RESUMO
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.
Assuntos
Ferroptose , Neoplasias , Humanos , Ácido Desidroascórbico/farmacologia , Gotículas Lipídicas , Morte Celular , Peroxidação de LipídeosRESUMO
GLUT1 is a facilitative glucose transporter that can transport oxidized vitamin C (i.e., dehydroascorbic acid) and complements the action of reduced vitamin C transporters. To identify the residues involved in human GLUT1's transport of dehydroascorbic acid, we performed docking studies in the 5 Å grid of the glucose-binding cavity of GLUT1. The interactions of the bicyclic hemiacetal form of dehydroascorbic acid with GLUT1 through hydrogen bonds with the -OH group of C3 and C5 were less favorable than the interactions with the sugars transported by GLUT1. The eight most relevant residues in such interactions (i.e., F26, Q161, I164, Q282, Y292, and W412) were mutated to alanine to perform functional studies for dehydroascorbic acid and the glucose analog, 2-deoxiglucose, in Xenopus laevis oocytes. All the mutants decreased the uptake of both substrates to less than 50%. The partial effect of the N317A mutant in transporting dehydroascorbic acid was associated with a 30% decrease in the Vmax compared to the wildtype GLUT1. The results show that both substrates share the eight residues studied in GLUT1, albeit with a differential contribution of N317. Our work, combining docking with functional studies, marks the first to identify structural determinants of oxidized vitamin C's transport via GLUT1.
Assuntos
Ácido Desidroascórbico , Transportador de Glucose Tipo 1 , Humanos , Ácido Ascórbico , Transporte Biológico , Ácido Desidroascórbico/metabolismo , Glucose , Transportador de Glucose Tipo 1/química , Transportador de Glucose Tipo 1/genéticaRESUMO
Aims: 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. Results: 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 in vitro and in situ 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. Innovation and Conclusion: 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. Antioxid. Redox Signal. 37, 538-559.
Assuntos
Ácido Ascórbico , Glioblastoma , Animais , Ácido Ascórbico/metabolismo , Ácido Ascórbico/farmacologia , Colágeno/metabolismo , Ácido Desidroascórbico/metabolismo , Ácido Desidroascórbico/farmacologia , Glucose/metabolismo , Cobaias , Humanos , Transportadores de Sódio Acoplados à Vitamina C/metabolismo , VitaminasRESUMO
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.
Assuntos
Proteínas de Transporte de Monossacarídeos , Neoplasias , Ácido Ascórbico , Transporte Biológico , Ácido Desidroascórbico , Glucose/metabolismo , Hexoses/metabolismo , Humanos , Proteínas de Transporte de Monossacarídeos/metabolismo , Neoplasias/diagnóstico , Neoplasias/terapiaRESUMO
Significance: 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. Recent Advances: Several studies performed recently in vivo and in vitro 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. Critical Issues: 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. Future Directions: 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. Antioxid. Redox Signal. 35, 61-74.
Assuntos
Ácido Ascórbico/metabolismo , Ácido Desidroascórbico/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Neoplasias/metabolismo , Transportadores de Sódio Acoplados à Vitamina C/metabolismo , Antioxidantes/metabolismo , Humanos , Mitocôndrias/metabolismoRESUMO
Oxidative stress and inflammation are crucial factors that increase with age. In the progression of multiple age-related diseases, antioxidants and bioactive compounds have been recognized as useful antiaging agents. Oxidized or reduced vitamin C exerts different actions on tissues and has different metabolism and uptake. In this study, we analyzed the antiaging effect of vitamin C, both oxidized and reduced forms, in renal aging using laser microdissection, quantitative reverse-transcription polymerase chain reaction, and immunohistochemical analyses. In the kidneys of old SAM mice (10 months of age), a model of accelerated senescence, vitamin C, especially in the oxidized form (dehydroascorbic acid [DHA]) improves renal histology and function. Serum creatinine levels and microalbuminuria also decrease after treatment with a decline in azotemia. In addition, sodium-vitamin C cotransporter isoform 1 levels, which were increased during aging, are normalized. In contrast, the pattern of glucose transporter 1 expression is not affected by aging or vitamin C treatment. We conclude that oxidized and reduced vitamin C are potent antiaging therapies and that DHA reverses the kidney damage observed in senescence-accelerated prone mouse 8 to a greater degree.
Assuntos
Ácido Ascórbico/farmacologia , Ácido Desidroascórbico/farmacologia , Inflamação/genética , Rim/efeitos dos fármacos , Transportadores de Sódio Acoplados à Vitamina C/genética , Envelhecimento/genética , Envelhecimento/patologia , Animais , Ácido Ascórbico/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 1/genética , Humanos , Inflamação/patologia , Rim/ultraestrutura , Camundongos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Under physiological conditions, vitamin C is the main antioxidant found in the central nervous system and is found in two states: reduced as ascorbic acid (AA) and oxidized as dehydroascorbic acid (DHA). However, under pathophysiological conditions, AA is oxidized to DHA. The oxidation of AA and subsequent production of DHA in neurons are associated with a decrease in GSH concentrations, alterations in glucose metabolism and neuronal death. To date, the endogenous molecules that act as intrinsic regulators of neuronal necroptosis under conditions of oxidative stress are unknown. Here, we show that treatment with AA regulates the expression of pro- and antiapoptotic genes. Vitamin C also regulates the expression of RIPK1/MLKL, whereas the oxidation of AA in neurons induces morphological alterations consistent with necroptosis and MLKL activation. The activation of necroptosis by AA oxidation in neurons results in bubble formation, loss of membrane integrity, and ultimately, cellular explosion. These data suggest that necroptosis is a target for cell death induced by vitamin C.
Assuntos
Ácido Ascórbico , Necroptose , Ácido Ascórbico/farmacologia , Ácido Desidroascórbico , Neurônios , Oxirredução , Estresse OxidativoRESUMO
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.
Assuntos
Ácido Ascórbico/uso terapêutico , Transporte Biológico/efeitos dos fármacos , Ácido Desidroascórbico/uso terapêutico , Neoplasias/tratamento farmacológico , Ácido Ascórbico/metabolismo , Ácido Desidroascórbico/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Oxirredução/efeitos dos fármacosRESUMO
Camu-camu, a typical Amazonian fruit, is known for the high vitamin C content of the peel and pulp. As vitamin C is widely used in the food, pharmaceutical, and cosmetics industries, it is of interest to study new sources, extraction techniques, and analytical methods for the identification and quantification of this compound. Here, evaluation was made of extraction and quantification methods, as well as the differences in vitamin C content according to the origin and part of the camu-camu fruit. The extraction techniques studied were pressurized liquid extraction (PLE), acid extraction, and maceration. The analytical methods evaluated were titrimetry and chromatography. Camu-camu samples were obtained from different regions, and the peel and pulp were studied separately. Acid extraction using sulfuric acid as solvent provided the highest vitamin C yields, while PLE, as a completely clean technique, proved to be a promising alternative for the recovery of ascorbic acid (L-AA). The application of an ultra-high performance liquid chromatography methodology (UHPLC-DAD) enabled the fast identification and quantification of L-AA and dehydroascorbic acid (DHAA), with high resolution, sensitivity, and specificity. The results obtained using the chromatographic and titration methods were not significantly different (pâ¯<â¯0.05), indicating that titrimetry is useful for routine analyses. L-AA and DHAA were found in the peel, but only L-AA was found in the pulp. The variation of vitamin C content among the lots could be explained by the edaphoclimatic conditions. The combination of a clean extraction technique and a fast analytical method is a promising approach for the determination of vitamin C in food products.
Assuntos
Ácido Ascórbico/análise , Frutas/química , Myrtaceae/química , Extratos Vegetais/química , Brasil , Cromatografia Líquida de Alta Pressão/métodos , Ácido Desidroascórbico/análise , Preparações Farmacêuticas/análise , Sensibilidade e Especificidade , SolventesRESUMO
The hypothesis presented here is that oxidative and/or nitrosative metabolism in the bivalve Mytilus edulis platensis is altered by the presence of planktonic toxins. Digestive glands (DG) were isolated from specimens collected in the Argentinean Sea during summer, winter and spring (in the presence of harmful planktonic toxins). The labile iron pool content was not significantly different in DG from animals collected in summer and winter, but was 2.3-fold increased in samples from spring compared to summer collected mollusks. The 2',7' dichlorofluorescein diacetate (DCFH-DA) oxidation, ascorbyl radical/ascorbate and lipid radical/α-tocopherol content ratios showed no significant differences between samples collected in winter and summer. However, spring collected samples showed significantly higher DCFH-DA oxidation rate and oxidative ratios in comparison to DG from mollusks collected in summer. Superoxide dismutase activity decreased by 75% in winter, and 93% in spring, compared to samples collected in summer. Glutathione S-transferase activity decreased by 89% in winter, and 30% in spring, compared to samples collected in summer. Catalase activity in winter animals increased by 3.8-fold in comparison to summer values, with no differences between spring and summer collected mollusks. Nitrite plus nitrate content was not significantly different among samples collected in the three seasons, but nitric oxide content was 8.5- and 2.7-fold higher in samples from winter and spring collected mollusks than values obtained in summer, respectively. These results showed the lack of effects of climatic changes on the integrative oxidative indexes; however, under exposure to toxins, both oxidative and nitrosative metabolisms were affected.