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Esposito T, Pentimalli F, Giordano A, Cortellino S. Vitamins and dietary supplements in cancer treatment: is there a need for increased usage? Expert Rev Anticancer Ther 2025:1-24. [PMID: 40322898 DOI: 10.1080/14737140.2025.2501077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 04/29/2025] [Indexed: 05/08/2025]
Abstract
INTRODUCTION Vitamins are essential for homeostasis and proper functioning of organisms. These micronutrients prevent tumor onset by functioning as antioxidants and enzymatic cofactors involved in anti-stress and immune responses, modulating epigenetic regulators, and shaping the microbiota composition. Unbalanced diets and sedentary lifestyles contribute to obesity, associated with increasing cancer risk. Cancer patients often exhibit vitamin deficiencies due to chronic inflammation, anticancer therapies, and tumor-induced metabolic changes, leading to malnutrition and cachexia. AREAS COVERED This review critically analyzes preclinical and clinical studies, sourced from PubMed and ClinicalTrials.gov databases, that investigate the potential benefits of vitamin supplementation and dietary interventions, such as intermittent fasting and ketogenic diets, in mouse tumor models and cancer patients. This analysis elucidates the limitations of such interventions and suggests optimal dietary strategies to prevent cancer and enhance patients' quality of life and prognosis. EXPERT OPINION To date, clinical studies have found no substantial benefit of over-the-counter vitamin supplements and dietary interventions on cancer patients' health and prognosis. To prevent the spread of useless and potentially harmful products by the nutraceutical industry, establishing a regulatory authority is necessary to monitor and ensure product quality and validity before commercialization.
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Affiliation(s)
- Teresa Esposito
- Department of Clinical Dietetics and Metabolic Diseases, Cavalier Raffaele Apicella Hospital, ASL Napoli 3 Sud, Naples, Italy
| | - Francesca Pentimalli
- Department of Medicine and Surgery, LUM University "Giuseppe De Gennaro", Bari, Italy
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Salvatore Cortellino
- Scuola Superiore Meridionale (SSM), Clinical and Translational Oncology, Naples, Italy
- S.H.R.O. Italia Foundation ETS, Turin, Italy
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2
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He X, Wang Q, Cheng X, Wang W, Li Y, Nan Y, Wu J, Xiu B, Jiang T, Bergholz JS, Gu H, Chen F, Fan G, Sun L, Xie S, Zou J, Lin S, Wei Y, Lee J, Asara JM, Zhang K, Cantley LC, Zhao JJ. Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response. Cell 2025; 188:1858-1877.e21. [PMID: 40023152 DOI: 10.1016/j.cell.2025.01.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 01/04/2025] [Accepted: 01/30/2025] [Indexed: 03/04/2025]
Abstract
Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form "vitcyl-lysine"-a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity in vitro and in vivo. The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC's cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.
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Affiliation(s)
- Xiadi He
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Center for Metabolic Diseases (Shanghai), Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Lifecycle Health Management Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qiwei Wang
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Xin Cheng
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Weihua Wang
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Yutong Li
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Yabing Nan
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Jiang Wu
- College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Bingqiu Xiu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Tao Jiang
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Johann S Bergholz
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Hao Gu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Fuhui Chen
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Guangjian Fan
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Lianhui Sun
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiao Tong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
| | - Shaozhen Xie
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Junjie Zou
- XtalPi Technology Co., Ltd., Shanghai 200131, China
| | - Sheng Lin
- XtalPi Technology Co., Ltd., Shanghai 200131, China
| | - Yun Wei
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA
| | - James Lee
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - John M Asara
- Division of Signal Transduction/Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Ke Zhang
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA
| | - Lewis C Cantley
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Jean J Zhao
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
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3
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Wang X, He J, Sun M, Wang S, Qu J, Shi H, Rao B. High-dose vitamin C as a metabolic treatment of cancer: a new dimension in the era of adjuvant and intensive therapy. Clin Transl Oncol 2025; 27:1366-1382. [PMID: 39259387 DOI: 10.1007/s12094-024-03553-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/04/2024] [Indexed: 09/13/2024]
Abstract
The anti-cancer mechanism of High-dose Vitamin C (HDVC) is mainly to participate in the Fenton reaction, hydroxylation reaction, and epigenetic modification, which leads to the energy crisis, metabolic collapse, and severe peroxidation stress that results in the proliferation inhibition or death of cancer cells. However, the mainstream view is that HDVC does not significantly improve cancer treatment outcomes. In clinical work and scientific research, we found that some drugs or therapies can significantly improve the anti-cancer effects of HDVC, such as PD-1 inhibitors that can increase the anti-cancer effects of cancerous HDVC by nearly three times. Here, the adjuvant and intensive therapy and synergistic mechanisms including HDVC combined application of chemoradiotherapies multi-vitamins, targeted drugs, immunotherapies, and oncolytic virus are discussed in detail. Adjuvant and intensive therapy of HDVC can significantly improve the therapeutic effect of HDVC in the metabolic treatment of cancer, but more clinical evidence is needed to support its clinical application.
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Affiliation(s)
- Xin Wang
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Center of Metabolism and Nutrition of Cancer, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China
| | - Jia He
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Center of Metabolism and Nutrition of Cancer, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China
| | - Minmin Sun
- CAS Engineering Laboratory for Nanozyme, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Shiwan Wang
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Center of Metabolism and Nutrition of Cancer, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China
| | - Jinxiu Qu
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Center of Metabolism and Nutrition of Cancer, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China
| | - Hanping Shi
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
- Center of Metabolism and Nutrition of Cancer, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
- Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China.
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.
- Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
| | - Benqiang Rao
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
- Center of Metabolism and Nutrition of Cancer, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
- Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China.
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.
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4
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Lykkesfeldt J, Carr AC, Tveden-Nyborg P. The pharmacology of vitamin C. Pharmacol Rev 2025; 77:100043. [PMID: 39986139 DOI: 10.1016/j.pharmr.2025.100043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 01/14/2025] [Indexed: 02/24/2025] Open
Abstract
Ascorbic acid, the reduced form of vitamin C, is a ubiquitous small carbohydrate. Despite decades of focused research, new metabolic functions of this universal electron donor are still being discovered and add to the complexity of our view of vitamin C in human health. Although praised as an unsurpassed water-soluble antioxidant in plasma and cells, the most interesting functions of vitamin C seem to be its roles as specific electron donor in numerous biological reactions ranging from the well-known hydroxylation of proline to cofactor for the epigenetic master regulators ten-eleven translocation enzymes and Jumonji domain-containing histone-lysine demethylases. Some of these functions may have important implications for disease prevention and treatment and have spiked renewed interest in, eg, vitamin C's potential in cancer therapy. Moreover, some fundamental pharmacokinetic properties of vitamin C remain to be established including if other mechanisms than passive diffusion governs the efflux of ascorbate anions from the cell. Taken together, there still seems to be much to learn about the pharmacology of vitamin C and its role in health and disease. This review explores new avenues of vitamin C and integrates our present knowledge of its pharmacology. SIGNIFICANCE STATEMENT: Vitamin C is involved in multiple biological reactions of which most are essential to human health. Hundreds of millions of people are considered deficient in vitamin C according to accepted guidelines, but little is known about the long-term consequences. Although the complexity of vitamin C's physiology and pharmacology has been widely disregarded in clinical studies for decades, it seems clear that a deeper understanding of particularly its pharmacology holds the key to unravel and possibly exploit the potential of vitamin C in disease prevention and therapy.
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Affiliation(s)
- Jens Lykkesfeldt
- Section of Biomedicine, Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Anitra C Carr
- Nutrition in Medicine Research Group, Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Pernille Tveden-Nyborg
- Section of Biomedicine, Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Kishimoto S, Crooks DR, Yasunori O, Kota Y, Yamamoto K, Linehan WM, Levine M, Krishna MC, Brender JR. Pharmacologic ascorbate induces transient hypoxia sensitizing pancreatic ductal adenocarcinoma to a hypoxia activated prodrug. Free Radic Biol Med 2024; 222:579-587. [PMID: 38992394 DOI: 10.1016/j.freeradbiomed.2024.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 07/05/2024] [Accepted: 07/08/2024] [Indexed: 07/13/2024]
Abstract
Hypoxic tumor microenvironments pose a significant challenge in cancer treatment. Hypoxia-activated prodrugs like evofosfamide aim to specifically target and eliminate these resistant cells. However, their effectiveness is often limited by reoxygenation after cell death. We hypothesized that ascorbate's pro-oxidant properties could be harnessed to induce transient hypoxia, enhancing the efficacy of evofosfamide by overcoming reoxygenation. To test this hypothesis, we investigated the sensitivity of MIA Paca-2 and A549 cancer cells to ascorbate in vitro and in vivo. Ascorbate induced a cytotoxic effect at 5 mM that could be alleviated by endogenous administration of catalase, suggesting a role for hydrogen peroxide in its cytotoxic mechanism. In vitro, Seahorse experiments indicated that the generation of hydrogen peroxide consumes oxygen, which is offset at later time points by a reduction in oxygen consumption due to hydrogen peroxide's cytotoxic effect. In vivo, photoacoustic imaging showed pharmacologic ascorbate treatment at sublethal levels triggered a complex, multi-phasic response in tumor oxygenation across both cell lines. Initially, ascorbate generated transient hypoxia within minutes through hydrogen peroxide production, via reactions that consume oxygen. This initial hypoxic phase peaked at around 150 s and then gradually subsided. However, at longer time scales (approximately 300 s) a vasodilation effect triggered by ascorbate resulted in increased blood flow and subsequent reoxygenation. Combining sublethal levels of i. p. Ascorbate with evofosfamide significantly prolonged tumor doubling time in MIA Paca-2 and A549 xenografts compared to either treatment alone. This improvement, however, was only observed in a subpopulation of tumors, highlighting the complexity of the oxygenation response.
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Affiliation(s)
- Shun Kishimoto
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Daniel R Crooks
- Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Clinical Cancer Metabolism Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Otowa Yasunori
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yamashita Kota
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Kazutoshi Yamamoto
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - W Marston Linehan
- Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Clinical Cancer Metabolism Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Mark Levine
- Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Murali C Krishna
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Jeffrey R Brender
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Molecular Imaging Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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6
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Yi Z, Yang X, Liang Y, Tong S. Iron oxide nanozymes enhanced by ascorbic acid for macrophage-based cancer therapy. NANOSCALE 2024; 16:14330-14338. [PMID: 39015956 PMCID: PMC11305150 DOI: 10.1039/d4nr01208a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 07/11/2024] [Indexed: 07/18/2024]
Abstract
In recent years, using pharmacological ascorbic acid has emerged as a promising therapeutic approach in cancer treatment, owing to its capacity to induce extracellular hydrogen peroxide (H2O2) production in solid tumors. The H2O2 is then converted into cytotoxic hydroxyl free radicals (HO˙) by redox-active Fe2+ inside cells. However, the high dosage of ascorbic acid required for efficacy is hampered by adverse effects such as kidney stone formation. In a recent study, we demonstrated the efficient catalytic conversion of H2O2 to HO˙ by wüstite (Fe1-xO) nanoparticles (WNPs) through a heterogenous Fenton reaction. Here, we explore whether WNPs can enhance the therapeutic potential of ascorbic acid, thus mitigating its dose-related limitations. Our findings reveal distinct pH dependencies for WNPs and ascorbic acid in the Fenton reaction and H2O2 generation, respectively. Importantly, WNPs exhibit the capability to either impede or enhance the cytotoxic effect of ascorbic acid, depending on the spatial segregation of the two reagents by cellular compartments. Furthermore, our study demonstrates that treatment with ascorbic acid promotes the polarization of WNP-loaded macrophages toward a pro-inflammatory M1 phenotype, significantly suppressing the growth of 4T1 breast cancer cells. This study highlights the importance of orchestrating the interplay between ascorbic acid and nanozymes in cancer therapy and presents a novel macrophage-based cell therapy approach.
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Affiliation(s)
- Zhongchao Yi
- Department of Biomedical Engineering, University of Kentucky, Lexington, Kentucky 40536, USA.
| | - Xiaoyue Yang
- Department of Biomedical Engineering, University of Kentucky, Lexington, Kentucky 40536, USA.
| | - Ying Liang
- New York Blood Center, New York, New York 10065, USA
| | - Sheng Tong
- Department of Biomedical Engineering, University of Kentucky, Lexington, Kentucky 40536, USA.
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Vernieri C, Ligorio F, Tripathy D, Longo VD. Cyclic fasting-mimicking diet in cancer treatment: Preclinical and clinical evidence. Cell Metab 2024; 36:1644-1667. [PMID: 39059383 DOI: 10.1016/j.cmet.2024.06.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 06/03/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024]
Abstract
In preclinical tumor models, cyclic fasting and fasting-mimicking diets (FMDs) produce antitumor effects that become synergistic when combined with a wide range of standard anticancer treatments while protecting normal tissues from treatment-induced adverse events. More recently, results of phase 1/2 clinical trials showed that cyclic FMD is safe, feasible, and associated with positive metabolic and immunomodulatory effects in patients with different tumor types, thus paving the way for larger clinical trials to investigate FMD anticancer activity in different clinical contexts. Here, we review the tumor-cell-autonomous and immune-system-mediated mechanisms of fasting/FMD antitumor effects, and we critically discuss new metabolic interventions that could synergize with nutrient starvation to boost its anticancer activity and prevent or reverse tumor resistance while minimizing toxicity to patients. Finally, we highlight potential future applications of FMD approaches in combination with standard anticancer strategies as well as strategies to implement the design and conduction of clinical trials.
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Affiliation(s)
- Claudio Vernieri
- Medical Oncology and Hematology-Oncology Department, University of Milan, 20122 Milan, Italy; IFOM ETS, the AIRC Institute of Molecular Oncology, 20139 Milan, Italy.
| | - Francesca Ligorio
- Medical Oncology and Hematology-Oncology Department, University of Milan, 20122 Milan, Italy; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Debu Tripathy
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Unit 1354, 1515 Holcombe Blvd, Houston, TX 77030-4009, USA
| | - Valter D Longo
- IFOM ETS, the AIRC Institute of Molecular Oncology, 20139 Milan, Italy; Longevity Institute, Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
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8
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Rocha HNM, Velasco LL, Batista GMS, Storch AS, Garcia VP, Teixeira GF, Mentzinger J, da Nóbrega ACL, Rocha NG. Ascorbic acid prevents stress-induced hypercoagulability in overweight and obese individuals. Sci Rep 2024; 14:3122. [PMID: 38326408 PMCID: PMC10850162 DOI: 10.1038/s41598-024-53794-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 02/05/2024] [Indexed: 02/09/2024] Open
Abstract
Ascorbic acid (AA) may contribute to restoring hemostatic balance after mental stress (MS) in overweight/obese adults. We aimed to determine the effects of AA administration on hemostatic responses to MS in overweight/obese men. Fourteen overweight/obesity men (27 ± 7 years; BMI: 29.7 ± 2.6 kg m-2) performed the Stroop color-word stress task for 5 min after non-simultaneous infusion of placebo (PL, 0.9% NaCl) and AA (3 g). Blood was collected at baseline, during MS, and 60 min after MS to measure: activated partial thromboplastin time, prothrombin time, and fibrinogen concentration, by coagulometer; platelet-derived microvesicles (PMV, mv/μL), by flow cytometry; nitrite (μM), by chemiluminescence. In PL session, MS led to decreases in PTs (stress, p = 0.03; 60 min, p < 0.001), PT-INR (stress, p < 0.001; 60 min, p < 0.01), aPTTs (60 min, p = 0.03), aPTT ratio (60 min, p = 0.04) and fibrinogen (60 min, p = 0.04), while increased PT activity (60 min, p = 0.01) when compared to baseline. Furthermore, AA increased PTs (60 min, p < 0.001), PT-INR (60 min, p = 0.03) and decreased PT activity (60 min, p < 0.001) and fibrinogen (stress, p = 0.04) when compared to PL. Nitrite was increased in response to stress during AA session (p < 0.001 vs PL). There was no difference in PMV. Ascorbic acid prevented the impaired hemostatic profile and improved nitrite response to stress in the overweight and obese adults.
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Affiliation(s)
- Helena N M Rocha
- Laboratory of Exercise Sciences, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, RJ, 24.020-150, Brazil
- Laboratory of Integrative Cardiometabology, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil
- National Institute of Science and Technology (INCT) - Physical (In)Activity and Exercise, National Council for Scientific and Technological Development (CNPq), Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil
| | - Larissa L Velasco
- Laboratory of Exercise Sciences, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, RJ, 24.020-150, Brazil
- Laboratory of Integrative Cardiometabology, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil
| | - Gabriel M S Batista
- Laboratory of Exercise Sciences, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, RJ, 24.020-150, Brazil
- Laboratory of Integrative Cardiometabology, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil
| | - Amanda S Storch
- Laboratory of Exercise Sciences, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, RJ, 24.020-150, Brazil
- Laboratory of Integrative Cardiometabology, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil
| | - Vinicius P Garcia
- Laboratory of Exercise Sciences, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, RJ, 24.020-150, Brazil
- Laboratory of Integrative Cardiometabology, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil
- National Institute of Science and Technology (INCT) - Physical (In)Activity and Exercise, National Council for Scientific and Technological Development (CNPq), Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil
| | - Gabriel F Teixeira
- Laboratory of Exercise Sciences, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, RJ, 24.020-150, Brazil
- Laboratory of Integrative Cardiometabology, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil
| | - Juliana Mentzinger
- Laboratory of Exercise Sciences, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, RJ, 24.020-150, Brazil
- Laboratory of Integrative Cardiometabology, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil
| | - Antonio C L da Nóbrega
- Laboratory of Exercise Sciences, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, RJ, 24.020-150, Brazil
- Laboratory of Integrative Cardiometabology, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil
- National Institute of Science and Technology (INCT) - Physical (In)Activity and Exercise, National Council for Scientific and Technological Development (CNPq), Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil
| | - Natália G Rocha
- Laboratory of Exercise Sciences, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, RJ, 24.020-150, Brazil.
- Laboratory of Integrative Cardiometabology, Department of Physiology and Pharmacology, Fluminense Federal University, Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil.
- National Institute of Science and Technology (INCT) - Physical (In)Activity and Exercise, National Council for Scientific and Technological Development (CNPq), Rua Alameda Barros Terra, Sala 110, São Domingos, Niterói, Rio de Janeiro, Brazil.
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9
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Sun W, Zhao B, Li J, Wang Y, Qi X, Ning N, Sun S, Li M, Yao Y, Ni T, Ma L, He J, Huang J, Yang Z, Chen Y, Sheng H, Mao E. Effect of high-dose intravenous vitamin C therapy on the prognosis in patients with moderately severe and severe acute pancreatitis: protocol of a prospective, randomized, double-blinded, placebo-controlled study. Front Med (Lausanne) 2023; 10:1278167. [PMID: 38020102 PMCID: PMC10665842 DOI: 10.3389/fmed.2023.1278167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
INTRODUCTION Acute pancreatitis is a common gastrointestinal disease. The mortality of patients affected by severe acute pancreatitis (SAP) remains high. It is unclear whether high-dose intravenous vitamin C (HDIVC) therapy could improve the prognosis of these patients. The current prospective, randomized, double-blinded, placebo-controlled study will explore the effect of high-dose intravenous vitamin C therapy on the prognosis in patients with moderately severe and severe acute pancreatitis. METHODS AND DESIGN A total of 418 participants with moderately severe and severe acute pancreatitis who meet the eligible criteria will be randomly assigned in a 1:1 ratio to receive treatment with HDIVC (200 mg/kg/24 h) or placebo (saline) for a period of 7 days. The primary outcome is 28-day mortality in these patients. The secondary outcomes include organ functions and interventions, laboratory tests, healthcare, and 90-day mortality. ETHICS AND DISSEMINATION This protocol was approved by the institutional ethics board of the Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Registration Number: 2019-90). The report of the study will be published in peer-reviewed journals and presented at conferences, both nationally and internationally. CLINICAL TRIAL REGISTRATION Chinese Clinical Trial Registry (ChiCTR1900022022). Version 1.5.
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Affiliation(s)
- Wenwu Sun
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bing Zhao
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiaoyan Li
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yihui Wang
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xing Qi
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ning Ning
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Silei Sun
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mengjiao Li
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Yao
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tongtian Ni
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Ma
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Juan He
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Huang
- Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhitao Yang
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huiqiu Sheng
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Enqiang Mao
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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10
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Zhang X, Zhang Y, Wang C, Wang X. TET (Ten-eleven translocation) family proteins: structure, biological functions and applications. Signal Transduct Target Ther 2023; 8:297. [PMID: 37563110 PMCID: PMC10415333 DOI: 10.1038/s41392-023-01537-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 05/24/2023] [Accepted: 06/05/2023] [Indexed: 08/12/2023] Open
Abstract
Ten-eleven translocation (TET) family proteins (TETs), specifically, TET1, TET2 and TET3, can modify DNA by oxidizing 5-methylcytosine (5mC) iteratively to yield 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxycytosine (5caC), and then two of these intermediates (5fC and 5caC) can be excised and return to unmethylated cytosines by thymine-DNA glycosylase (TDG)-mediated base excision repair. Because DNA methylation and demethylation play an important role in numerous biological processes, including zygote formation, embryogenesis, spatial learning and immune homeostasis, the regulation of TETs functions is complicated, and dysregulation of their functions is implicated in many diseases such as myeloid malignancies. In addition, recent studies have demonstrated that TET2 is able to catalyze the hydroxymethylation of RNA to perform post-transcriptional regulation. Notably, catalytic-independent functions of TETs in certain biological contexts have been identified, further highlighting their multifunctional roles. Interestingly, by reactivating the expression of selected target genes, accumulated evidences support the potential therapeutic use of TETs-based DNA methylation editing tools in disorders associated with epigenetic silencing. In this review, we summarize recent key findings in TETs functions, activity regulators at various levels, technological advances in the detection of 5hmC, the main TETs oxidative product, and TETs emerging applications in epigenetic editing. Furthermore, we discuss existing challenges and future directions in this field.
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Affiliation(s)
- Xinchao Zhang
- Department of Pathology, Ruijin Hospital and College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yue Zhang
- Department of Pathology, Ruijin Hospital and College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chaofu Wang
- Department of Pathology, Ruijin Hospital and College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Xu Wang
- Department of Pathology, Ruijin Hospital and College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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11
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Kietzmann T. Vitamin C: From nutrition to oxygen sensing and epigenetics. Redox Biol 2023; 63:102753. [PMID: 37263060 PMCID: PMC10245123 DOI: 10.1016/j.redox.2023.102753] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/09/2023] [Accepted: 05/16/2023] [Indexed: 06/03/2023] Open
Abstract
Vitamin C is unbeatable - at least when it comes to sales. Of all the vitamin preparations, those containing vitamin C sell best. This is surprising because vitamin C deficiency is extremely rare. Nevertheless, there is still controversy about whether the additional intake of vitamin C supplements is essential for our health. In this context, the possible additional benefit is in most cases merely reduced to the known effect as an antioxidant. However, new findings in recent years on the mechanisms of oxygen-sensing and epigenetic control underpin the multifaceted role of vitamin C in a biological context and have therefore renewed interest in it. In the present article, therefore, known facts are linked to these new key data. In addition, available clinical data on vitamin C use of cancer therapy are summarized.
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Affiliation(s)
- Thomas Kietzmann
- University of Oulu, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, P.O. Box 3000, 90014, Oulu, Finland.
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12
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Farasati Far B, Behnoush AH, Ghondaghsaz E, Habibi MA, Khalaji A. The interplay between vitamin C and thyroid. Endocrinol Diabetes Metab 2023; 6:e432. [PMID: 37246589 PMCID: PMC10335618 DOI: 10.1002/edm2.432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/13/2023] [Accepted: 05/20/2023] [Indexed: 05/30/2023] Open
Abstract
INTRODUCTION Vitamin C (ascorbic acid) is a water-soluble vitamin, that plays a key role in the prevention and treatment of scurvy. As vitamin C is an antioxidant and thyroid function may be affected and may affect vitamin C levels, for the first time, we aimed to provide a detailed review of all human studies evaluating the different roles of vitamin C in the thyroid gland. Thyroid cancers, goitre, Graves' disease and other causes of hyperthyroidism and hypothyroidism were the conditions discussed in this study. Furthermore, vitamin C addition to other medications such as levothyroxine was also reviewed. METHODS In this study, we reviewed the relevant literature regarding the association between vitamin C and thyroid diseases using original studies from PubMed, Scopus, Embase, and Web of Science. RESULTS In this review, we found anti-cancer effects for intravenous (IV) administration of vitamin C in addition to the beneficial effects of using it in combination with radiotherapy and chemotherapy. As autoimmune diseases affect some antioxidant markers, some studies reported a significant difference in blood vitamin C levels in patients with autoimmune thyroid diseases such as Graves' disease. Despite many studies evaluating the effects of IV administration of vitamin C in mentioned diseases, there is a lack of evidence for oral consumption of vitamin C. CONCLUSIONS To conclude, there is a lack of evidence, especially clinical trials, for the therapeutic effects of vitamin C on thyroid diseases; however, promising results were reported in some studies in the literature.
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Affiliation(s)
| | | | - Elina Ghondaghsaz
- Undergraduate Program in NeuroscienceUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Mohammad Amin Habibi
- Gene, Cell & Tissue Research InstituteTehran University of Medical ScienceTehranIran
- Clinical Research Development CenterQom University of Medical SciencesQomIran
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13
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He X, Wei Y, Wu J, Wang Q, Bergholz JS, Gu H, Zou J, Lin S, Wang W, Xie S, Jiang T, Lee J, Asara JM, Zhang K, Cantley LC, Zhao JJ. Lysine vitcylation is a novel vitamin C-derived protein modification that enhances STAT1-mediated immune response. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.27.546774. [PMID: 37425798 PMCID: PMC10327172 DOI: 10.1101/2023.06.27.546774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Vitamin C (vitC) is a vital nutrient for health and also used as a therapeutic agent in diseases such as cancer. However, the mechanisms underlying vitC's effects remain elusive. Here we report that vitC directly modifies lysine without enzymes to form vitcyl-lysine, termed "vitcylation", in a dose-, pH-, and sequence-dependent manner across diverse proteins in cells. We further discover that vitC vitcylates K298 site of STAT1, which impairs its interaction with the phosphatase PTPN2, preventing STAT1 Y701 dephosphorylation and leading to increased STAT1-mediated IFN pathway activation in tumor cells. As a result, these cells have increased MHC/HLA class-I expression and activate immune cells in co-cultures. Tumors collected from vitC-treated tumor-bearing mice have enhanced vitcylation, STAT1 phosphorylation and antigen presentation. The identification of vitcylation as a novel PTM and the characterization of its effect in tumor cells opens a new avenue for understanding vitC in cellular processes, disease mechanisms, and therapeutics.
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14
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Bag K, Pal AK, Basu S, Singla M, Sarkar B, Chatterji D, Maiti PK, Ghosh A, Jayaraman N. C-4-Modified Isotetrones Prevent Biofilm Growth and Persister Cell Resuscitation in Mycobacterium smegmatis. ACS OMEGA 2023; 8:20513-20523. [PMID: 37323400 PMCID: PMC10268289 DOI: 10.1021/acsomega.3c00822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 04/28/2023] [Indexed: 06/17/2023]
Abstract
Hyperphosphorylated nucleotide (p)ppGpp, synthesized by Rel protein, regulates the stringent response pathway responsible for biofilm and persister cell growth in mycobacteria. The discovery of vitamin C as an inhibitor of Rel protein activities raises the prospect of tetrone lactones to prevent such pathways. The closely related isotetrone lactone derivatives are identified herein as inhibitors of the above processes in a mycobacterium. Synthesis and biochemical evaluations show that an isotetrone possessing phenyl substituent at C-4 inhibit the biofilm formation at 400 μg mL-1, 84 h post-exposure, followed by moderate inhibition by the isotetrone possessing the p-hydroxyphenyl substituent. The latter isotetrone inhibits the growth of persister cells at 400 μg mL-1 f.c. when monitored for 2 weeks, under PBS starvation. Isotetrones also potentiate the inhibition of antibiotic-tolerant regrowth of cells by ciprofloxacin (0.75 μg mL-1) and thus act as bioenhancers. Molecular dynamics studies show that isotetrone derivatives bind to the RelMsm protein more efficiently than vitamin C at a binding site possessing serine, threonine, lysine, and arginine.
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Affiliation(s)
- Kingshuk Bag
- Department
of Organic Chemistry, Indian Institute of
Science, Bangalore 560 012, India
| | - Aditya Kumar Pal
- Molecular
Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India
| | - Subhadip Basu
- Department
of Physics, Indian Institute of Science, Bangalore 560 012, India
| | - Mamta Singla
- Molecular
Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India
| | - Biplab Sarkar
- Molecular
Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India
| | - Dipankar Chatterji
- Molecular
Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India
| | - Prabal Kumar Maiti
- Department
of Physics, Indian Institute of Science, Bangalore 560 012, India
| | - Anirban Ghosh
- Molecular
Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India
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15
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Donati G, Nicoli P, Verrecchia A, Vallelonga V, Croci O, Rodighiero S, Audano M, Cassina L, Ghsein A, Binelli G, Boletta A, Mitro N, Amati B. Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC-driven lymphoma. EMBO Mol Med 2023:e16910. [PMID: 37158102 DOI: 10.15252/emmm.202216910] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 04/13/2023] [Accepted: 04/21/2023] [Indexed: 05/10/2023] Open
Abstract
MYC is a key oncogenic driver in multiple tumor types, but concomitantly endows cancer cells with a series of vulnerabilities that provide opportunities for targeted pharmacological intervention. For example, drugs that suppress mitochondrial respiration selectively kill MYC-overexpressing cells. Here, we unravel the mechanistic basis for this synthetic lethal interaction and exploit it to improve the anticancer effects of the respiratory complex I inhibitor IACS-010759. In a B-lymphoid cell line, ectopic MYC activity and treatment with IACS-010759 added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced either with inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to act as a pro-oxidant at high doses. In these conditions, ascorbate synergized with IACS-010759 to kill MYC-overexpressing cells in vitro and reinforced its therapeutic action against human B-cell lymphoma xenografts. Hence, complex I inhibition and high-dose ascorbate might improve the outcome of patients affected by high-grade lymphomas and potentially other MYC-driven cancers.
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Affiliation(s)
- Giulio Donati
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | - Paola Nicoli
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | | | | | - Ottavio Croci
- Center for Genomic Science of IIT@SEMM, Milan, Italy
| | | | - Matteo Audano
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Laura Cassina
- IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Aya Ghsein
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | - Giorgio Binelli
- Dipartimento di Biotecnologie e Scienze della Vita, Università dell'Insubria, Varese, Italy
| | | | - Nico Mitro
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Bruno Amati
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
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16
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Leischner C, Marongiu L, Piotrowsky A, Niessner H, Venturelli S, Burkard M, Renner O. Relevant Membrane Transport Proteins as Possible Gatekeepers for Effective Pharmacological Ascorbate Treatment in Cancer. Antioxidants (Basel) 2023; 12:antiox12040916. [PMID: 37107291 PMCID: PMC10135768 DOI: 10.3390/antiox12040916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/23/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Despite the increasing number of newly diagnosed malignancies worldwide, therapeutic options for some tumor diseases are unfortunately still limited. Interestingly, preclinical but also some clinical data suggest that the administration of pharmacological ascorbate seems to respond well, especially in some aggressively growing tumor entities. The membrane transport and channel proteins are highly relevant for the use of pharmacological ascorbate in cancer therapy and are involved in the transfer of active substances such as ascorbate, hydrogen peroxide, and iron that predominantly must enter malignant cells to induce antiproliferative effects and especially ferroptosis. In this review, the relevant conveying proteins from cellular surfaces are presented as an integral part of the efficacy of pharmacological ascorbate, considering the already known genetic and functional features in tumor tissues. Accordingly, candidates for diagnostic markers and therapeutic targets are mentioned.
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Affiliation(s)
- Christian Leischner
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Luigi Marongiu
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
- Department of Internal Medicine VIII, University Hospital Tuebingen, Otfried-Mueller-Straße 10, 72076 Tuebingen, Germany
| | - Alban Piotrowsky
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Heike Niessner
- Department of Dermatology, Division of Dermatooncology, University of Tuebingen, Liebermeisterstraße 25, 72076 Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", 72076 Tuebingen, Germany
| | - Sascha Venturelli
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
- Institute of Physiology, Department of Vegetative and Clinical Physiology, University of Tuebingen, Wilhelmstraße 56, 72074 Tuebingen, Germany
| | - Markus Burkard
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Olga Renner
- Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
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17
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Zuo Y, Zheng Z, Huang Y, He J, Zang L, Ren T, Cao X, Miao Y, Yuan Y, Liu Y, Ma F, Dai J, Tian S, Ding Q, Zheng H. Vitamin C promotes ACE2 degradation and protects against SARS-CoV-2 infection. EMBO Rep 2023; 24:e56374. [PMID: 36876523 PMCID: PMC10074088 DOI: 10.15252/embr.202256374] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 02/01/2023] [Accepted: 02/13/2023] [Indexed: 03/07/2023] Open
Abstract
ACE2 is a major receptor for cellular entry of SARS-CoV-2. Despite advances in targeting ACE2 to inhibit SARS-CoV-2 binding, strategies to flexibly and sufficiently reduce ACE2 levels for the prevention of SARS-CoV-2 infection have not been explored. Here, we reveal vitamin C (VitC) administration as a potent strategy to prevent SARS-CoV-2 infection. VitC reduces ACE2 protein levels in a dose-dependent manner, while even a partial reduction in ACE2 levels can greatly inhibit SARS-CoV-2 infection. Further studies reveal that USP50 is a crucial regulator of ACE2 levels. VitC blocks the USP50-ACE2 interaction, thus promoting K48-linked polyubiquitination of ACE2 at Lys788 and subsequent degradation of ACE2 without affecting its transcriptional expression. Importantly, VitC administration reduces host ACE2 levels and greatly blocks SARS-CoV-2 infection in mice. This study reveals that ACE2 protein levels are down-regulated by an essential nutrient, VitC, thereby enhancing protection against infection of SARS-CoV-2 and its variants.
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Affiliation(s)
- Yibo Zuo
- International Institute of Infection and ImmunityInstitutes of Biology and Medical Sciences, Soochow UniversitySuzhouChina
- Jiangsu Key Laboratory of Infection and Immunity, Soochow UniversitySuzhouChina
| | - Zhijin Zheng
- International Institute of Infection and ImmunityInstitutes of Biology and Medical Sciences, Soochow UniversitySuzhouChina
- Jiangsu Key Laboratory of Infection and Immunity, Soochow UniversitySuzhouChina
| | - Yingkang Huang
- CAMS Key Laboratory of Synthetic Biology Regulatory ElementsChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Suzhou Institute of Systems MedicineSuzhouChina
| | - Jiuyi He
- International Institute of Infection and ImmunityInstitutes of Biology and Medical Sciences, Soochow UniversitySuzhouChina
- Jiangsu Key Laboratory of Infection and Immunity, Soochow UniversitySuzhouChina
| | - Lichao Zang
- The Third Affiliated Hospital of Soochow University, ChangzhouSoochow UniversitySuzhouChina
| | - Tengfei Ren
- International Institute of Infection and ImmunityInstitutes of Biology and Medical Sciences, Soochow UniversitySuzhouChina
- Jiangsu Key Laboratory of Infection and Immunity, Soochow UniversitySuzhouChina
| | - Xinhua Cao
- International Institute of Infection and ImmunityInstitutes of Biology and Medical Sciences, Soochow UniversitySuzhouChina
- Jiangsu Key Laboratory of Infection and Immunity, Soochow UniversitySuzhouChina
| | - Ying Miao
- International Institute of Infection and ImmunityInstitutes of Biology and Medical Sciences, Soochow UniversitySuzhouChina
- Jiangsu Key Laboratory of Infection and Immunity, Soochow UniversitySuzhouChina
| | - Yukang Yuan
- International Institute of Infection and ImmunityInstitutes of Biology and Medical Sciences, Soochow UniversitySuzhouChina
- Jiangsu Key Laboratory of Infection and Immunity, Soochow UniversitySuzhouChina
| | - Yanli Liu
- College of Pharmaceutical Sciences, Soochow UniversitySuzhouChina
| | - Feng Ma
- CAMS Key Laboratory of Synthetic Biology Regulatory ElementsChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Suzhou Institute of Systems MedicineSuzhouChina
| | - Jianfeng Dai
- International Institute of Infection and ImmunityInstitutes of Biology and Medical Sciences, Soochow UniversitySuzhouChina
- Jiangsu Key Laboratory of Infection and Immunity, Soochow UniversitySuzhouChina
| | - Sheng Tian
- College of Pharmaceutical Sciences, Soochow UniversitySuzhouChina
| | - Qiang Ding
- Center for Infectious Disease Research, School of Medicine, Beijing Advanced Innovation Center for Structural BiologyTsinghua UniversityBeijingChina
| | - Hui Zheng
- International Institute of Infection and ImmunityInstitutes of Biology and Medical Sciences, Soochow UniversitySuzhouChina
- Jiangsu Key Laboratory of Infection and Immunity, Soochow UniversitySuzhouChina
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18
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Overcoming EGFR Resistance in Metastatic Colorectal Cancer Using Vitamin C: A Review. Biomedicines 2023; 11:biomedicines11030678. [PMID: 36979659 PMCID: PMC10045351 DOI: 10.3390/biomedicines11030678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 12/21/2022] [Accepted: 12/28/2022] [Indexed: 02/26/2023] Open
Abstract
Targeted monoclonal antibody therapy against Epidermal Growth Factor Receptor (EGFR) is a leading treatment modality against metastatic colorectal cancer (mCRC). However, with the emergence of KRAS and BRAF mutations, resistance was inevitable. Cells harboring these mutations overexpress Glucose Transporter 1 (GLUT1) and sodium-dependent vitamin C transporter 2 (SVCT2), which enables intracellular vitamin C transport, leading to reactive oxygen species generation and finally cell death. Therefore, high dose vitamin C is proposed to overcome this resistance. A comprehensive search strategy was adopted using Pubmed and MEDLINE databases (up to 11 August 2022). There are not enough randomized clinical trials to support its use in the clinical management of mCRC, except for a subgroup analysis from a phase III study. High dose vitamin C shows a promising role in overcoming EGFR resistance in mCRC with wild KRAS mutation with resistance to anti-epidermal growth factor inhibitors and in patients with KRAS and BRAF mutations.
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19
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Wen YF, Culhane-Pera KA, Pergament SL, Moua Y, Vue B, Yang T, Lo M, Sun B, Knights D, Straka RJ. Hmong microbiome ANd Gout, Obesity, Vitamin C (HMANGO-C): A phase II clinical study protocol. PLoS One 2023; 18:e0279830. [PMID: 36724193 PMCID: PMC9891498 DOI: 10.1371/journal.pone.0279830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 11/29/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Hmong men in Minnesota exhibit a high prevalence of gout and hyperuricemia. Although evidence of vitamin C's effectiveness as a treatment for gout is mixed, analysis of therapeutic benefit based on an individual's multiomic signature may identify predictive markers of treatment success. OBJECTIVES The primary objective of the Hmong Microbiome ANd Gout, Obesity, Vitamin C (HMANGO-C) study was to assess the effectiveness of vitamin C on serum urate in Hmong adults with and without gout/hyperuricemia. The secondary objectives were to assess if 1) vitamin C impacts the taxonomic and functional patterns of microbiota; 2) taxonomic and functional patterns of microbiota impact vitamin C's urate-lowering effects; 3) genetic variations impact vitamin C's urate-lowering effects; 4) differential microbial biomarkers exist for patients with or without gout; and 5) there is an association between obesity, gut microbiota and gout/hyperuricemia. METHODS This prospective open-labelled clinical trial was guided by community-based participatory research principles and conducted under research safety restrictions for SARS-CoV-2. We aimed to enroll a convenient sample of 180 Hmong adults (120 with gout/hyperuricemia and 60 without gout/hyperuricemia) who provided medical, demographic, dietary and anthropometric information. Participants took vitamin C 500mg twice daily for 8 weeks and provided pre-and post- samples of blood and urine for urate measurements as well as stool samples for gut microbiome. Salivary DNA was also collected for genetic markers relevant to uric acid disposition. EXPECTED RESULTS We expected to quantify the impact of vitamin C on serum urate in Hmong adults with and without gout/hyperuricemia. The outcome will enhance our understanding of how gut microbiome and genomic variants impact the urate-lowering of vitamin C and associations between obesity, gut microbiota and gout/hyperuricemia. Ultimately, findings may improve our understanding of the causes and potential interventions that could be used to address health disparities in the prevalence and management of gout in this underserved population. TRIAL REGISTRATION ClinicalTrials.gov NCT04938024 (first posted: 06/24/2021).
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Affiliation(s)
- Ya-Feng Wen
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Kathleen A. Culhane-Pera
- Minnesota Community Care, St. Paul, Minnesota, United States of America
- SoLaHmo Partnership for Health and Wellness, Community-University Health Care Center, Minneapolis, Minnesota, United States of America
| | - Shannon L. Pergament
- SoLaHmo Partnership for Health and Wellness, Community-University Health Care Center, Minneapolis, Minnesota, United States of America
| | - Yeng Moua
- SoLaHmo Partnership for Health and Wellness, Community-University Health Care Center, Minneapolis, Minnesota, United States of America
| | - Bai Vue
- SoLaHmo Partnership for Health and Wellness, Community-University Health Care Center, Minneapolis, Minnesota, United States of America
| | - Toua Yang
- SoLaHmo Partnership for Health and Wellness, Community-University Health Care Center, Minneapolis, Minnesota, United States of America
| | - Muaj Lo
- Minnesota Community Care, St. Paul, Minnesota, United States of America
| | - Boguang Sun
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Dan Knights
- Bioinformatics and Computational Biology Program, University of Minnesota, Minneapolis, Minnesota, United States of America
- Biotechnology Institute, University of Minnesota, Minneapolis, Minnesota, United States of America
- Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Robert J. Straka
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, United States of America
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20
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Brabson JP, Leesang T, Yap YS, Wang J, Lam MQ, Fang B, Dolgalev I, Barbieri DA, Strippoli V, Bañuelos CP, Mohammad S, Lyon P, Chaudhry S, Donich D, Swirski A, Roberts E, Diaz I, Karl D, Dos Santos HG, Shiekhattar R, Neel BG, Nimer SD, Verdun RE, Bilbao D, Figueroa ME, Cimmino L. Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia. Cell Rep 2023; 42:112027. [PMID: 36848231 PMCID: PMC9989506 DOI: 10.1016/j.celrep.2023.112027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 10/24/2022] [Accepted: 01/10/2023] [Indexed: 01/25/2023] Open
Abstract
TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.
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Affiliation(s)
- John P Brabson
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Tiffany Leesang
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Yoon Sing Yap
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Jingjing Wang
- Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Minh Q Lam
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Byron Fang
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Igor Dolgalev
- Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Daniela A Barbieri
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Victoria Strippoli
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Carolina P Bañuelos
- Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Sofia Mohammad
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Peter Lyon
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Sana Chaudhry
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Dane Donich
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Anna Swirski
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Evan Roberts
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Ivelisse Diaz
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Daniel Karl
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Helena Gomes Dos Santos
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Ramin Shiekhattar
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Benjamin G Neel
- Laura and Isaac Perlmutter Cancer Center and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Stephen D Nimer
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Ramiro E Verdun
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Daniel Bilbao
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Maria E Figueroa
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Luisa Cimmino
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
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21
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Burkard M, Niessner H, Leischner C, Piotrowsky A, Renner O, Marongiu L, Lauer UM, Busch C, Sinnberg T, Venturelli S. High-Dose Ascorbate in Combination with Anti-PD1 Checkpoint Inhibition as Treatment Option for Malignant Melanoma. Cells 2023; 12:254. [PMID: 36672190 PMCID: PMC9857291 DOI: 10.3390/cells12020254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/14/2022] [Accepted: 01/03/2023] [Indexed: 01/11/2023] Open
Abstract
Ascorbate acts as a prooxidant when administered parenterally at high supraphysiological doses, which results in the generation of hydrogen peroxide in dependence on oxygen. Most cancer cells are susceptible to the emerging reactive oxygen species (ROS). Accordingly, we evaluated high-dose ascorbate for the treatment of the B16F10 melanoma model. To investigate the effects of ascorbate on the B16F10 cell line in vitro, viability, cellular impedance, and ROS production were analyzed. In vivo, C57BL/6NCrl mice were subcutaneously injected into the right flank with B16F10 cells and tumor-bearing mice were treated intraperitoneally with ascorbate (3 g/kg bodyweight), immunotherapy (anti-programmed cell death protein 1 (PD1) antibody J43; 2 mg/kg bodyweight), or both treatments combined. The efficacy and toxicity were analyzed by measuring the respective tumor sizes and mouse weights accompanied by histological analysis of the protein levels of proliferating cell nuclear antigen (Pcna), glucose transporter 1 (Glut-1), and CD3. Treatment of B16F10 melanoma-carrying mice with high-dose ascorbate yielded plasma levels in the pharmacologically effective range, and ascorbate showed efficacy as a monotherapy and when combined with PD1 inhibition. Our data suggest the applicability of ascorbate as an additional therapeutic agent that can be safely combined with immunotherapy and has the potential to potentiate anti-PD1-based immune checkpoint blockades.
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Affiliation(s)
- Markus Burkard
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Heike Niessner
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
- Division of Dermatooncology, Department of Dermatology, University of Tuebingen, Liebermeisterstraße 25, 72076 Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, 72076 Tuebingen, Germany
| | - Christian Leischner
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Alban Piotrowsky
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Olga Renner
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
| | - Luigi Marongiu
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
- Department of Internal Medicine VIII, University Hospital Tuebingen, Otfried-Mueller-Straße 10, 72076 Tuebingen, Germany
| | - Ulrich M. Lauer
- Department of Internal Medicine VIII, University Hospital Tuebingen, Otfried-Mueller-Straße 10, 72076 Tuebingen, Germany
| | - Christian Busch
- Dermatologie zum Delfin, Stadthausstraße 12, 8400 Winterthur, Switzerland
| | - Tobias Sinnberg
- Division of Dermatooncology, Department of Dermatology, University of Tuebingen, Liebermeisterstraße 25, 72076 Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, 72076 Tuebingen, Germany
- Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Sascha Venturelli
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
- Department of Vegetative and Clinical Physiology, Institute of Physiology, University of Tuebingen, Wilhelmstraße 56, 72074 Tuebingen, Germany
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22
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Damuka N, Bashetti N, Mintz A, Bansode AH, Miller M, Krizan I, Furdui C, Bhoopal B, Gollapelli KK, Shanmukha Kumar JV, Deep G, Dugan G, Cline M, Solingapuram Sai KK. [ 18F]KS1, a novel ascorbate-based ligand images ROS in tumor models of rodents and nonhuman primates. Biomed Pharmacother 2022; 156:113937. [PMID: 36411624 PMCID: PMC11017304 DOI: 10.1016/j.biopha.2022.113937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 11/20/2022] Open
Abstract
Over production of reactive oxygen species (ROS) caused by altered redox regulation of signaling pathways is common in many types of cancers. While PET imaging is recognized as the standard tool for cancer imaging, there are no clinically-approved PET radiotracers for ROS-imaging in cancer diagnosis and treatment. An ascorbate-based radio ligand promises to meet this urgent need. Our laboratory recently synthesized [18F] KS1, a fluoroethoxy furanose ring-containing ascorbate derivative, to track ROS in prostate tumor-bearing mice. Here we report cell uptake assays of [18F]KS1 with different ROS-regulating agents, PET imaging in head and neck squamous cell carcinoma (HNSCC) mice, and doxorubicin-induced rats; PET imaging in healthy and irradiated hepatic tumor-bearing rhesus to demonstrate its translational potential. Our preliminary evaluations demonstrated that KS1 do not generate ROS in tumor cells at tracer-level concentrations and tumor-killing properties at pharmacologic doses. [18F]KS1 uptake was low in HNSCC pretreated with ROS blockers, and high with ROS inducers. Tumors in high ROS-expressing SCC-61 took up significantly more [18F]KS1 than rSCC-61 (low-ROS expressing HNSCC); high uptake in doxorubicin-treated rats compared to saline-treated controls. Rodent biodistribution and PET imaging of [18F]KS1 in healthy rhesus monkeys demonstrated its favorable safety, pharmacokinetic properties with excellent washout profile, within 3.0 h of radiotracer administration. High uptake of [18F]KS1 in liver tumor tissues of the irradiated hepatic tumor-bearing monkey showed target selectivity. Our strong data in vitro, in vivo, and ex vivo here supports the high translational utility of [18F]KS1 to image ROS.
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Affiliation(s)
- Naresh Damuka
- Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Nagaraju Bashetti
- Department of Chemistry, Koneru Lakshmaiah Education Foundation, Andhra Pradesh, India
| | - Akiva Mintz
- Department of Radiology, Columbia University, New York, NY, United States
| | - Avinash H Bansode
- Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Mack Miller
- Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Ivan Krizan
- Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Cristina Furdui
- Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Bhuvanachandra Bhoopal
- Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | | | - J V Shanmukha Kumar
- Department of Chemistry, Koneru Lakshmaiah Education Foundation, Andhra Pradesh, India
| | - Gagan Deep
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Greg Dugan
- Department of Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Mark Cline
- Department of Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
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23
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Mohseni S, Tabatabaei-Malazy O, Ejtahed HS, Qorbani M, Azadbakht L, Khashayar P, Larijani B. Effect of vitamins C and E on cancer survival; a systematic review. Daru 2022; 30:427-441. [PMID: 36136247 PMCID: PMC9715902 DOI: 10.1007/s40199-022-00451-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 09/16/2022] [Indexed: 10/14/2022] Open
Abstract
PURPOSE Association between vitamins C (VC)/ E (VE) and cancer survival is inconsistent. This systematic review is aimed to summarize trials for effects of VC/VE on cancer survival. METHODS Relevant English trials were retrieved from PubMed, Cochrane Library, Embase, Web of Science, Scopus databases, and Clinicaltrials.gov through 21/June/2022. Inclusion criteria were all trials which assessed sole/combinations intake of VC/VE on survival rate, mortality, or remission of any cancer. Exclusion criteria were observational and animal studies. RESULTS We reached 30 trials conducted on 38,936 patients with various cancers. Due to severe methodological heterogeneity, meta-analysis was impossible. High dose VC + chemotherapy or radiation was safe with an overall survival (OS) 182 days - 21.5 months. Sole oral or intravenous high dose VC was safe with non-significant change in OS (2.9-8.2 months). VE plus chemotherapy was safe, resulted in stabling diseases for 5 years in 70- 86.7% of patients and OS 109 months. It was found 60% and 16% non-significant reductions in adjusted hazard ratio (HR) deaths or recurrence by 200 mg/d tocotrienol + tamoxifen in breast cancer, respectively. Sole intake of 200-3200 mg/d tocotrienol before resectable pancreatic cancer was safe and significantly increased cancer cells' apoptosis. Combination VC and VE was non-significantly reduced 7% in rate of neoplastic gastric polyp. CONCLUSION Although our study is supported improvement of survival and progression rates of cancers by VC/VE, more high quality trials with large sample sizes are required to confirm. PROSPERO REGISTRATION NUMBER CRD42020152795.
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Affiliation(s)
- Shahrzad Mohseni
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ozra Tabatabaei-Malazy
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanieh-Sadat Ejtahed
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mostafa Qorbani
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Leila Azadbakht
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Patricia Khashayar
- Center for microsystem technology, Imec and Ghent University, 9052 Gent, Zwijnaarde, Belgium
- Osteoporosis Research Center, Endocrinology & Metabolism Clinical Science Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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24
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Wang F, He MM, Xiao J, Zhang YQ, Yuan XL, Fang WJ, Zhang Y, Wang W, Hu XH, Ma ZG, Yao YC, Zhuang ZX, Zhou FX, Ying JE, Yuan Y, Zou QF, Guo ZQ, Wu XY, Jin Y, Mai ZJ, Wang ZQ, Qiu H, Guo Y, Shi SM, Chen SZ, Luo HY, Zhang DS, Wang FH, Li YH, Xu RH. A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study). Clin Cancer Res 2022; 28:4232-4239. [PMID: 35929990 PMCID: PMC9527503 DOI: 10.1158/1078-0432.ccr-22-0655] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/14/2022] [Accepted: 08/02/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription. RESULTS The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only. CONCLUSIONS High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.
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Affiliation(s)
- Feng Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
- Corresponding Authors: Rui-Hua Xu, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China. Phone: 86-20-8734-3468; E-mail: ; and Feng-Hua Wang,
| | - Ming-Ming He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
| | - Jian Xiao
- The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Yan-Qiao Zhang
- Harbin Medical University Cancer Hospital, Harbin, P.R. China
| | - Xiang-Lin Yuan
- Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Wei-Jia Fang
- The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P.R. China
| | - Yan Zhang
- The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Wei Wang
- The First People's Hospital of Foshan, Foshan, P.R. China
| | - Xiao-Hua Hu
- The First Affiliated Hospital of Guangxi Medical University, Nanning, P.R. China
| | - Zhi-Gang Ma
- Harbin Medical University Cancer Hospital, Harbin, P.R. China
| | - Yi-Chen Yao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
| | - Zhi-Xiang Zhuang
- The Second Affiliated Hospital of Soochow University, Soochow, P.R. China
| | - Fu-Xiang Zhou
- Zhongnan Hospital of Wuhan University, Hubei Clinical Cancer Study Center, Wuhan, P.R. China
| | - Jie-Er Ying
- Zhejiang Cancer Hospital, Hangzhou, P.R. China
| | - Ying Yuan
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P.R. China
| | - Qing-Feng Zou
- Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou, P.R. China
| | - Zeng-Qing Guo
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, P.R. China
| | - Xiang-Yuan Wu
- The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Ying Jin
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
| | - Zong-Jiong Mai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
| | - Zhi-Qiang Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
| | - Hong Qiu
- Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Ying Guo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Si-Mei Shi
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
| | - Shuang-Zhen Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
| | - Hui-Yan Luo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
| | - Dong-Sheng Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
| | - Feng-Hua Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
| | - Yu-Hong Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
| | - Rui-Hua Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P.R. China
- Corresponding Authors: Rui-Hua Xu, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China. Phone: 86-20-8734-3468; E-mail: ; and Feng-Hua Wang,
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Maekawa T, Miyake T, Tani M, Uemoto S. Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment. Front Oncol 2022; 12:981547. [PMID: 36203466 PMCID: PMC9531273 DOI: 10.3389/fonc.2022.981547] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/25/2022] [Indexed: 11/13/2022] Open
Abstract
Ascorbic acid has attracted substantial attention for its potential antitumor effects by acting as an antioxidant in vivo and as a cofactor in diverse enzymatic reactions. However, solid proof of its clinical efficacy against cancer and the mechanism behind its effect have not been established. Moreover, cancer forms cancer-specific microenvironments and interacts with various cells, such as cancer-associated fibroblasts (CAFs), to maintain cancer growth and progression; however, the effect of ascorbic acid on the cancer microenvironment is unclear. This review discusses the effects and mechanisms of ascorbic acid on cancer, including the role of ascorbic acid concentration. In addition, we present future perspectives on the effects of ascorbic acid on cancer cells and the CAF microenvironment. Ascorbic acid has a variety of effects, which contributes to the complexity of these effects. Oral administration of ascorbic acid results in low blood concentrations (<0.2 mM) and acts as a cofactor for antioxidant effects, collagen secretion, and HIFα degradation. In contrast, intravenous treatment achieves large blood concentrations (>1 mM) and has oxidative-promoting actions that exert anticancer effects via reactive oxygen species. Therefore, intravenous administration at high concentrations is required to achieve the desired effects on cancer cells during treatment. Partial data on the effect of ascorbic acid on fibroblasts indicate that it may also modulate collagen secretion in CAFs and impart tumor-suppressive effects. Thus, future studies should verify the effect of ascorbic acid on CAFs. The findings of this review can be used to guide further research and clinical trials.
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Affiliation(s)
- Takeru Maekawa
- Division of Gastrointestinal, Breast, Pediatric, and General Surgery, Department of Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Toru Miyake
- Division of Gastrointestinal, Breast, Pediatric, and General Surgery, Department of Surgery, Shiga University of Medical Science, Otsu, Japan
- *Correspondence: Toru Miyake,
| | - Masaji Tani
- Division of Gastrointestinal, Breast, Pediatric, and General Surgery, Department of Surgery, Shiga University of Medical Science, Otsu, Japan
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Izzo R, Trimarco V, Mone P, Aloè T, Capra Marzani M, Diana A, Fazio G, Mallardo M, Maniscalco M, Marazzi G, Messina N, Mininni S, Mussi C, Pelaia G, Pennisi A, Santus P, Scarpelli F, Tursi F, Zanforlin A, Santulli G, Trimarco B. Combining L-Arginine with vitamin C improves long-COVID symptoms: The LINCOLN Survey. Pharmacol Res 2022; 183:106360. [PMID: 35868478 PMCID: PMC9295384 DOI: 10.1016/j.phrs.2022.106360] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms. METHODS We designed a survey (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), assessing several symptoms that have been associated with Long-COVID to be administered nationwide to COVID-19 survivors; the survey also included effort perception, measured using the Borg scale. Patients receiving the survey were divided in two groups, with a 2:1 ratio: the first group included patients that received L-Arginine + Vitamin C, whereas the second group received a multivitamin combination (alternative treatment). RESULTS 1390 patients successfully completed the survey. Following a 30-day treatment in both groups, the survey revealed that patients in the L-Arginine + Vitamin C treatment arm had significantly lower scores compared to patients who had received the multivitamin combination. There were no other significant differences between the two groups. When examining effort perception, we observed a significantly lower value (p < 0.0001) in patients receiving L-Arginine + Vitamin C compared to the alternative-treatment arm. CONCLUSIONS Our survey indicates that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of attenuating its typical symptoms and improving effort perception.
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Affiliation(s)
- Raffaele Izzo
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Valentina Trimarco
- Department of Neuroscience, Reproductive Sciences and Dentistry, Federico II University, Naples, Italy
| | - Pasquale Mone
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
| | | | | | | | | | | | | | | | | | - Simone Mininni
- Associazione Scientifica Interdisciplinare Aggiornamento Medico (ASIAM), Florence, Italy
| | - Chiara Mussi
- Department of Biomedical and Metabolic Sciences and Neuroscience, University of Modena and Reggio Emilia, Modena, Italy
| | - Girolamo Pelaia
- Department of Health Science, Magna Graecia University, Catanzaro, Italy
| | | | | | | | | | | | - Gaetano Santulli
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy; Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA.
| | - Bruno Trimarco
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
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27
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Metabolic targeting of malignant tumors: a need for systemic approach. J Cancer Res Clin Oncol 2022; 149:2115-2138. [PMID: 35925428 DOI: 10.1007/s00432-022-04212-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/14/2022] [Indexed: 12/09/2022]
Abstract
PURPOSE Dysregulated metabolism is now recognized as a fundamental hallmark of carcinogenesis inducing aggressive features and additional hallmarks. In this review, well-established metabolic changes displayed by tumors are highlighted in a comprehensive manner and corresponding therapeutical targets are discussed to set up a framework for integrating basic research findings with clinical translation in oncology setting. METHODS Recent manuscripts of high research impact and relevant to the field from PubMed (2000-2021) have been reviewed for this article. RESULTS Metabolic pathway disruption during tumor evolution is a dynamic process potentiating cell survival, dormancy, proliferation and invasion even under dismal conditions. Apart from cancer cells, though, tumor microenvironment has an acting role as extracellular metabolites, pH alterations and stromal cells reciprocally interact with malignant cells, ultimately dictating tumor-promoting responses, disabling anti-tumor immunity and promoting resistance to treatments. CONCLUSION In the field of cancer metabolism, there are several emerging prognostic and therapeutic targets either in the form of gene expression, enzyme activity or metabolites which could be exploited for clinical purposes; both standard-of-care and novel treatments may be evaluated in the context of metabolism rewiring and indeed, synergistic effects between metabolism-targeting and other therapies would be an attractive perspective for further research.
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28
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Chen P, Reed G, Jiang J, Wang Y, Sunega J, Dong R, Ma Y, Esparham A, Ferrell R, Levine M, Drisko J, Chen Q. Pharmacokinetic Evaluation of Intravenous Vitamin C: A Classic Pharmacokinetic Study. Clin Pharmacokinet 2022; 61:1237-1249. [PMID: 35750958 PMCID: PMC9439974 DOI: 10.1007/s40262-022-01142-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2022] [Indexed: 02/03/2023]
Abstract
PURPOSE Intravenous vitamin C (IVC) is used in a variety of disorders with limited supporting pharmacokinetic data. Herein we report a pharmacokinetic study in healthy volunteers and cancer participants with IVC doses in the range of 1-100 g. METHODS A pharmacokinetic study was conducted in 21 healthy volunteers and 12 oncology participants. Healthy participants received IVC infusions of 1-100 g; oncology participants received IVC infusions of 25-100 g. Serial blood and complete urine samples were collected pre-infusion and for 24 h post-infusion. Pharmacokinetic parameters were computed using noncompartmental methods. Adverse events were monitored during the study. RESULTS In both cohorts, IVC exhibited first-order kinetics at doses up to 75 g. At 100 g, maximum concentration (Cmax) plateaued in both groups, whereas area under the concentration-time curve (AUC) only plateaued in the healthy group. IVC was primarily excreted through urine. No saturation of clearance was observed; however, the mean 24-h total IVC excretion in urine for all doses was lower in oncology participants (89% of dose) than in healthy participants at 100 g (99%). No significant adverse events were observed; thus, maximum tolerated dose (MTD) was not reached. CONCLUSION IVC followed first-order pharmacokinetics up to 75 g and at up to 100 g had complete renal clearance in 24 h. IVC up to 100 g elicited no adverse effects or significant physiological/biochemical changes and appears to be safe. These data can be used to rectify existing misinformation and to guide future clinical trials. REGISTRATION ClinicalTrials.gov identifier number NCT01833351.
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Affiliation(s)
- Ping Chen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Greg Reed
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Joyce Jiang
- Division of Epidemiology, Biostatistics, and Environmental Health School of Public Health, University of Memphis, Memphis, TN, USA
| | - Yaohui Wang
- Molecular and Clinical Nutrition Section, Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD, USA
| | - Jean Sunega
- Department of Rehabilitation Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Ruochen Dong
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Yan Ma
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Anna Esparham
- Division of Neurology, Children's Mercy Hospital, Kansas City, MO, USA
| | - Ryan Ferrell
- Department or Cardiovascular Medicine, University of Kansas Health System, Kansas City, KS, USA
| | - Mark Levine
- Molecular and Clinical Nutrition Section, Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD, USA
| | - Jeanne Drisko
- Department of Internal Medicine, Integrative Medicine Research, University of Kansas Medical Center, Kansas City, KS, USA.
| | - Qi Chen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
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Ascorbate as a Bioactive Compound in Cancer Therapy: The Old Classic Strikes Back. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123818. [PMID: 35744943 PMCID: PMC9229419 DOI: 10.3390/molecules27123818] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/01/2022] [Accepted: 06/08/2022] [Indexed: 11/17/2022]
Abstract
Cancer is a disease of high mortality, and its prevalence has increased steadily in the last few years. However, during the last decade, the development of modern chemotherapy schemes, new radiotherapy techniques, targeted therapies and immunotherapy has brought new hope in the treatment of these diseases. Unfortunately, cancer therapies are also associated with frequent and, sometimes, severe adverse events. Ascorbate (ascorbic acid or vitamin C) is a potent water-soluble antioxidant that is produced in most mammals but is not synthesised endogenously in humans, which lack enzymes for its synthesis. Ascorbate has antioxidant effects that correspond closely to the dose administered. Interestingly, this natural antioxidant induces oxidative stress when given intravenously at a high dose, a paradoxical effect due to its interactions with iron. Importantly, this deleterious property of ascorbate can result in increased cell death. Although, historically, ascorbate has been reported to exhibit anti-tumour properties, this effect has been questioned due to the lack of available mechanistic detail. Recently, new evidence has emerged implicating ferroptosis in several types of oxidative stress-mediated cell death, such as those associated with ischemia–reperfusion. This effect could be positively modulated by the interaction of iron and high ascorbate dosing, particularly in cell systems having a high mitotic index. In addition, it has been reported that ascorbate may behave as an adjuvant of favourable anti-tumour effects in cancer therapies such as radiotherapy, radio-chemotherapy, chemotherapy, immunotherapy, or even in monotherapy, as it facilitates tumour cell death through the generation of reactive oxygen species and ferroptosis. In this review, we provide evidence supporting the view that ascorbate should be revisited to develop novel, safe strategies in the treatment of cancer to achieve their application in human medicine.
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Di Tano M, Longo VD. Fasting and cancer: from yeast to mammals. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 373:81-106. [PMID: 36283768 DOI: 10.1016/bs.ircmb.2022.02.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Fasting and fasting mimicking diets extend lifespan and healthspan in mouse models and decrease risk factors for cancer and other age-related pathologies in humans. Normal cells respond to fasting and the consequent decrease in nutrients by down-regulating proto-oncogene pathways to enter a stress-resistant mode, which protects them from different cancer therapies. In contrast, oncogene mutations and the constitutive activation of pathways including RAS, AKT, and PKA allow cancer cells to disobey fasting-dependent anti-growth signal. Importantly, in different tumor types, fasting potentiates the toxicity of various therapies by increasing reactive oxygen species and oxidative stress, which ultimately leads to DNA damage and cell death. This effect is not limited to chemotherapy, since periodic fasting/FMD cycles potentiate the effects of tyrosine kinase inhibitors, hormone therapy, radiotherapy, and pharmacological doses of vitamin C. In addition, the anticancer effects of fasting/FMD can also be tumor-independent and involve an immunotherapy-like activation of T cell-dependent attack of tumor cells. Supported by a range of pre-clinical studies, clinical trials are beginning to confirm the safety and efficacy of fasting/FMD cycles in improving the potential of different cancer therapies, while decreasing side effects to healthy cells and tissues.
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Affiliation(s)
- Maira Di Tano
- IFOM, FIRC Institute of Molecular Oncology, Milan, Italy
| | - Valter D Longo
- IFOM, FIRC Institute of Molecular Oncology, Milan, Italy; Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA, United States.
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Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14112608. [PMID: 35681589 PMCID: PMC9179307 DOI: 10.3390/cancers14112608] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/21/2022] [Accepted: 05/23/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The tumor microenvironment (TME) is a complicated network, and several promising TME-targeted therapies, such as immunotherapy and targeted therapies, are now facing problems over low response rates and drug resistance. Vitamin C (VitC) has been extensively studied as a dietary nutrient and multi-targeted natural drug for fighting against tumor cells. The focus has been recently on its crucial functions in the TME. Here, we discuss the potential mechanisms of VitC in several specialized microenvironments, characterize the current status of its preclinical and clinical applications, and offer suggestions for future studies. This article is intended to provide basic researchers and clinicians with a detailed picture of VitC targeting the tumor microenvironment. Abstract Based on the enhanced knowledge on the tumor microenvironment (TME), a more comprehensive treatment landscape for targeting the TME has emerged. This microenvironment provides multiple therapeutic targets due to its diverse characteristics, leading to numerous TME-targeted strategies. With multifaced activities targeting tumors and the TME, vitamin C is renown as a promising candidate for combination therapy. In this review, we present new advances in how vitamin C reshapes the TME in the immune, hypoxic, metabolic, acidic, neurological, mechanical, and microbial dimensions. These findings will open new possibilities for multiple therapeutic avenues in the fight against cancer. We also review the available preclinical and clinical evidence of vitamin C combined with established therapies, highlighting vitamin C as an adjuvant that can be exploited for novel therapeutics. Finally, we discuss unresolved questions and directions that merit further investigation.
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Hunyady J. The Result of Vitamin C Treatment of Patients with Cancer: Conditions Influencing the Effectiveness. Int J Mol Sci 2022; 23:ijms23084380. [PMID: 35457200 PMCID: PMC9030840 DOI: 10.3390/ijms23084380] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 04/08/2022] [Accepted: 04/10/2022] [Indexed: 11/16/2022] Open
Abstract
Vitamin C (ascorbic acid, AA) is a weak sugar acid structurally related to glucose. All known physiological and biochemical functions of AA are due to its action as an electron donor. Ascorbate readily undergoes pH-dependent autoxidation creating hydrogen peroxide (H2O2). In vitro evidence suggests that vitamin C functions at low concentrations as an antioxidant while high concentration is pro-oxidant. Thus, both characters of AA might be translated into clinical benefits. In vitro obtained results and murine experiments consequently prove the cytotoxic effect of AA on cancer cells, but current clinical evidence for high-dose intravenous (i.v.) vitamin C's therapeutic effect is ambiguous. The difference might be caused by the missing knowledge of AA's actions. In the literature, there are many publications regarding vitamin C and cancer. Review papers of systematic analysis of human interventional and observational studies assessing i.v. AA for cancer patients' use helps the overview of the extensive literature. Based on the results of four review articles and the Cancer Information Summary of the National Cancer Institute's results, we analyzed 20 publications related to high-dose intravenous vitamin C therapy (HAAT). The analyzed results indicate that HAAT might be a useful cancer-treating tool in certain circumstances. The AA's cytotoxic effect is hypoxia-induced factor dependent. It impacts only the anoxic cells, using the Warburg metabolism. It prevents tumor growth. Accordingly, discontinuation of treatment leads to repeated expansion of the tumor. We believe that the clinical use of HAAT in cancer treatment should be reassessed. The accumulation of more study results on HAAT is desperately needed.
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Affiliation(s)
- János Hunyady
- Department of Dermatology, Medical Faculty, University of Debrecen, 4032 Debrecen, Hungary
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33
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Role of Vitamin C in Selected Malignant Neoplasms in Women. Nutrients 2022; 14:nu14040882. [PMID: 35215535 PMCID: PMC8876016 DOI: 10.3390/nu14040882] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/12/2022] [Accepted: 02/17/2022] [Indexed: 12/14/2022] Open
Abstract
Since the first reports describing the anti-cancer properties of vitamin C published several decades ago, its actual effectiveness in fighting cancer has been under investigation and widely discussed. Some scientific reports indicate that vitamin C in high concentrations can contribute to effective and selective destruction of cancer cells. Furthermore, preclinical and clinical studies have shown that relatively high doses of vitamin C administered intravenously in ‘pharmacological concentrations’ may not only be well-tolerated, but significantly improve patients’ quality of life. This seems to be particularly important, especially for terminal cancer patients. However, the relatively high frequency of vitamin C use by cancer patients means that the potential clinical benefits may not be obvious. For this reason, in this review article, we focus on the articles published mainly in the last two decades, describing possible beneficial effects of vitamin C in preventing and treating selected malignant neoplasms in women, including breast, cervical, endometrial, and ovarian cancer. According to the reviewed studies, vitamin C use may contribute to an improvement of the overall quality of life of patients, among others, by reducing chemotherapy-related side effects. Nevertheless, new clinical trials are needed to collect stronger evidence of the role of this nutrient in supportive cancer treatment.
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Bedhiafi T, Inchakalody VP, Fernandes Q, Mestiri S, Billa N, Uddin S, Merhi M, Dermime S. The potential role of vitamin C in empowering cancer immunotherapy. Biomed Pharmacother 2022; 146:112553. [PMID: 34923342 DOI: 10.1016/j.biopha.2021.112553] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 12/01/2021] [Accepted: 12/13/2021] [Indexed: 12/12/2022] Open
Abstract
Vitamin C also known as L-ascorbic acid is a nutrient naturally occurring in many fruits and vegetables and widely known for its potent antioxidant activity. Several studies have highlighted the importance of using high dose vitamin C as an adjuvant anti-cancer therapy. Interestingly, it has been shown that vitamin C is able to modulate the anti-cancer immune response and to help to overcome the resistance to immune checkpoints blockade (ICB) drugs such as cytotoxic T-lymphocyte antigen 4 (CLTA-4) and programmed cell death ligand 1 (PD-L1/PD-1) inhibitors. Indeed, it was reported that vitamin C regulates several mechanisms developed by cancer cells to escape T cells immune response and resist ICB. Understanding the role of vitamin C in the anti-tumor immune response will pave the way to the development of novel combination therapies that would enhance the response of cancer patients to ICB immunotherapy. In this review, we discuss the effect of vitamin C on the immune system and its potential role in empowering cancer immunotherapy through its pro-oxidant potential, its ability to modulate epigenetic factors and its capacity to regulate the expression of different cytokines involved in the immune response.
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Affiliation(s)
- Takwa Bedhiafi
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Varghese Philipose Inchakalody
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Queenie Fernandes
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; College of Medicine, Qatar University, Doha, Qatar
| | - Sarra Mestiri
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | | | - Shahab Uddin
- Translational Research Institute and dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha 2713, Qatar
| | - Maysaloun Merhi
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.
| | - Said Dermime
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
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35
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Vitamin C and cancer risk and treatment. POSTEP HIG MED DOSW 2022. [DOI: 10.2478/ahem-2021-0031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Vitamin C (L-ascorbic acid) works as a strong reductant, radical scavenger, and protector of cell membranes against primary peroxidative damage in tissues and in the extracellular fluid. L-ascorbic acid is involved in the synthesis of collagen and many other biologically relevant substances, enzyme activity, xenobiotic detoxification, and prevention of forming carcinogenic nitrosamines. It also plays a role in the immune system. Numerous data indicate that cancer patients suffer from vitamin C deficiency. Studies show that people with a low vitamin C intake have an increased risk of head and neck cancers as well as lung, gastric, pancreatic, cervical, rectal, or breast cancer. On the other hand, there is no clinical evidence to support the thesis that antioxidant supplements (including vitamin C) prevent cancer. Observational trials investigating high doses of intravenous L-ascorbic acid in previously treated cancer patients have shown that it allows an increase in quality of life and may improve physical, mental, and emotional functions, as well as reducing adverse effects of standard anticancer treatment, including fatigue, nausea, vomiting, and appetite loss. So far, there were a few randomized controlled trials and they have not reported any statistically significant improvements in the overall or progression-free survival with vitamin C, as compared to the control arm. However, preclinical data indicating a role of L-ascorbic acid in modulation of immune response and its involvement in epigenome remodeling suggest its new potential clinical applications in cancer patients, especially in combination with immunotherapy. It seems reasonable to further investigate the value of vitamin C as a supportive treatment or in combination with anticancer targeted therapy.
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36
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Nandhini N, Malviya D, Parashar S, Pandey C, Nath SS, Tripathi M. Comparison of the effects of vitamin C and thiamine on refractory hypotension in patients with sepsis: A randomized controlled trial. Int J Crit Illn Inj Sci 2022; 12:138-145. [PMID: 36506923 PMCID: PMC9728072 DOI: 10.4103/ijciis.ijciis_107_21] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/28/2022] [Accepted: 02/02/2022] [Indexed: 12/15/2022] Open
Abstract
Background The study aimed to compare the effect of thiamine and ascorbic acid (AA) on mortality, sequential organ failure assessment (SOFA) score, duration and dose of vasopressor support, and need for renal replacement therapy (RRT) in patients with septic shock with refractory hypotension. Methods Consenting adult patients with septic shock and refractory hypotension were included in this study. Patients were divided into three groups: Group A received 100 ml of balanced salt solution 8 hourly, Group B received 2 mg/kg of thiamine 8 hourly, Group C received 25 mg/kg of AA 8 hourly intravenous (IV) for 72 h. All patients received IV infusion of hydrocortisone 200 mg/day for 72 h. Serum lactate, dose and duration of vasopressor support, SOFA score, need for RRT and hospital mortality were analyzed. Results The SOFA Score was significantly lower in Group B than in Group A and C at 24, 48, and 72 h. Dosage of norepinephrine was lower in Group B at 66 h and after that, whereas in Groups A and C, it was comparable at all time points. Mortality in Group B was significantly lower but comparable in Groups A and C. The need for RRT was significantly lower in Group B (44%) compared to the control group (88%) but comparable in Group C (76%). Conclusion In patients with septic shock treated with hydrocortisone, co-treatment with thiamine led to earlier correction of organ dysfunction, reduced need for RRT, and improved mortality compared to patients treated with AA or balanced salt solution. The addition of AA did not yield measurable benefits beyond hydrocortisone alone.
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Affiliation(s)
- N Nandhini
- Department of Anesthesiology and Critical Care Medicine, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Deepak Malviya
- Department of Anesthesiology and Critical Care Medicine, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Samiksha Parashar
- Department of Anesthesiology and Critical Care Medicine, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Chandrakant Pandey
- Department of Anesthesiology, Medanta Hospital, Lucknow, Uttar Pradesh, India
| | - Soumya Sankar Nath
- Department of Anesthesiology and Critical Care Medicine, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India,Address for correspondence: Dr. Soumya Sankar Nath, Department of Anaesthesiology and Critical Care Medicine, Dr. Ram Manohar Lohia Institute of Medical Sciences, Vibhuti Khand, Lucknow - 226 010, Uttar Pradesh, India. E-mail:
| | - Manoj Tripathi
- Department of Anesthesiology and Critical Care Medicine, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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Gao L, Chong E, Pendharkar S, Phillips A, Ke L, Li W, Windsor JA. The Challenges and Effects of Ascorbic Acid Treatment of Acute Pancreatitis: A Systematic Review and Meta-Analysis of Preclinical and Clinical Studies. Front Nutr 2021; 8:734558. [PMID: 34765629 PMCID: PMC8576576 DOI: 10.3389/fnut.2021.734558] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/22/2021] [Indexed: 12/22/2022] Open
Abstract
Background: Oxidative stress has been implicated in the pathogenesis of acute pancreatitis (AP), and ascorbic acid (AA), as an important endogenous antioxidant substance, has been shown to reduce AP severity in preclinical studies. However, the effects of AA supplementation in clinical settings remain controversial. Methods: PubMed, EMBASE, MEDLINE, and SCOPUS databases were searched, and both preclinical and clinical studies were included. For clinical trials, the primary outcome was incidence of organ failure, and for preclinical studies, the primary outcome was histopathological scores of pancreatic injuries. Results: Meta-analysis of clinical trials showed that compared with controls, AA administration did not reduce the incidence of organ failure or mortality during hospitalization but was associated with significantly reduced length of hospital stay. Meta-analysis of preclinical studies showed that AA supplementation reduced pancreatic injury, demonstrated as decreased histological scores and serum amylase, lipase levels. Conclusion: AA administration has no effect on survival or organ failure in patients with AP but may reduce the length of hospital stay. However, the evidence to date remains sparse, scattered, and of suboptimal quality, making it difficult to draw any firm conclusion on the clinical benefits of AA in AP.
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Affiliation(s)
- Lin Gao
- Department of Critical Care Medicine, Center of Severe Acute Pancreatitis (CSAP), Jinling Hospital, Medical School of Nanjing University, Nanjing, China.,Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Eric Chong
- Faculty of Medical and Health Sciences, Surgical and Translational Research Centre, School of Medicine, University of Auckland, Auckland, New Zealand
| | - Sayali Pendharkar
- Faculty of Medical and Health Sciences, Surgical and Translational Research Centre, School of Medicine, University of Auckland, Auckland, New Zealand
| | - Anthony Phillips
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand.,Faculty of Medical and Health Sciences, Surgical and Translational Research Centre, School of Medicine, University of Auckland, Auckland, New Zealand
| | - Lu Ke
- Department of Critical Care Medicine, Center of Severe Acute Pancreatitis (CSAP), Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Weiqin Li
- Department of Critical Care Medicine, Center of Severe Acute Pancreatitis (CSAP), Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - John Albert Windsor
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand.,Faculty of Medical and Health Sciences, Surgical and Translational Research Centre, School of Medicine, University of Auckland, Auckland, New Zealand
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38
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Böttger F, Vallés-Martí A, Cahn L, Jimenez CR. High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:343. [PMID: 34717701 PMCID: PMC8557029 DOI: 10.1186/s13046-021-02134-y] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/07/2021] [Indexed: 12/21/2022]
Abstract
Mounting evidence indicates that vitamin C has the potential to be a potent anti-cancer agent when administered intravenously and in high doses (high-dose IVC). Early phase clinical trials have confirmed safety and indicated efficacy of IVC in eradicating tumour cells of various cancer types. In recent years, the multi-targeting effects of vitamin C were unravelled, demonstrating a role as cancer-specific, pro-oxidative cytotoxic agent, anti-cancer epigenetic regulator and immune modulator, reversing epithelial-to-mesenchymal transition, inhibiting hypoxia and oncogenic kinase signalling and boosting immune response. Moreover, high-dose IVC is powerful as an adjuvant treatment for cancer, acting synergistically with many standard (chemo-) therapies, as well as a method for mitigating the toxic side-effects of chemotherapy. Despite the rationale and ample evidence, strong clinical data and phase III studies are lacking. Therefore, there is a need for more extensive awareness of the use of this highly promising, non-toxic cancer treatment in the clinical setting. In this review, we provide an elaborate overview of pre-clinical and clinical studies using high-dose IVC as anti-cancer agent, as well as a detailed evaluation of the main known molecular mechanisms involved. A special focus is put on global molecular profiling studies in this respect. In addition, an outlook on future implications of high-dose vitamin C in cancer treatment is presented and recommendations for further research are discussed.
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Affiliation(s)
- Franziska Böttger
- Department of Medical Oncology, Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam UMC, Location VU University Medical Center, 1081 HV, Amsterdam, the Netherlands
| | - Andrea Vallés-Martí
- Department of Medical Oncology, Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam UMC, Location VU University Medical Center, 1081 HV, Amsterdam, the Netherlands
| | - Loraine Cahn
- Department of Medical Oncology, Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam UMC, Location VU University Medical Center, 1081 HV, Amsterdam, the Netherlands
| | - Connie R Jimenez
- Department of Medical Oncology, Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam UMC, Location VU University Medical Center, 1081 HV, Amsterdam, the Netherlands.
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Cancer Therapy Challenge: It Is Time to Look in the "St. Patrick's Well" of the Nature. Int J Mol Sci 2021; 22:ijms221910380. [PMID: 34638721 PMCID: PMC8508794 DOI: 10.3390/ijms221910380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/16/2021] [Accepted: 09/21/2021] [Indexed: 12/26/2022] Open
Abstract
Cancer still remains a leading cause of death despite improvements in diagnosis, drug discovery and therapy approach. Therefore, there is a strong need to improve methodologies as well as to increase the number of approaches available. Natural compounds of different origins (i.e., from fungi, plants, microbes, etc.) represent an interesting approach for fighting cancer. In particular, synergistic strategies may represent an intriguing approach, combining natural compounds with classic chemotherapeutic drugs to increase therapeutic efficacy and lower the required drug concentrations. In this review, we focus primarily on those natural compounds utilized in synergistic approached to treating cancer, with particular attention to those compounds that have gained the most research interest.
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Agarwal A, Hager DN, Sevransky JE. Any Role of High-Dose Vitamin C for Septic Shock in 2021? Semin Respir Crit Care Med 2021; 42:672-682. [PMID: 34544184 DOI: 10.1055/s-0041-1733986] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
While the use of vitamin C as a therapeutic agent has been investigated since the 1950s, there has been substantial recent interest in the role of vitamin C supplementation in critical illness and particularly, sepsis and septic shock. Humans cannot synthesize vitamin C and rely on exogenous intake to maintain a plasma concentration of approximately 70 to 80 μmol/L. Vitamin C, in healthy humans, is involved with antioxidant function, wound healing, endothelial function, and catecholamine synthesis. Its function in the human body informs the theoretical basis for why vitamin C supplementation may be beneficial in sepsis/septic shock.Critically ill patients can be vitamin C deficient due to low dietary intake, increased metabolic demands, inefficient recycling of vitamin C metabolites, and loss due to renal replacement therapy. Intravenous supplementation is required to achieve supraphysiologic serum levels of vitamin C. While some clinical studies of intravenous vitamin C supplementation in sepsis have shown improvements in secondary outcome measures, none of the randomized clinical trials have shown differences between vitamin C supplementation and standard of care and/or placebo in the primary outcome measures of the trials. There are some ongoing studies of high-dose vitamin C administration in patients with sepsis and coronavirus disease 2019; the majority of evidence so far does not support the routine supplementation of vitamin C in patients with sepsis or septic shock.
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Affiliation(s)
- Ankita Agarwal
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, Georgia
| | - David N Hager
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Jonathan E Sevransky
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, Georgia.,Emory Critical Care Center, Emory University, Atlanta, Georgia
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41
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Targeting Reactive Oxygen Species Capacity of Tumor Cells with Repurposed Drug as an Anticancer Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8532940. [PMID: 34539975 PMCID: PMC8443364 DOI: 10.1155/2021/8532940] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/16/2021] [Indexed: 12/24/2022]
Abstract
Accumulating evidence shows that elevated levels of reactive oxygen species (ROS) are associated with cancer initiation, growth, and response to therapies. As concentrations increase, ROS influence cancer development in a paradoxical way, either triggering tumorigenesis and supporting the proliferation of cancer cells at moderate levels of ROS or causing cancer cell death at high levels of ROS. Thus, ROS can be considered an attractive target for therapy of cancer and two apparently contradictory but virtually complementary therapeutic strategies for the regulation of ROS to treat cancer. Despite tremendous resources being invested in prevention and treatment for cancer, cancer remains a leading cause of human deaths and brings a heavy burden to humans worldwide. Chemotherapy remains the key treatment for cancer therapy, but it produces harmful side effects. Meanwhile, the process of de novo development of new anticancer drugs generally needs increasing cost, long development cycle, and high risk of failure. The use of ROS-based repurposed drugs may be one of the promising ways to overcome current cancer treatment challenges. In this review, we briefly introduce the source and regulation of ROS and then focus on the status of repurposed drugs based on ROS regulation for cancer therapy and propose the challenges and direction of ROS-mediated cancer treatment.
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42
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Vitamin C supplementation promotes mental vitality in healthy young adults: results from a cross-sectional analysis and a randomized, double-blind, placebo-controlled trial. Eur J Nutr 2021; 61:447-459. [PMID: 34476568 PMCID: PMC8783887 DOI: 10.1007/s00394-021-02656-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 08/04/2021] [Indexed: 12/14/2022]
Abstract
Purpose We aimed to investigate the link of vitamin C status with vitality and psychological functions in a cross-sectional study, and examine their causal relationship through a randomized controlled trial (RCT). Methods We first conducted a population-based cross-sectional investigation of healthy young adults (n = 214, 20–39 years), and analyzed the associations of serum vitamin C concentrations with vitality (fatigue and attention) and mood status (stress, depression, and positive and negative affect) using Pearson’s correlation and multiple linear regression analyses. Next, we performed a double-blind RCT in healthy subjects whose serum vitamin C concentrations were inadequate (< 50 μmol/L). Subjects were randomly allocated to receive 500 mg of vitamin C twice a day for 4 weeks (n = 24) or a placebo (n = 22). We assessed vitality, which included fatigue, attention, work engagement, and self-control resources, and measured mood status, including stress, depression, positive and negative affect, and anxiety. ELISA determined serum brain-derived neurotrophic factor (BDNF), and a Stroop color–word test evaluated attention capacity and processing speed. Results In the cross-sectional data, the serum vitamin C concentration was positively associated with the level of attention (r = 0.16, p = 0.02; standardized β = 0.21, p = 0.003), while no significant associations with the levels of fatigue and mood variables being found. In the RCT, compared to the placebo, the vitamin C supplementation significantly increased attention (p = 0.03) and work absorption (p = 0.03) with distinct tendency of improvement on fatigue (p = 0.06) and comprehensive work engagement (p = 0.07). The vitamin C supplementation did not affect mood and serum concentrations of BDNF. However, in the Stroop color–word test, the subjects supplemented with vitamin C showed better performance than those in the placebo group (p = 0.04). Conclusion Inadequate vitamin C status is related to a low level of mental vitality. Vitamin C supplementation effectively increased work motivation and attentional focus and contributed to better performance on cognitive tasks requiring sustained attention. Trial registration number and date of registration Cross-sectional study: KCT0005074 (cris.nih.go.kr)/1 June, 2020 (retrospectively registered). Intervention study: KCT0004276 (cris.nih.go.kr)/4 September, 2019. Supplementary Information The online version contains supplementary material available at 10.1007/s00394-021-02656-3.
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Kim H, Shaqeel A, Han S, Kang J, Yun J, Lee M, Lee S, Kim J, Noh S, Choi M, Lee J. In Situ Formation of Ag Nanoparticles for Fiber Strain Sensors: Toward Textile-Based Wearable Applications. ACS APPLIED MATERIALS & INTERFACES 2021; 13:39868-39879. [PMID: 34383459 DOI: 10.1021/acsami.1c09879] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Wearable electronic devices have attracted significant attention as important components in several applications. Among various wearable electronic devices, interest in textile electronic devices is increasing because of their high deformability and portability in daily life. To develop textile electronic devices, fiber-based electronic devices should be fundamentally studied. Here, we report a stretchable and sensitive fiber strain sensor fabricated using only harmless materials during an in situ formation process. Despite using a mild and harmless reducing agent instead of typical strong and hazardous reducing agents, the developed fiber strain sensors feature a low initial electrical resistance of 0.9 Ω/cm, a wide strain sensing range (220%), high sensitivity (∼5.8 × 104), negligible hysteresis, and high stability against repeated stretching-releasing deformation (5000 cycles). By applying the fiber sensors to various textiles, we demonstrate that the smart textile system can monitor various gestures in real-time and help users maintain accurate posture during exercise. These results will provide meaningful insights into the development of next-generation wearable applications.
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Affiliation(s)
- Hwajoong Kim
- Soft Biomedical Devices Lab, Department of Robotics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu-si 42988, Republic of Korea
| | - Ammar Shaqeel
- Laboratory of Biosensors and Bioelectronics, Institute for Biomedical Engineering, ETH Zürich, Zurich 8092, Switzerland
| | - Solbi Han
- Soft Biomedical Devices Lab, Department of Robotics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu-si 42988, Republic of Korea
| | - Junseo Kang
- Soft Biomedical Devices Lab, Department of Robotics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu-si 42988, Republic of Korea
| | - Jieun Yun
- Soft Biomedical Devices Lab, Department of Robotics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu-si 42988, Republic of Korea
| | - Mugeun Lee
- Soft Biomedical Devices Lab, Department of Robotics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu-si 42988, Republic of Korea
| | - Seonggyu Lee
- Soft Biomedical Devices Lab, Department of Robotics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu-si 42988, Republic of Korea
| | - Jinho Kim
- Soft Biomedical Devices Lab, Department of Robotics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu-si 42988, Republic of Korea
| | - Seungbeom Noh
- Soft Biomedical Devices Lab, Department of Robotics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu-si 42988, Republic of Korea
| | - Minyoung Choi
- Soft Biomedical Devices Lab, Department of Robotics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu-si 42988, Republic of Korea
| | - Jaehong Lee
- Soft Biomedical Devices Lab, Department of Robotics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu-si 42988, Republic of Korea
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Hoppe C, Freuding M, Büntzel J, Münstedt K, Hübner J. Clinical efficacy and safety of oral and intravenous vitamin C use in patients with malignant diseases. J Cancer Res Clin Oncol 2021; 147:3025-3042. [PMID: 34402972 PMCID: PMC8397678 DOI: 10.1007/s00432-021-03759-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 08/07/2021] [Indexed: 11/27/2022]
Abstract
Background Vitamin C, also called ascorbic acid, is a water-soluble antioxidant and free radical scavenger. It is required in the body for numerous metabolic functions and is involved in the development of proteins and connective tissue. Methods In April 2020, a systematic search was carried out on five electronic databases (Medline, Embase, Cochrane, Cinahl, PsycINFO) to find studies on the use, efficacy and safety of a complementary therapy with vitamin C in oncological patients. Results Out of the initial 23,195 search results, 21 studies with 1961 patients were included in this review. Five of the included studies (n = 417) were randomized controlled trials (RCTs). The remaining 16 studies belonged to a lower class of evidence. The patients who were treated with vitamin C suffered from various malignant diseases, some in an advanced and palliative stage. Vitamin C was applied intravenously or orally. It was either the only treatment or was combined with chemo- or radiotherapy. Endpoints included the development of the disease-related symptoms, quality of life, mortality, progression-free survival and safety of vitamin C. The studies were of moderate quality and showed either no effect of vitamin C or a positive trend, although this has rarely been statistically proven in group comparisons. No or only slight side effects with both oral and intravenous administration of vitamin C were reported. Conclusion Oral intake of vitamin C does not appear to have any effect in patients with malignancies. Data are heterogeneous for intravenous administration. There are no RCTs with statistical group comparisons.
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Affiliation(s)
- Catalina Hoppe
- Klinik für Innere Medizin II, Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Germany.
| | - Maren Freuding
- Klinik für Innere Medizin II, Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Germany
| | - Jens Büntzel
- Klinik für HNO-Erkrankungen, Kopf-Hals-Chirurgie, Interdisziplinäre Palliativstation, Südharz Klinikum Nordhausen, Dr.-Robert-Koch-Straße 39, 99734, Nordhausen, Germany
| | - Karsten Münstedt
- Gynäkologie und Geburtshilfe, Ortenau Klinikum Offenburg-Kehl, Ebertplatz 12, 77654, Offenburg, Germany
| | - Jutta Hübner
- Klinik für Innere Medizin II, Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Germany
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Mikkelsen SU, Gillberg L, Lykkesfeldt J, Grønbæk K. The role of vitamin C in epigenetic cancer therapy. Free Radic Biol Med 2021; 170:179-193. [PMID: 33789122 DOI: 10.1016/j.freeradbiomed.2021.03.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 12/27/2022]
Abstract
The role of vitamin C in the treatment of cancer has been subject to controversy for decades. Within the past 10 years, mechanistic insight into the importance of vitamin C in epigenetic regulation has provided a new rationale for its potential anti-cancer effects. At physiological concentrations, vitamin C is a potent antioxidant and thereby co-factor for a range of enzymes including the Fe(II)- and α-ketoglutarate-dependent dioxygenases that represent some of the most important epigenetic regulators; the ten-eleven translocation (TET) methylcytosine dioxygenases and the Jumonji-C domain-containing histone demethylases. Epigenetic deregulation is a hallmark of many cancers and reduced activity of these enzymes or somatic loss-of-function mutations in the genes encoding them, are observed in many cancer types. The present review outlines the growing literature on the role of vitamin C in epigenetic therapy of cancer. In the vast majority of in vitro, animal and clinical studies included in this review, vitamin C showed ability across cancer types to increase the hydroxylation of 5-methylcytosine to 5-hydroxymethylcytosine catalyzed by the TET enzymes - the first step in DNA demethylation. Most consistently, vitamin C in combination with the class of epigenetic drugs, DNA methyltransferase inhibitors, has demonstrated efficacy in the treatment of hematological malignancies in both preclinical and the limited number of available clinical studies. Yet, the pertinent question of what is the optimal dose of vitamin C in cancer studies remains to be answered. High-quality randomized placebo-controlled trials are needed to determine whether supplementation with vitamin C may benefit subgroups of patients with (pre-)cancer.
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Affiliation(s)
- Stine Ulrik Mikkelsen
- Department of Hematology, Rigshospitalet, Juliane Maries Vej 10, 2100, Copenhagen, Denmark; Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, Building 2, 3rd Floor, 2200, Copenhagen, Denmark
| | - Linn Gillberg
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Jens Lykkesfeldt
- Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1st Floor, 1870, Frederiksberg, Denmark
| | - Kirsten Grønbæk
- Department of Hematology, Rigshospitalet, Juliane Maries Vej 10, 2100, Copenhagen, Denmark; Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, Building 2, 3rd Floor, 2200, Copenhagen, Denmark; DanStem, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
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Patelli G, Tosi F, Amatu A, Mauri G, Curaba A, Patanè DA, Pani A, Scaglione F, Siena S, Sartore-Bianchi A. Strategies to tackle RAS-mutated metastatic colorectal cancer. ESMO Open 2021; 6:100156. [PMID: 34044286 PMCID: PMC8167159 DOI: 10.1016/j.esmoop.2021.100156] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/18/2022] Open
Abstract
The RAS oncogene is among the most commonly mutated in cancer. RAS mutations are identified in about half of patients diagnosed with metastatic colorectal cancer (mCRC), conferring poor prognosis and lack of response to anti-epidermal growth factor receptor (EGFR) antibodies. In the last decades, several investigational attempts failed in directly targeting RAS mutations, thus RAS was historically regarded as 'undruggable'. Recently, novel specific KRASG12C inhibitors showed promising results in different solid tumors, including mCRC, renewing interest in this biomarker as a target. In this review, we discuss different strategies of RAS targeting in mCRC, according to literature data in both clinical and preclinical settings. We recognized five main strategies focusing on those more promising: direct RAS targeting, targeting the mitogen-activated protein kinase (MAPK) pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and finally other miscellaneous approaches. Direct KRASG12C inhibition is emerging as the most promising strategy in mCRC as well as in other solid malignancies. However, despite good disease control rates, tumor response and duration of response are still limited in mCRC. At this regard, combinational approaches with anti-epidermal growth factor receptor drugs or checkpoint inhibitors have been proposed to enhance treatment efficacy, based on encouraging results achieved in preclinical studies. Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRASG12C. In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as 'undruggable' and future avenues are now opening for translation in the clinic in mCRC.
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Affiliation(s)
- G Patelli
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy
| | - F Tosi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - A Amatu
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - G Mauri
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy
| | - A Curaba
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy
| | - D A Patanè
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy
| | - A Pani
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy
| | - F Scaglione
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Clinical Pharmacology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - S Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy
| | - A Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy.
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Renner O, Burkard M, Michels H, Vollbracht C, Sinnberg T, Venturelli S. Parenteral high‑dose ascorbate - A possible approach for the treatment of glioblastoma (Review). Int J Oncol 2021; 58:35. [PMID: 33955499 PMCID: PMC8104923 DOI: 10.3892/ijo.2021.5215] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/05/2021] [Indexed: 12/14/2022] Open
Abstract
For glioblastoma, the treatment with standard of care therapy comprising resection, radiation, and temozolomide results in overall survival of approximately 14-18 months after initial diagnosis. Even though several new therapy approaches are under investigation, it is difficult to achieve life prolongation and/or improvement of patient's quality of life. The aggressiveness and progression of glioblastoma is initially orchestrated by the biological complexity of its genetic phenotype and ability to respond to cancer therapy via changing its molecular patterns, thereby developing resistance. Recent clinical studies of pharmacological ascorbate have demonstrated its safety and potential efficacy in different cancer entities regarding patient's quality of life and prolongation of survival. In this review article, the actual glioblastoma treatment possibilities are summarized, the evidence for pharmacological ascorbate in glioblastoma treatment is examined and questions are posed to identify current gaps of knowledge regarding accessibility of ascorbate to the tumor area. Experiments with glioblastoma cell lines and tumor xenografts have demonstrated that high-dose ascorbate induces cytotoxicity and oxidative stress largely selectively in malignant cells compared to normal cells suggesting ascorbate as a potential therapeutic agent. Further investigations in larger cohorts and randomized placebo-controlled trials should be performed to confirm these findings as well as to improve delivery strategies to the brain, through the inherent barriers and ultimately to the malignant cells.
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Affiliation(s)
- Olga Renner
- Department of Nutritional Biochemistry, University of Hohenheim, D‑70599 Stuttgart, Germany
| | - Markus Burkard
- Department of Nutritional Biochemistry, University of Hohenheim, D‑70599 Stuttgart, Germany
| | - Holger Michels
- Pascoe Pharmazeutische Praeparate GmbH, D‑35394 Giessen, Germany
| | | | - Tobias Sinnberg
- Department of Dermatology, University Hospital Tuebingen, D‑72076 Tuebingen, Germany
| | - Sascha Venturelli
- Department of Nutritional Biochemistry, University of Hohenheim, D‑70599 Stuttgart, Germany
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48
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Pearson AG, Pullar JM, Cook J, Spencer ES, Vissers MC, Carr AC, Hampton MB. Peroxiredoxin 2 oxidation reveals hydrogen peroxide generation within erythrocytes during high-dose vitamin C administration. Redox Biol 2021; 43:101980. [PMID: 33905956 PMCID: PMC8099772 DOI: 10.1016/j.redox.2021.101980] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/23/2021] [Accepted: 04/13/2021] [Indexed: 12/14/2022] Open
Abstract
Intravenous infusion of high dose (>10 g) vitamin C (IVC) is a common alternative cancer therapy. IVC results in millimolar levels of circulating ascorbate, which is proposed to generate cytotoxic quantities of H2O2 in the presence of transition metal ions. In this study we report on the in vitro and in vivo effects of millimolar ascorbate on erythrocytes. Addition of ascorbate to whole blood increased erythrocyte intracellular ascorbate approximately 35-fold. Within 10 min of ascorbate addition, we detected increased oxidation of erythrocyte peroxiredoxin 2 (Prx2), a major thiol antioxidant protein and a sensitive marker of H2O2 production. Up to 50% of Prx2 was present in the oxidised form after 60 min. The presence of extracellular catalase, removal of plasma or the addition of a metal chelator did not prevent ascorbate-induced Prx2 oxidation, suggesting that the H2O2 responsible for Prx2 oxidation was generated within the erythrocyte. Ascorbate is known to increase the rate of haemoglobin autoxidation and H2O2 production. Through spectral monitoring of oxidised haemoglobin we estimated a generation rate of 15 μM H2O2/min inside erythrocytes. We also investigated changes in erythrocyte ascorbate concentration and Prx2 oxidation following IVC infusion in a cohort of patients with cancer. Plasma ascorbate levels ranged from 7.8 to 35 mM immediately post infusion, while erythrocyte ascorbate levels reached 1.5–3.4 mM 4 h after beginning infusion. Transient oxidation of erythrocyte Prx2 was observed. We conclude that erythrocytes accumulate ascorbate during IVC infusion, providing a significant reservoir of ascorbate, and this ascorbate increases H2O2 generation within the cells. The consequence of increased erythrocyte Prx2 oxidation warrants further investigation.
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Affiliation(s)
- Andree G Pearson
- Centre for Free Radical Research, Department of Pathology & Biomedical Science, University of Otago, Christchurch, New Zealand.
| | - Juliet M Pullar
- Centre for Free Radical Research, Department of Pathology & Biomedical Science, University of Otago, Christchurch, New Zealand
| | - John Cook
- New Brighton Health Care, Christchurch, New Zealand
| | - Emma S Spencer
- Nutrition in Medicine Research Group, Department of Pathology & Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Margreet Cm Vissers
- Centre for Free Radical Research, Department of Pathology & Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Anitra C Carr
- Nutrition in Medicine Research Group, Department of Pathology & Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Mark B Hampton
- Centre for Free Radical Research, Department of Pathology & Biomedical Science, University of Otago, Christchurch, New Zealand.
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49
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Vollbracht C, Kraft K. Feasibility of Vitamin C in the Treatment of Post Viral Fatigue with Focus on Long COVID, Based on a Systematic Review of IV Vitamin C on Fatigue. Nutrients 2021; 13:1154. [PMID: 33807280 PMCID: PMC8066596 DOI: 10.3390/nu13041154] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 12/13/2022] Open
Abstract
Fatigue is common not only in cancer patients but also after viral and other infections. Effective treatment options are still very rare. Therefore, the present knowledge on the pathophysiology of fatigue and the potential positive impact of treatment with vitamin C is illustrated. Additionally, the effectiveness of high-dose IV vitamin C in fatigue resulting from various diseases was assessed by a systematic literature review in order to assess the feasibility of vitamin C in post-viral, especially in long COVID, fatigue. Nine clinical studies with 720 participants were identified. Three of the four controlled trials observed a significant decrease in fatigue scores in the vitamin C group compared to the control group. Four of the five observational or before-and-after studies observed a significant reduction in pre-post levels of fatigue. Attendant symptoms of fatigue such as sleep disturbances, lack of concentration, depression, and pain were also frequently alleviated. Oxidative stress, inflammation, and circulatory disorders, which are important contributors to fatigue, are also discussed in long COVID fatigue. Thus, the antioxidant, anti-inflammatory, endothelial-restoring, and immunomodulatory effects of high-dose IV vitamin C might be a suitable treatment option.
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Affiliation(s)
- Claudia Vollbracht
- Medical Science Department, Pascoe Pharmazeutische Präparate GmbH, 35383 Giessen, Germany
- Department of Internal Medicine, University Medicine Rostock, 18057 Rostock, Germany;
| | - Karin Kraft
- Department of Internal Medicine, University Medicine Rostock, 18057 Rostock, Germany;
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50
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Crake RLI, Burgess ER, Royds JA, Phillips E, Vissers MCM, Dachs GU. The Role of 2-Oxoglutarate Dependent Dioxygenases in Gliomas and Glioblastomas: A Review of Epigenetic Reprogramming and Hypoxic Response. Front Oncol 2021; 11:619300. [PMID: 33842321 PMCID: PMC8027507 DOI: 10.3389/fonc.2021.619300] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/25/2021] [Indexed: 12/30/2022] Open
Abstract
Gliomas are a heterogeneous group of cancers that predominantly arise from glial cells in the brain, but may also arise from neural stem cells, encompassing low-grade glioma and high-grade glioblastoma. Whereas better diagnosis and new treatments have improved patient survival for many cancers, glioblastomas remain challenging with a highly unfavorable prognosis. This review discusses a super-family of enzymes, the 2-oxoglutarate dependent dioxygenase enzymes (2-OGDD) that control numerous processes including epigenetic modifications and oxygen sensing, and considers their many roles in the pathology of gliomas. We specifically describe in more detail the DNA and histone demethylases, and the hypoxia-inducible factor hydroxylases in the context of glioma, and discuss the substrate and cofactor requirements of the 2-OGDD enzymes. Better understanding of how these enzymes contribute to gliomas could lead to the development of new treatment strategies.
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Affiliation(s)
- Rebekah L. I. Crake
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
| | - Eleanor R. Burgess
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
| | - Janice A. Royds
- Department of Pathology, University of Otago, Dunedin, New Zealand
| | - Elisabeth Phillips
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
| | - Margreet C. M. Vissers
- Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
| | - Gabi U. Dachs
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
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