ascorbic-acid and Carcinogenesis

TET2 is one of the most frequently mutated genes in myeloid neoplasms. TET2 loss-of-function perturbs myeloid differentiation and causes clonal expansion. Despite extensive knowledge regarding biochemical mechanisms underlying distorted myeloid differentiation, targeted therapies are lagging. Here we review known biochemical mechanisms and candidate therapies that emerge from this. Specifically, we discuss the potential utility of vitamin C to compensate for TET-dioxygenase deficiency, to thereby restore the biochemical function. An alternative approach exploits the TET-deficient state for synthetic lethality, exploiting the fact that a minimum level of TET-dioxygenase activity is required for cell survival, rendering TET2-mutant malignant cells selectively vulnerable to inhibitors of TET-function.

Topics: Ascorbic Acid; Carcinogenesis; Dioxygenases; DNA Methylation; DNA-Binding Proteins; Hematopoiesis; Humans; Proto-Oncogene Proteins

Topics: Animals; Antioxidants; Ascorbic Acid; Carcinogenesis; Gastric Juice; Helicobacter Infections; Helicobacter pylori; Humans; Phytochemicals; Stomach Neoplasms

Vitamin C is implicated in various bodily functions due to its unique properties in redox homeostasis. Moreover, vitamin C also plays a great role in restoring the activity of 2-oxoglutarate and Fe

Topics: Ascorbic Acid; Basic Helix-Loop-Helix Transcription Factors; Brain Neoplasms; Breast Neoplasms; Carcinogenesis; Dehydroascorbic Acid; Dioxygenases; DNA Methylation; DNA-Binding Proteins; Epigenesis, Genetic; Female; Glioma; Glucose Transport Proteins, Facilitative; Hematologic Neoplasms; Homeostasis; Humans; Hypoxia-Inducible Factor 1; Ketoglutaric Acids; Male; Melanoma; Mixed Function Oxygenases; Neoplasms; Oxidation-Reduction; Polymorphism, Genetic; Prostatic Neoplasms; Proto-Oncogene Proteins; Sodium-Coupled Vitamin C Transporters; Vitamins

Vitamin C is an antioxidant that may scavenge reactive oxygen species preventing DNA damage and other effects important in cancer transformation. Dietary vitamin C from natural sources is taken with other compounds affecting its bioavailability and biological effects. High pharmacological doses of vitamin C may induce prooxidant effects, detrimental for cancer cells. An oxidized form of vitamin C, dehydroascorbate, is transported through glucose transporters, and cancer cells switch from oxidative phosphorylation to glycolysis in energy production so an excess of vitamin C may limit glucose transport and ATP production resulting in energetic crisis and cell death. Vitamin C may change the metabolomic and epigenetic profiles of cancer cells, and activation of ten-eleven translocation (TET) proteins and downregulation of pluripotency factors by the vitamin may eradicate cancer stem cells. Metastasis, the main reason of cancer-related deaths, requires breakage of anatomical barriers containing collagen, whose synthesis is promoted by vitamin C. Vitamin C induces degradation of hypoxia-inducible factor, HIF-1, essential for the survival of tumor cells in hypoxic conditions. Dietary vitamin C may stimulate the immune system through activation of NK and T cells and monocytes. Pharmacological doses of vitamin C may inhibit cancer transformation in several pathways, but further studies are needed to address both mechanistic and clinical aspects of this effect.

Topics: Animals; Antioxidants; Ascorbic Acid; Carcinogenesis; Chemokine CCL1; Dietary Supplements; Gene Expression Regulation, Neoplastic; Glucose; Glycolysis; Humans; Immunologic Surveillance; Killer Cells, Natural; Neoplasms; Oxidants

DNA 5-hydroxymethylcytosine (5hmC) is produced by dynamic 5mC oxidation process contributing to tissue specification, and loss of 5hmC has been reported in multiple cancers including genitourinary cancers. However, 5hmC is also cell-type specific, and its variability may exist between differentiated tumor cells and cancer stem cells. Thus, cancer-associated changes in 5hmC may be contributed by distinct sets of tumor cells within the tumor tissues.. Here, we applied a sensitive immunoprecipitation-based method (hMeDIP-seq) to analyze 5hmC changes during genitourinary carcinogenesis (including prostate, urothelial and kidney). We confirmed the tissue-specific distribution of 5hmC in genitourinary tissues and identified regional gain and global loss of 5hmC coexisting in genitourinary cancers. The genes with gain of 5hmC during tumorigenesis were functionally enriched in regulating stemness and hypoxia, whereas were associated with poor clinical prognosis irrespective of their differences in tumor type. We identified that gain of 5hmC occurred in soft fibrin gel-induced 3D tumor spheres with a tumor-repopulating phenotype in two prostate cancer cell lines, 22RV1 and PC3, compared with conventional two-dimensional (2D) rigid dishes. Then, we defined a malignant signature derived from the differentially hydroxymethylated regions affected genes of cancer stem-like cells, which could predict a worse clinical outcome and identified phenotypically malignant populations of cells from prostate cancer tumors. Notably, an oxidation-resistant vitamin C derivative, ascorbyl phosphate magnesium, restored 5hmC and killed the cancer stem cell-like cells leading to apoptosis in prostate cancer cell lines.. Collectively, our study dissects the regional gain of 5hmC in maintaining cancer stem-like cells and related to poor prognosis, which provides proof of concept for an epigenetic differentiation therapy with vitamin C by 5hmC reprogramming.

Topics: 5-Methylcytosine; Ascorbic Acid; Carcinogenesis; DNA; DNA Methylation; Fibrin; Humans; Magnesium; Male; Phosphates; Prostatic Neoplasms; Urogenital Neoplasms

Cumulative studies have indicated that high-dose vitamin C has antitumor effects against a variety of cancers. However, the molecular mechanisms underlying these inhibitory effects against tumorigenesis and metastasis, particularly in relation to pancreatic cancer, are unclear. Here, we report that vitamin C at high concentrations impairs the growth and survival of pancreatic ductal adenocarcinoma (PDAC) cells by inhibiting glucose metabolism. Vitamin C was also found to trigger apoptosis in a caspase-independent manner. We further demonstrate that it suppresses the invasion and metastasis of PDAC cells by inhibiting the Wnt/β-catenin-mediated epithelial-mesenchymal transition (EMT). Taken together, our results suggest that vitamin C has therapeutic effects against pancreatic cancer.

Topics: Ascorbic Acid; beta Catenin; Carcinogenesis; Carcinoma, Pancreatic Ductal; Caspases; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Glucose; Humans; Pancreatic Neoplasms; Wnt Signaling Pathway

Anaplastic thyroid cancer (ATC) is a rare but highly lethal disease. So far, there is no available established treatment which can prolong its survival. In this regard, effective therapies are urgently needed. Vitamin C widely serves as an anti-cancer agent. However, the potential effects of vitamin C against thyroid tumorigenesis remained unclear. The present study demonstrated that vitamin C could significantly inhibit ATC cells growth through ferroptosis activation, evidenced by the GPX4 inactivation, ROS accumulation and iron-dependent lipid peroxidation. Our results demonstrated that vitamin C treatment induced ferritinophagy and subsequent degradation of ferritin, leading to the release of free iron. Excessive iron further triggered ROS generation via Fenton reaction. The positive feedback mediated by ROS and iron sustained lipid peroxidation and further resulted in ferroptosis of ATC cells. The better understanding of the anti-cancer mechanisms of vitamin C provides a potential strategy for ATC therapy.

Topics: Antineoplastic Agents; Ascorbic Acid; Autophagy; Carcinogenesis; Cell Proliferation; Ferritins; Ferroptosis; Humans; Lipid Peroxidation; Oxidative Stress; Phospholipid Hydroperoxide Glutathione Peroxidase; Reactive Oxygen Species; Thyroid Carcinoma, Anaplastic

DNA methylation plays an important role in thyroid oncogenesis. The aim of this study was to investigate the connection between global and local DNA methylation status and to establish the levels of important DNA methylation regulators (TET family and DNMT1) in thyroid tumours: follicular adenoma-FA, papillary thyroid carcinoma-PTC (classic papillary thyroid carcinoma-cPTC and papillary thyroid carcinoma follicular variant fvPTC).. Global DNA methylation profile in thyroid tumours tissue (41 paired samples) was assessed by 5-methylcytosine and 5-hydroxymethylcytosine levels evaluation (ELISA), along with TETs and DNMT1 genes expression quantification. Also, it was investigated for the first time TET1 and TET2 promoter's methylation in thyroid tumours. BRAF V600E mutation and RET/PTC translocation testing were performed on all investigated samples. In vitro studies upon DNA methylation in K1 thyroid cancer cells were performed with demethylating agents (5-AzaC and vitamin C).. TET1 and TET2 displayed a significantly reduced gene expression level in PTC, while DNMT1 gene presented a high level of expression. PTC samples presented increased levels of 5-methylcytosine and low levels of 5-hydroxymethylcytosine. 5-methylcytosine levels were associated with TET1/TET2 expression levels. TET1 gene expression was significantly lower in patients positive for BRAF mutation and with RET/PTC rearrangement. TET2 gene was found hypermethylated in thyroid carcinoma patients overall, especially in PTC-follicular variant samples (p= 0.0002), where TET2 gene expression levels were significantly reduced (p= 0.0031). Furthermore, the data indicate for all thyroid cancer patients a good sensitivity (81.08%) and specificity (86.49%) regarding the use of TET1 (p< 0.0001), and TET2 (71.79%, 64.10%, p= 0.0001) hypermethylation as biomarkers for thyroid oncogenesis.. These results suggest that TET1/TET2 gene expression and methylation may serve as potential diagnostic tools for thyroid neoplasia. Our study showed that the methylation of TET1 increases in malignant thyroid tumours. fvPTC patients presented lower methylation levels compared to cPTC and could be a discriminatory factor between two cancer types and benign lesions. TET2 is a poorer discriminator between FA and fvPTC, but it can be useful for cPTC identification. K1-cells treated with demethylating agents showed a demethylation effect, especially upon TET2 gene. The cumulative effect of L-AA and 5-AzaC proved to have a potent combined demethylating effect on genes promoter's activation and could open new perspectives for thyroid cancer therapy.

Topics: Adenocarcinoma, Follicular; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Azacitidine; Biomarkers, Tumor; Carcinogenesis; Cell Line, Tumor; Dioxygenases; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; DNA-Binding Proteins; Drug Screening Assays, Antitumor; Epigenesis, Genetic; Feasibility Studies; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Mixed Function Oxygenases; Promoter Regions, Genetic; Proto-Oncogene Proteins; Sensitivity and Specificity; Thyroid Cancer, Papillary; Thyroid Gland; Thyroid Neoplasms; Young Adult

Topics: Aldehyde Reductase; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Carcinogenesis; Chemical and Drug Induced Liver Injury; Diethylnitrosamine; Liver; Liver Function Tests; Mice, Inbred C57BL; Mice, Knockout; Survival Analysis

Stem-cell fate can be influenced by metabolite levels in culture, but it is not known whether physiological variations in metabolite levels in normal tissues regulate stem-cell function in vivo. Here we describe a metabolomics method for the analysis of rare cell populations isolated directly from tissues and use it to compare mouse haematopoietic stem cells (HSCs) to restricted haematopoietic progenitors. Each haematopoietic cell type had a distinct metabolic signature. Human and mouse HSCs had unusually high levels of ascorbate, which decreased with differentiation. Systemic ascorbate depletion in mice increased HSC frequency and function, in part by reducing the function of Tet2, a dioxygenase tumour suppressor. Ascorbate depletion cooperated with Flt3 internal tandem duplication (Flt3

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Carcinogenesis; Dioxygenases; DNA-Binding Proteins; Female; fms-Like Tyrosine Kinase 3; Hematopoietic Stem Cells; Humans; Leukemia; Male; Metabolomics; Mice; Myelopoiesis; Proto-Oncogene Proteins

Chemoprevention is considered as one of the most promising and realistic approaches in the prevention of lung cancer. Chrysin, a naturally occurring dietary flavone widely found in Passiflora family of plants and honey, has been studied extensively for its chemopreventive properties. The objective of present study is to divulge the chemopreventive role of chrysin against benzo(a)pyrene [B(a)P] induced lung carcinogenesis in Swiss albino mice.. B(a)P was administered orally (50mg/kg body weight) twice a week for four weeks to induce lung cancer in mice. The body weight, lung weight, tumor incidence, lipid peroxidation, carcinoembryonic antigen, enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) and non-enzymatic antioxidants (reduced glutathione, vitamin E and vitamin C) were estimated. Further, histopathological analysis of lung tissue and western blotting analysis of PCNA, COX-2 and NF-κB were also carried out.. Administration of B(a)P resulted in increased lipid peroxides and carcinoembryonic antigen with concomitant decrease in the levels of both enzymatic antioxidants and non-enzymatic antioxidants. Chrysin treatment (250mg/kg body weight) significantly attenuated all these changes thereby showing potent anti lung cancer effect. Further, the anticancer effect of chrysin was confirmed by histopathology of lungs, and immunoblotting analysis of PCNA, COX-2 and NF-κB, where chrysin supplementation downregulated the expression of these proteins and maintained cellular homeostasis.. Overall, these findings confirm the chemopreventive potential of chrysin against B(a)P induced lung cancer in Swiss albino mice.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Benzo(a)pyrene; Carcinogenesis; Catalase; Chemoprevention; Diet; Disease Models, Animal; Flavones; Flavonoids; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Lipid Peroxidation; Lung; Lung Neoplasms; Male; Mice; NF-kappa B; Superoxide Dismutase; Vitamin E

Genetic modification, such as the addition of exogenous genes to the MSC genome, is crucial to their use as cellular vehicles. Due to the risks associated with viral vectors such as insertional mutagenesis, the safer nonviral vectors have drawn a great deal of attention.. VEGF, bFGF, vitamin C, and insulin-transferrin-selenium-X were supplemented in the MSC culture medium. The cells' proliferation and survival capacity was measured by MTT, determination of the cumulative number of cells, and a colony-forming efficiency assay. The plasmid pHr2-NL was constructed and nucleofected into MSCs. The recombinants were selected using G418 and characterized using PCR and Southern blotting.. BFGF is critical to MSC growth and it acted synergistically with vitamin C, VEGF, and ITS-X, causing the cells to expand significantly. The neomycin gene was targeted to the rDNA locus of human MSCs using a nonviral human ribosomal targeting vector. The recombinant MSCs retained multipotential differentiation capacity, typical levels of hMSC surface marker expression, and a normal karyotype, and none were tumorigenic in nude mice.. Exogenous genes can be targeted to the rDNA locus of human MSCs while maintaining the characteristics of MSCs. This is the first nonviral gene targeting of hMSCs.

Topics: Animals; Antigens, Surface; Ascorbic Acid; Carcinogenesis; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA, Ribosomal; Fibroblast Growth Factor 2; Gene Targeting; Genetic Loci; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Karyotyping; Mesenchymal Stem Cells; Mice; Mice, Nude; Mutagenesis, Site-Directed; Selenium; Transferrin; Vascular Endothelial Growth Factor A; Viruses