Vitamin C Suppresses Pancreatic Carcinogenesis through the Inhibition of Both Glucose Metabolism and Wnt Signaling

Kim, Ji Hye; Hwang, Sein; Lee, Jihye; Im, Se Seul; Son, Jaekyoung

doi:10.3390/ijms232012249

Cited by 12 publications

(8 citation statements)

References 48 publications

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“…Similarly, upon 24h of VitC treatment, the majority of cell lines showed a decrease in TGF-β and IL6 JAK-STAT3 signalling, two key immunosuppressive pathways in PDAC tumours that can positively regulate and attract myeloid-derived suppressor cells and regulatory T cells to the tumour microenvironment(63). Furthermore, Wnt/β-catenin signalling, which also holds an immunosuppressive role in PDAC tumours(64), was found to be reduced upon VitC, in line with previous studies in PDAC(65).…”

Section: Resultssupporting

confidence: 89%

“…To some extent, beta catenin could be involved in VitC sensitivity in cancer cells since it plays a key role in heme synthesis, glucose uptake and fatty acid metabolism, and positively regulates Lgulonolactone oxidase, crucial for VitC biosynthesis (78). Furthermore, VitC has been recently shown to inhibit EMT in PDAC via the Wnt/beta catenin pathway (65), which underscores VitC's multi-targeting capability in cancer. Besides, mTOR was the pathway most significantly associated with reduced VitC sensitivity.…”

Section: Mitochondrial Functions Iron and Oxidative Stress Levelsmentioning

confidence: 99%

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Large pan-cancer cell screen coupled to (phospho-)proteomics underscores high-dose vitamin C as a potent anti-cancer agent

Vallés-Martí,

Böttger,

Yau

et al. 2023

Preprint

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Increasing preclinical and clinical evidence has positioned high-dose vitamin C as a promising anti-cancer treatment that merits more clinical attention. Multiple cytotoxicity mechanisms have been described, including pro-oxidant effects. To contribute to the preclinical understanding of the broad pan-cancer effects of high-dose vitamin C in a global manner, we determined the IC50 of a large panel of cancer cell lines (n=51) representing 7 solid tumour types and generated proteome data. The majority of cell lines were highly sensitive (IC50 range 0.036-10mM, mean 1.7 ± 0.4 mM), well below a clinically achievable dose. The proteome data (>5000 proteins per sample), showed that high sensitivity is associated with proliferation, as indicated by functional enrichment of cell cycle, RNA splicing and chromatin organization, while lower sensitivity is linked to extracellular vesicles, glycolysis, fatty acid metabolism and mitochondria. Moreover, (phospho-)proteome analysis of on-treatment vitamin C effects on four pancreatic ductal adenocarcinoma (PDAC) cells dosed at a range of IC50 values (Hs766 T, 2 mM; Capan-2, 0.6 mM; PANC-1, 0.14 mM and Suit-2, 0.1 mM) revealed, next to cell line specific effects, down-modulation of AKT-MTOR signalling and immune suppressive signalling, while IFN-α response was enhanced upon vitamin C. Altogether, our comprehensive pharmacological and (phospho-)proteome analysis is the first to assess cancer vulnerabilities and effects of vitamin C on a large cancer cell line panel and underscores the potential of high-dose vitamin C as an anti-cancer agent.

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Section: Resultssupporting

confidence: 89%

Section: Mitochondrial Functions Iron and Oxidative Stress Levelsmentioning

confidence: 99%

Large pan-cancer cell screen coupled to (phospho-)proteomics underscores high-dose vitamin C as a potent anti-cancer agent

Vallés-Martí,

Böttger,

Yau

et al. 2023

Preprint

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show abstract

“…Similar results have been demonstrated in melanoma cells [ 103 ]. Further, vitamin C may inhibit tumorigenesis via mitochondrial dysregulation [ 104 ]. In pancreatic adenocarcinoma cell lines, vitamin C supplementation resulted in decreased cell growth via the inhibition of glucose metabolism without altering the levels of ROS [ 104 ].…”

Section: Vitamin Cmentioning

confidence: 99%

“…Further, vitamin C may inhibit tumorigenesis via mitochondrial dysregulation [ 104 ]. In pancreatic adenocarcinoma cell lines, vitamin C supplementation resulted in decreased cell growth via the inhibition of glucose metabolism without altering the levels of ROS [ 104 ]. The mechanism by which this occurs is largely unknown but is believed to be related to mitochondrial dysregulation because the addition of pyruvate to the medium rescued cancer cells from death.…”

Section: Vitamin Cmentioning

confidence: 99%

Antioxidant and Anti-Tumor Effects of Dietary Vitamins A, C, and E

et al. 2023

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Oxidative stress, a condition characterized by an imbalance between pro-oxidant molecules and antioxidant defense systems, is increasingly recognized as a key contributor to cancer development. This is because the reactive oxygen species (ROS) generated during oxidative stress can damage DNA, proteins, and lipids to facilitate mutations and other cellular changes that promote cancer growth. Antioxidant supplementation is a potential strategy for decreasing cancer incidence; by reducing oxidative stress, DNA damage and other deleterious cellular changes may be attenuated. Several clinical trials have been conducted to investigate the role of antioxidant supplements in cancer prevention. Some studies have found that antioxidant supplements, such as vitamin A, vitamin C, and vitamin E, can reduce the risk of certain types of cancer. On the other hand, some studies posit an increased risk of cancer with antioxidant supplement use. In this review, we will provide an overview of the current understanding of the role of oxidative stress in cancer formation, as well as the potential benefits of antioxidant supplementation in cancer prevention. Additionally, we will discuss both preclinical and clinical studies highlighting the potentials and limitations of preventive antioxidant strategies.

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“…In addition, AA has been shown to alter cancer metabolism. 163,[167][168][169][170] A preclinical study of AA plus buformin on AML cell lines shows that AA inhibits glucose metabolism through interfering with hexokinase 1/2 and GLUT1 functions in hematopoietic cells as well as depletes ATP production. 171 Currently, a phase 2 clinical trial of AA in combination with metformin in some solid tumours is ongoing (NCT04033107).…”

Section: Aa and Clinical Studiesmentioning

confidence: 99%

Ascorbic acid in cancer management – time for a second look

Ogochukwu

2023

Eur J Clin Exp Med

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Introduction and aim. Over the past decades, the hypotheses that ascorbic acid (AA) can play a role as an anti-neoplastic therapy have generated many conflicting reports. Despite the controversies, mounting evidence has shown that AA has the potential to play a role as an anti-neoplastic agent. Recent studies have unraveled its pharmacokinetics and various mechanism of action on cancer cells. This has spawned different preclinical studies with reports of good activities against various cancers. Material and methods. A review of the literature regarding ascorbic acid in the management of cancer was performed using the PubMed database. The research was limited to abstracts and available full-text articles. Analysis of the literature. Clinical trials have also demonstrated its safety and tolerability across different dosages. AA has been noted as a multitargeting agent that acts as a pro-oxidative cytotoxic agent, anti-cancer epigenetic regulator and immune modulator. AA has also been shown act synergistically with standard chemotherapy regimens in different cancers. Despite its potentials, phase III clinical trials are seriously lacking. The recent phase III VITALITY study shows that AA may play a role as an adjunct targeted therapy for ras-mutated cancers. Therefore, there is need to for more standardized clinical trials to help identify cancer subtypes and AA combination regimens that can show the most benefits. In this review, the pleiotropic mechanism of action of AA was explored as well as various preclinical and clinical studies in cancer therapy. In addition, recommendations were also made for effective strategies towards an AA and standard cancer regimens in treatment as well as future directions. Ascorbic acid has been shown to induce cell death in various cancer types through different mechanisms of action. Several clinical trials and case reports have shown its efficacy in combination chemotherapy, and the pharmacological route of action can be either intravenous or oral. However, it can impair the actions of some drugs when given in combination. Also, dosage should be determined for maximal pharmacologic action. Conclusion. Ascorbic acid has the potential to provide safe and cost-effective antineoplastic treatment option especially in combination therapy. Its potential needs to be further investigated through clinical trials.

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Vitamin C Suppresses Pancreatic Carcinogenesis through the Inhibition of Both Glucose Metabolism and Wnt Signaling

Cited by 12 publications

References 48 publications

Large pan-cancer cell screen coupled to (phospho-)proteomics underscores high-dose vitamin C as a potent anti-cancer agent

Large pan-cancer cell screen coupled to (phospho-)proteomics underscores high-dose vitamin C as a potent anti-cancer agent

Antioxidant and Anti-Tumor Effects of Dietary Vitamins A, C, and E

Ascorbic acid in cancer management – time for a second look

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