pluripotent cells, where it has been shown that vitamin C substantially improves the efficiency and quality of reprogrammed cells. Thus, for a proper effect of vitamin C on neurogenesis and differentiation, its function as an enzymatic cofactor, modulator of gene expression and antioxidant is essential, as is proper recycling from DHA to AA by various supporting cells in the CNS.
PubMed: 37424994
DOI: 10.3389/fnins.2023.1155758 -
Pflugers Archiv : European Journal of... Sep 2020Glucose transport is intimately linked to red blood cell physiology. Glucose is the unique energy source for these cells, and defects in glucose metabolism or transport... (Review)
Review
Glucose transport is intimately linked to red blood cell physiology. Glucose is the unique energy source for these cells, and defects in glucose metabolism or transport activity are associated with impaired red blood cell morphology and deformability leading to reduced lifespan. In vertebrate erythrocytes, glucose transport is mediated by GLUT1 (in humans) or GLUT4 transporters. These proteins also account for dehydroascorbic acid (DHA) transport through erythrocyte membrane. The peculiarities of glucose transporters and the red blood cell pathologies involving GLUT1 are summarized in the present review.
Topics: Anemia, Hemolytic; Animals; Carbohydrate Metabolism, Inborn Errors; Erythrocytes; Glucose Transporter Type 1; Humans; Monosaccharide Transport Proteins
PubMed: 32474749
DOI: 10.1007/s00424-020-02406-0 -
Heart & Lung : the Journal of Critical... 2023There is currently a need to identify metabolomic responses to acute exercise in chronic obstructive pulmonary disease (COPD).
BACKGROUND
There is currently a need to identify metabolomic responses to acute exercise in chronic obstructive pulmonary disease (COPD).
OBJECTIVE
We investigated the metabolomic, oxidative, and inflammatory responses to constant (CE) and intermittent (IE) work rate exercises in COPD.
METHODS
Sixteen males with COPD performed a symptom-limited incremental cycle exercise test (ICE). Metabolomic, oxidative, and inflammatory responses to CE and IE (based on the performance of ICE) were analyzed in the plasma.
RESULTS
Fructose-6-phosphate, 3-phosphoglyceric acid, l-carnitine, and acylcarnitines levels were significantly decreased, whereas alpha-ketoglutaric, malic, 2-hydroxybutyric, and 3-hydroxybutyric acids were increased, after CE and IE (p<0.05). Increases in citric, isocitric, and lactic acids, as well as decreases in pyruvic and oxalic acids, were only present with IE (p<0.05). Isoleucine was decreased after both exercises (p<0.05). We observed an increase in inosine-5'-diphosphate, uric acid, ascorbic acid, and pantothenic acid, as well as a decrease in 5-hydroxymethyluridine, threonic acid, and dehydroascorbic acid, after IE (p<0.05). Catalase, reduced glutathione, and total antioxidant status difference values for both exercises were similar (p>0.05). The change in glutathione peroxidase (GPx) with CE was more significant than that with IE (p = 0.004). The superoxide dismutase change was greater with IE than with CE (p = 0.015). There were no significant changes in inflammatory markers after exercise (p>0.05).
CONCLUSION
CE and IE cause isoleucine, l-carnitine, and acylcarnitine levels to decrease, whereas ketone bodies were increased, thus indicating the energy metabolism shift from carbohydrates to amino acid utilization and lipid metabolism in COPD. Compared with CE, IE produces significant changes in more metabolomics in terms of carbohydrates, lipids, amino acids, nucleotides, and vitamins. Acute CE and IE alter circulating GPx levels in COPD.
Topics: Male; Humans; Isoleucine; Exercise; Carnitine; Pulmonary Disease, Chronic Obstructive; Oxidative Stress; Carbohydrates
PubMed: 36724589
DOI: 10.1016/j.hrtlng.2023.01.011 -
Scientific Reports Sep 2023To explore potential metabolomics biomarkers in predicting post-herpetic neuralgia (PHN) induced by herpes zoster (HZ). A total of 90 eligible patients were...
To explore potential metabolomics biomarkers in predicting post-herpetic neuralgia (PHN) induced by herpes zoster (HZ). A total of 90 eligible patients were prospectively enrolled and assigned into an acute pain (ACP) group and a PHN group. Serum samples were collected before clinical intervention to perform metabolomics profiling analyses using gas chromatography mass spectrometry (GC-MS). Key metabolites were identified using partial least squares discriminant analysis (PLS-DA). A binary logistic regression was used to build a combined biomarker model to predict PHN from ACP. The discriminating efficiency of the combined biomarker model was investigated and validated by internal validation. Six metabolites were identified as the key metabolites related to PHN. All these metabolites (N-Acetyl-5-hydroxytryptaMine, glucose, dehydroascorbic acid, isopropyl-beta-D-thiogalactopyranoside, 1,5-anhydro-D-sorbitol, and glutamic acid) were found elevated in the PHN group. Pathway analyses showed that glucose-alanine cycle, tryptophan metabolism, tyrosine metabolism, lactose degradation, malate-aspartate shuttle were top five metabolic pathways evolved in PHN. The AUC was 0.85 (95% CI 0.76-0.93) for the combined biomarker model, and was 0.91 (95% CI 0.84-1.00) for the internal validation data set to predict PHN. Metabolomics analyses of key metabolites could be used to predict PHN induced by HZ.
Topics: Humans; Neuralgia, Postherpetic; Chickenpox; Varicella Zoster Virus Infection; Metabolomics; Herpes Zoster; Acute Pain; Glucose
PubMed: 37697028
DOI: 10.1038/s41598-023-42363-z -
Trends in Endocrinology and Metabolism:... Apr 2021Cancer cells increase their metabolic activity by enhancing glucose uptake through overexpression of hexose transporters (Gluts). Gluts also have the capacity to... (Review)
Review
Cancer cells increase their metabolic activity by enhancing glucose uptake through overexpression of hexose transporters (Gluts). Gluts also have the capacity to transport other molecules besides glucose, including fructose, mannose, and dehydroascorbic acid (DHA), the oxidized form of vitamin C. The majority of research studies in this field have focused on the role of glucose transport and metabolism in cancer, leaving a substantial gap in our knowledge of the contribution of other hexoses and DHA in cancer biology. Here, we summarize the most recent advances in understanding the role that the multifunctional transport capacity of Gluts plays in biological and clinical aspects of cancer, and how these characteristics can be exploited in the search for novel diagnostic and therapeutic strategies.
Topics: Ascorbic Acid; Biological Transport; Dehydroascorbic Acid; Glucose; Hexoses; Humans; Monosaccharide Transport Proteins; Neoplasms
PubMed: 33518451
DOI: 10.1016/j.tem.2020.12.006 -
Antioxidants & Redox Signaling Sep 2022Glioblastoma (GB) is one of the most aggressive brain tumors. These tumors modify their metabolism, increasing the expression of glucose transporters, GLUTs, which...
Glioblastoma (GB) is one of the most aggressive brain tumors. These tumors modify their metabolism, increasing the expression of glucose transporters, GLUTs, which incorporate glucose and the oxidized form of vitamin C, dehydroascorbic acid (DHA). We hypothesized that GB cells preferentially take up DHA, which is intracellularly reduced and compartmentalized into the endoplasmic reticulum (ER), promoting collagen biosynthesis and an aggressive phenotype. Our results showed that GB cells take up DHA using GLUT1, while GLUT3 and sodium-dependent vitamin C transporter 2 (SVCT2) are preferably intracellular. Using a baculoviral system and reticulum-enriched extracts, we determined that SVCT2 is mainly located in the ER and corresponds to a short isoform. Ascorbic acid (AA) was compartmentalized, stimulating collagen IV secretion and increasing and cell migration. Finally, orthotopic xenografts induced in immunocompetent guinea pigs showed that vitamin C deficiency retained collagen, reduced blood vessel invasion, and affected glomeruloid vasculature formation, all pathological conditions associated with malignancy. We propose a functional role for vitamin C in GB development and progression. Vitamin C is incorporated into the ER of GB cells, where it favors the synthesis of collagen, thus impacting tumor development. Collagen secreted by tumor cells favors the formation of the glomeruloid vasculature and enhances perivascular invasion. . 37, 538-559.
Topics: Animals; Ascorbic Acid; Collagen; Dehydroascorbic Acid; Glioblastoma; Glucose; Guinea Pigs; Humans; Sodium-Coupled Vitamin C Transporters; Vitamins
PubMed: 35166128
DOI: 10.1089/ars.2021.0089