condition found tbRes List
VitC, Vitamin C (Ascorbic Acid): Click to Expand ⟱
Features:
High-dose vitamin C: Some studies have suggested that high-dose vitamin C may be effective in treating certain types of cancer, such as ovarian cancer and pancreatic cancer.
Symptoms of vitamin C deficiency include fatigue, weakness, poor wound healing, ecchymoses, xerosis, lower extremity edema, and musculoskeletal pain—most of them are often observed in end-stage cancer patients. -Vitamin C is an essential nutrient involved in the repair of tissue, the formation of collagen, and the enzymatic production of certain neurotransmitters. It is required for the functioning of several enzymes and is important for immune system function.
-Ascorbic Acid, Different levels in different Organs
Homeostasis ranging from about 0.2 mM in the muscle and heart, and up to 10 mM in the brain and adrenal gland. -(Note the Oncomagnetic success in the brain also was then under conditions of high Vitamin C)

-Ascorbic acid is an electron donor
Ascorbic Acid, can be a Pro-oxidant
"The pro-oxidative activity of ascorbic acid (Figure 2) is associated with the interaction with transition metal ions (especially iron and copper). Under conditions of high, millimolar ascorbate concentration, vitamin C catalyzes the reduction of free transition metal ions, which causes the formation of oxygen radicals."
Ascorbic Acid, formation of H2O2 (Hydrogen Peroxide)
Many studies indicate the toxicity of ascorbate to cancer cells. Much evidence indicates that the underlying phenomenon is the pro-oxidative activity of ascorbate, which induces the formation of H2O2 and oxidative stress.
"ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H(2)O(2)"
-High dose VitC therapy may not be for those with kidney problems
-Oral supplement up to 10g/day?
-Direct regulator of TET↑
-caution for (G6PD-) deficient patients receiving vitamin C infusions

-Note plasma half-life 30mins to 1hr, 1.5-2hr elimination half-life.
oral BioAv water soluble, but has limitiations as 100mg yeilds 60uM/L in plasma, but 1000mg only yeilds 85uM/L. mM concentration are required for effectiveness on cancer cells. Hence why IV administration is common. Boosting HIF increases the intracellular uptake of oxidized VitC
Pathways:
- high dose induces ROS production in cancer cells. Otherwise well known antioxidant in normal cells.
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, Caspases↑, DNA damage↑, cl-PARP↑,
- Lowers AntiOxidant defense in Cancer Cells: NRF2↓, TrxR↓**, SOD↓, GSH↓ Catalase↓ HO1↓ GPx↓
- Raises AntiOxidant defense in Normal Cells: ROS↓">ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : NLRP3↓, IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, TIMP2, IGF-1↓, VEGF↓, NF-κB↓,
- reactivate genes thereby inhibiting cancer cell growth : P53↑, TET↑
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, CDK2↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, TNF-α↓, ERK↓, EMT↓, TET1↓,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, ECAR↓, GRP78↑, Glucose↓, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓,
- Others: PI3K↓, AKT↓, STAT↓, AMPK, ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Hepatoprotective,

- Selectivity: Cancer Cells vs Normal Cells


ROS, Reactive Oxygen Species: Click to Expand ⟱
Source: HalifaxProj (inhibit)
Type:
Reactive oxygen species (ROS) are highly reactive molecules that contain oxygen and can lead to oxidative stress in cells. They play a dual role in cancer biology, acting as both promoters and suppressors of cancer.
ROS can cause oxidative damage to DNA, leading to mutations that may contribute to cancer initiation and progression. So normally you want to inhibit ROS to prevent cell mutations.
However excessive ROS can induce apoptosis (programmed cell death) in cancer cells, potentially limiting tumor growth. Chemotherapy typically raises ROS.

"Reactive oxygen species (ROS) are two electron reduction products of oxygen, including superoxide anion, hydrogen peroxide, hydroxyl radical, lipid peroxides, protein peroxides and peroxides formed in nucleic acids 1. They are maintained in a dynamic balance by a series of reduction-oxidation (redox) reactions in biological systems and act as signaling molecules to drive cellular regulatory pathways."
"During different stages of cancer formation, abnormal ROS levels play paradoxical roles in cell growth and death 8. A physiological concentration of ROS that maintained in equilibrium is necessary for normal cell survival. Ectopic ROS accumulation promotes cell proliferation and consequently induces malignant transformation of normal cells by initiating pathological conversion of physiological signaling networks. Excessive ROS levels lead to cell death by damaging cellular components, including proteins, lipid bilayers, and chromosomes. Therefore, both scavenging abnormally elevated ROS to prevent early neoplasia and facilitating ROS production to specifically kill cancer cells are promising anticancer therapeutic strategies, in spite of their contradictoriness and complexity."
"ROS are the collection of derivatives of molecular oxygen that occur in biology, which can be categorized into two types, free radicals and non-radical species. The non-radical species are hydrogen peroxide (H 2O 2 ), organic hydroperoxides (ROOH), singlet molecular oxygen ( 1 O 2 ), electronically excited carbonyl, ozone (O3 ), hypochlorous acid (HOCl, and hypobromous acid HOBr). Free radical species are super-oxide anion radical (O 2•−), hydroxyl radical (•OH), peroxyl radical (ROO•) and alkoxyl radical (RO•) [130]. Any imbalance of ROS can lead to adverse effects. H2 O 2 and O 2 •− are the main redox signalling agents. The cellular concentration of H2 O 2 is about 10−8 M, which is almost a thousand times more than that of O2 •−".
"Radicals are molecules with an odd number of electrons in the outer shell [393,394]. A pair of radicals can be formed by breaking a chemical bond or electron transfer between two molecules."

Recent investigations have documented that polyphenols with good antioxidant activity may exhibit pro-oxidant activity in the presence of copper ions, which can induce apoptosis in various cancer cell lines but not in normal cells. "We have shown that such cell growth inhibition by polyphenols in cancer cells is reversed by copper-specific sequestering agent neocuproine to a significant extent whereas iron and zinc chelators are relatively ineffective, thus confirming the role of endogenous copper in the cytotoxic action of polyphenols against cancer cells. Therefore, this mechanism of mobilization of endogenous copper." > Ions could be one of the important mechanisms for the cytotoxic action of plant polyphenols against cancer cells and is possibly a common mechanism for all plant polyphenols. In fact, similar results obtained with four different polyphenolic compounds in this study, namely apigenin, luteolin, EGCG, and resveratrol, strengthen this idea.
Interestingly, the normal breast epithelial MCF10A cells have earlier been shown to possess no detectable copper as opposed to breast cancer cells [24], which may explain their resistance to polyphenols apigenin- and luteolin-induced growth inhibition as observed here (Fig. 1). We have earlier proposed [25] that this preferential cytotoxicity of plant polyphenols toward cancer cells is explained by the observation made several years earlier, which showed that copper levels in cancer cells are significantly elevated in various malignancies. Thus, because of higher intracellular copper levels in cancer cells, it may be predicted that the cytotoxic concentrations of polyphenols required would be lower in these cells as compared to normal cells."

Majority of ROS are produced as a by-product of oxidative phosphorylation, high levels of ROS are detected in almost all cancers.
-It is well established that during ER stress, cytosolic calcium released from the ER is taken up by the mitochondrion to stimulate ROS overgeneration and the release of cytochrome c, both of which lead to apoptosis.

Note: Products that may raise ROS can be found using this database, by:
Filtering on the target of ROS, and selecting the Effect Direction of ↑

Targets to raise ROS (to kill cancer cells):
• NADPH oxidases (NOX): NOX enzymes are involved in the production of ROS.
    -Targeting NOX enzymes can increase ROS levels and induce cancer cell death.
    -eNOX2 inhibition leads to a high NADH/NAD⁺ ratio which can lead to increased ROS
• Mitochondrial complex I: Inhibiting can increase ROS production
• P53: Activating p53 can increase ROS levels(by inducing the expression of pro-oxidant genes)
• Nrf2: regulates the expression of antioxidant genes. Inhibiting Nrf2 can increase ROS levels
• Glutathione (GSH): an antioxidant. Depleting GSH can increase ROS levels
• Catalase: Catalase converts H2O2 into H2O+O. Inhibiting catalase can increase ROS levels
• SOD1: converts superoxide into hydrogen peroxide. Inhibiting SOD1 can increase ROS levels
• PI3K/AKT pathway: regulates cell survival and metabolism. Inhibiting can increase ROS levels
• HIF-1α: regulates genes involved in metabolism and angiogenesis. Inhibiting HIF-1α can increase ROS
• Glycolysis: Inhibiting glycolysis can increase ROS levels • Fatty acid oxidation: Cancer cells often rely on fatty acid oxidation for energy production.
-Inhibiting fatty acid oxidation can increase ROS levels
• ER stress: Endoplasmic reticulum (ER) stress can increase ROS levels
• Autophagy: process by which cells recycle damaged organelles and proteins.
-Inhibiting autophagy can increase ROS levels and induce cancer cell death.
• KEAP1/Nrf2 pathway: regulates the expression of antioxidant genes.
    -Inhibiting KEAP1 or activating Nrf2 can increase ROS levels and induce cancer cell death.
• DJ-1: regulates the expression of antioxidant genes. Inhibiting DJ-1 can increase ROS levels
• PARK2: regulates the expression of antioxidant genes. Inhibiting PARK2 can increase ROS levels
• SIRT1:regulates the expression of antioxidant genes. Inhibiting SIRT1 can increase ROS levels
• AMPK: regulates energy metabolism and can increase ROS levels when activated.
• mTOR: regulates cell growth and metabolism. Inhibiting mTOR can increase ROS levels
• HSP90: regulates protein folding and can increase ROS levels when inhibited.
• Proteasome: degrades damaged proteins. Inhibiting the proteasome can increase ROS levels
• Lipid peroxidation: a process by which lipids are oxidized, leading to the production of ROS.
    -Increasing lipid peroxidation can increase ROS levels
• Ferroptosis: form of cell death that is regulated by iron and lipid peroxidation.
    -Increasing ferroptosis can increase ROS levels
• Mitochondrial permeability transition pore (mPTP): regulates mitochondrial permeability.
    -Opening the mPTP can increase ROS levels
• BCL-2 family proteins: regulate apoptosis and can increase ROS levels when inhibited.
• Caspase-independent cell death: a form of cell death that is regulated by ROS.
    -Increasing caspase-independent cell death can increase ROS levels
• DNA damage response: regulates the repair of DNA damage. Increasing DNA damage can increase ROS
• Epigenetic regulation: process by which gene expression is regulated.
    -Increasing epigenetic regulation can increase ROS levels

-PKM2, but not PKM1, can be inhibited by direct oxidation of cysteine 358 as an adaptive response to increased intracellular reactive oxygen species (ROS)

ProOxidant Strategy:(inhibit the Melavonate Pathway (likely will also inhibit GPx)
-HydroxyCitrate (HCA) found as supplement online and typically used in a dose of about 1.5g/day or more
-Atorvastatin typically 40-80mg/day
-Dipyridamole typically 200mg 2x/day
-Lycopene typically 100mg/day range

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy

Scientific Papers found: Click to Expand⟱
2580- ART/DHA,  VitC,    Effects of Antioxidants and Pro-oxidants on Cytotoxicity of Dihydroartemisinin to Molt-4 Human Leukemia Cells
- in-vitro, AML, NA
eff↓, Compared to control, ascorbate and H 2 O 2 both caused a significant decrease in cell count both at 24-h (p<0.05 and p<0.0001 for ascorbate and H 2 O 2 , respectively)
other↝, Vitamin C, a common supplement, has been shown to act as both a ROS generator in the presence of iron and copper (15) and as an antioxidant
ROS↑, From our results, we can postulate that ROS generation is causing cell death independently and in combination with DHA
eff↓, Ascorbate can convert ferric iron into ferrous iron (18), the active form that reacts with artemisinin, generating short lived free radicals.
eff↓, If this happens in the stomach of a person who is consuming artemisinin along with ascorbate, ascorbate will convert ferric iron in foods to the ferrous form, which may react with artemisinin locally, making the therapy less effective

1846- dietFMD,  VitC,    A fasting-mimicking diet and vitamin C: turning anti-aging strategies against cancer
- Study, Var, NA
TumCG↓, FMDs delay tumor progression
ChemoSen↑, potentiate chemotherapy efficacy
ChemoSideEff↓, while protecting healthy tissues from chemo-associated side effects in different cancer models
ROS↑, presence of metals, and particularly iron, high dose of vitamin C exerts a pro-oxidant action by generating hydrogen peroxide and hydroxyl radicals via Fenton chemistry
Fenton↑,
H2O2↑,
eff↑, we show that FMD cycles potentiate high-dose vitamin C anti-cancer effects in a range of cancer types
HO-1↓, KRAS-mutant cancer cells respond to vitamin C treatment by up-regulating HO-1, and consequently limiting vitamin C pro-oxidant action. FMD is able to revert HO-1 up-regulation
DNAdam↑, increase in free reactive iron and oxygen species causing DNA damage and cell death
eff↑, we found that the nontoxic FMD + vitamin C combination therapy is as effective as oxaliplatin + vitamin C in delaying tumor progression while the triple FMD, vitamin C and chemotherapy combination treatment is the most effective.

1847- dietFMD,  VitC,    Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers
- in-vitro, PC, PANC1
TumCG↓, Fasting-mimicking diets delay tumor progression
ChemoSen↑, sensitize a wide range of tumors to chemotherapy
eff↑, vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1
HO-1↓, FMD reverses the effect of vitamin C on HO-1(downregulating HO-1)
Ferritin↓,
Iron↑, consequently increasing reactive iron, oxygen species, and cell death
ROS↑, Vitamin C’s pro-oxidant action is strictly dependent on metal-ion redox chemistry. In particular, free iron was shown to be a key player in vitamin C-induced cytotoxic effects
TumCD↑,
IGF-1↓, effects on the insulin-like growth factor 1 (IGF-1)
eff↓, When cancer cells were grown under STS conditions before and during treatment, vitamin C-mediated toxicity was strongly enhanced
eff↓, Conversely, KRAS-wild-type CRC (SW48, HT29), prostate cancer (PC-3), ovarian cancer (COV362) cell lines and a normal colon cell line (CCD841CoN) were resistant to vitamin C when used both as a single agent and in combination with STS

1721- Lyco,  RES,  VitC,    Lycopene, resveratrol, vitamin C and FeSO4 increase damage produced by pro-oxidant carcinogen 4-nitroquinoline-1-oxide in Drosophila melanogaster: Xenobiotic metabolism implications.
- in-vitro, Pca, PC3 - in-vitro, Lung, A549 - in-vitro, Cerv, HeLa - in-vitro, BC, MCF-7 - in-vitro, Liver, HepG2
ROS↑, We propose that the basal levels of the XM's enzymes in the ST cross interacted with a putative pro-oxidant activity of the compounds added to the pro-oxidant effects of 4-NQO.

582- MF,  immuno,  VitC,    Magnetic field boosted ferroptosis-like cell death and responsive MRI using hybrid vesicles for cancer immunotherapy
- in-vitro, Pca, TRAMP-C1 - in-vivo, NA, NA
Fenton↑, boost, Ascorbic acid (AA, C6H8O6) can act as an electron-donor
Ferroptosis↑, HCSVs and MF efficiently inhibited TRAMP-C1 growth through ferroptosis-mediated cell death.
ROS↑, The generated ferrous ions, inducing stronger Fenton-like oxidation than ferric ions, triggered the higher accumulation of ROS, and finally inhibited tumor cell growth
TumCG↓, Collectively, it was proved that the exogenous magnetic field-boosted Fenton reaction efficiently inhibit tumor growth.
Iron↑, after 10-min MF treatment, the increase of ferrous ions was found in 0.1 h
GPx4↓, combination treatment of MF and HCSVs downregulated GPX4

587- MF,  VitC,    Effect of stationary magnetic field strengths of 150 and 200 mT on reactive oxygen species production in soybean
ROS↑,
SOD↓,
other↓, ascorbic acid content decreased

786- Mg,  VitC,    A narrative review on the role of magnesium in immune regulation, inflammation, infectious diseases, and cancer
Risk↓, boasts a significant anti-cancer effect.
*VitD↑, Mg is also essential for the synthesis and distribution of vitamin D
*pH↝, Additionally, the presence of Mg2+ plays a crucial role in regulating the levels of "intracellular free Ca2+ and intracellular pH"
*ROS↓, mitochondrial ROS inhibition (study in frail elderly patients)
TumCG↓, Mg in the diet slowed tumor development in young male rats
eff↑, Mg can enhance the anti-cancer effects of AA. (related to SVCT2 expression)

1254- PI,  VitC,    Piperlongumine combined with vitamin C as a new adjuvant therapy against gastric cancer regulates the ROS–STAT3 pathway
- in-vivo, GC, NA
STAT3⇅, PL effectively suppressed STAT3 activation while VC caused abnormal activation of STAT3.
eff↑, combination of PL and VC exhibited a stronger apoptotic effect compared with either agent alone
ROS↑, PL and VC effectively induced apoptosis of GC cells through oxidative stress.
Apoptosis↑, 15 µM PL and 3 mM VC caused more than 60% apoptosis in two GC cell lines.

918- QC,  CUR,  VitC,    Anti- and pro-oxidant effects of oxidized quercetin, curcumin or curcumin-related compounds with thiols or ascorbate as measured by the induction period method
- Analysis, NA, NA
ROS↑, CUR enhances the prooxidant activity of ascorbate(vit C)
ROS↑, Under anaerobic conditions, QUE, with a catechol ring, may be more prooxidant than CUR, with a phenol ring.

3112- VitC,    Antioxidative and Anti-Inflammatory Activity of Ascorbic Acid
- Review, Nor, NA
*ROS↓, ascorbate as a free radical scavenger but also summarizes its antioxidant action
*antiOx↑,
*SOD↑, activation of antioxidant enzymes, such as superoxide dismutase, catalase, or glutathione peroxidase.
*Catalase↑,
*GPx↑,
*NRF2↑, ascorbate promotes the activity of transcription factors (Nrf2, Ref-1, AP-1), which enables the expression of genes encoding antioxidant proteins
*AP-1↑,
*Inflam↓, Thus, through its antioxidant properties, the molecule prevents inflammation mediated by lipid peroxidation.
*CRP↓, CRP level in human plasma is significantly reduced by ascorbate supplementation
IFN-γ↓,

3114- VitC,    Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression
- in-vitro, AML, NA
TET2↑, Treatment with vitamin C, a cofactor of Fe2+ and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs
eff↑, enhances the efficacy of PARP inhibition in suppressing leukemia progression.
ROS↑, High levels of vitamin C can lead to reactive oxygen species (ROS) production via the Fenton reaction
Fenton↑,
Hif1a↓, One study suggested that vitamin C decreases viability of human leukemia cell lines by promoting downregulation of HIF1α and the anti-apoptotic genes, BCL2, BCL2L1, and MCL1

3108- VitC,  QC,    The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells
- in-vitro, BC, MDA-MB-231 - in-vitro, Lung, A549
NRF2↓, significant decrease in the expression of Nrf2 mRNA and protein levels following the treatment of breast cancer cells with VC and Q
HO-1↓, In the MDA-MB 231 and MCF-7 cell lines, HO1 was significantly suppressed following treatment with VC and Q
ROS↑, It was demonstrated that ROS levels significantly increased in tumor cells treated with VC and Q.
NRF2⇅, it was demonstrated that treatment of MDA-MB 231 cells with 25 µM Q increased the expression of Nrf2, while 50 and 75 µM Q decreased the mRNA levels of Nrf2.

3107- VitC,    Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment
- Review, Var, NA
Risk↓, VitC supplementation resulted in dose-dependent reductions in all-cause mortality and the risk of various cancers
*ROS↓, Vitamin C (VitC) at the physiological dose (μM) is known to exhibit antioxidant properties.
ROS↑, However, it functions as a prooxidant at the pharmacological dose (mM) achieved by intravenous administration.
VEGF↓, VitC suppressed tumor angiogenesis in colon cancer-bearing mice by downregulating the expression and secretion of VEGF-A and VEGF-D
COX2↓, VitC impairs COX-2 activity and inhibits VEGF mRNA expression in melanoma cells in a time-dependent manner
ER Stress↑, VitC increases the ER stress-mediated breast cancer apoptosis via activation of the IRE-JNK-CHOP signaling pathway, an effect independent of ROS
IRE1↑,
JNK↑,
CHOP↑,
Hif1a↓, On the one hand, VitC directly inhibits HIF-1α-mediated glycolysis-related genes expression and the downstream acidic metabolites
eff↑, ROS generated by VitC treatment exerts a synergistic effect with other glycolysis inhibitors, providing a combined therapeutic strategy
Glycolysis↓,
MMPs↓, VitC inhibits a variety of metalloproteinases (MMPs) mRNA, which degrade ECM and release growth factors that drive tumor metastasis
TumMeta↓,
YAP/TEAD↓, VitC treatment reduces YAP1 expression while upregulating SYNPO-2; therefore, inhibiting metastasis of TNBC
eff↑, VitC enhances the killing efficiency of Hep G2 cells by low-dose sorafenib in vitro.
TET1↑, VitC stimulation of TET2 activity in the renal cell carcinoma

3106- VitC,    Protective effect of vitamin C on oxidative stress: a randomized controlled trial
- Trial, Nor, NA
*ROS↓, Vitamin C was suggested to reduce oxidative stress among subjects with atrophic gastritis.

2485- VitC,  TACE,    High-Dose Vitamin C Promotes Regression of Multiple Pulmonary Metastases Originating from Hepatocellular Carcinoma
- Case Report, HCC, NA
ROS↑, high-dose vitamin C can act as a prooxidant, conferring selective toxic effects on cancer cells.
Dose↝, Twenty grams of vitamin C in 250 mL normal saline was initially administered via an ante-cubital vein twice a week in September 2011. To neutralize acidic pH (3.5-5.0) of vitamin C, it was mixed with NaHCO3, resulting in pH 6.2
Dose↝, high-dose vitamin C administration was continued for more than a year. In July 2013, she finally decided to undergo TACE
TumCG↓, Hepatocellular carcinoma regressed completely after the fourth TACE treatment (
Remission↑, describe a case of regression of multiple pulmonary metastases after treatment with high-dose vitamin C, which enabled a subsequent trial of TACE, eventually leading to complete remission

3104- VitC,    Pro- and Antioxidant Effects of Vitamin C in Cancer in correspondence to Its Dietary and Pharmacological Concentrations
*antiOx↑, Vitamin C is an antioxidant that may scavenge reactive oxygen species preventing DNA damage and other effects important in cancer transformation
*ROS↓,
*DNAdam↓,
ROS↑, High pharmacological doses of vitamin C may induce prooxidant effects, detrimental for cancer cells.
TET1↑, Vitamin C may change the metabolomic and epigenetic profiles of cancer cells, and activation of ten-eleven translocation (TET) proteins and downregulation of pluripotency factors by the vitamin may eradicate cancer stem cells.
CSCs↓,
HIF-1↓, Vitamin C induces degradation of hypoxia-inducible factor, HIF-1, essential for the survival of tumor cells in hypoxic conditions
BioAv↑, Flavonoids may modulate bioavailability of vitamin C. Animal studies with flavonoid-rich extracts or purified plant flavonoids showed an enhanced uptake of vitamin C when it was administered together with flavonoids
selectivity↑, Chen et al. demonstrated that intravenous administration of ascorbic acid at high concentrations was toxic for many types of cancer cells in xenografts in mice with no effect on normal cells

3103- VitC,    Effect of Vitamin C on Reactive Oxygen Species Formation in Erythrocytes of Sickle Cell Anemia Patients
- Human, Nor, NA
*ROS↓, Vitamin C reduced ROS formation in HbSS cells. Future studies should focus on a role for Vitamin C as a safe, cheap addition to maintenance therapy of sickle cell patients.

3102- VitC,    Two Faces of Vitamin C—Antioxidative and Pro-Oxidative Agent
- Review, Var, NA - Review, Stroke, NA
*radioP↑, evidence that vitamin C has radioprotective properties.
*Dose↝, recommended daily dose of vitamin C is on average 75 mg for women and 90 mg for men
ROS↑, Under conditions of high, millimolar ascorbate concentration, vitamin C catalyzes the reduction of free transition metal ions, which causes the formation of oxygen radicals. elevated iron levels recognized in cancer cells
*neuroP↑, Ascorbate appears to be a significant neuroprotector
other↓, It is believed that high-dose vitamin C supplementation may be protective and reduce the size of ischemia
*ROS↓, Vitamin C appears to quench ROS, which contributes to the stabilization of the mitochondrial membrane
*MMP↑,

3101- VitC,    Vitamin C stimulates or attenuates reactive oxygen and nitrogen species (ROS, RNS) production depending on cell state: Quantitative amperometric measurements of oxidative bursts at PLB-985 and RAW 264.7 cells at the single cell level
- in-vitro, Nor, RAW264.7 - in-vitro, AML, PLB-985
*antiOx↑, widely publicized as a universal anti-oxidant
*ROS↓, H-atom donors or radical scavengers (AA, vitamins E, Q, glutathione, etc.) present in aerobic cells regulate reactive oxygen and nitrogen species (ROS and RNS) by quenching them to avoid RNS and ROS-induced profound damages to surrounding cells and t
*RNS↓,
ROS↑, PLB‑985(cancer) cells that exhibited enhanced ROS production following AA treatment

114- VitC,  QC,    Chemoprevention of prostate cancer cells by vitamin C plus quercetin: role of Nrf2 in inducing oxidative stress
- in-vitro, Pca, PC3 - in-vitro, NA, DU145
GPx↓,
GSR↓,
NQO1↓,
NRF2↓,
ROS↑,

3150- VitC,    Vitamin C: A Review on its Role in the Management of Metabolic Syndrome
- Review, Obesity, NA
*glucose↓, Vitamin C supplementation resulted in significant decreases in blood glucose 16, BP 17, TG and LDL-C 1
*BG↓,
*antiOx↑, vitamin C is a powerful antioxidant because it acts as a reducing agent preventing other compounds from being oxidised.
*ROS↓,

3148- VitC,    Antioxidants in brain tumors: current therapeutic significance and future prospects
- Review, Var, NA
*antiOx↑, At dietary concentrations, vitamin C exhibits an antioxidant mechanism and prevent tumorigenesis [74]. Vitamin C prevents DNA damage by reducing OS, thereby preventing carcinogenesis
*ROS↓,
chemoP↑, Vitamin C exhibits both chemopreventive and chemotherapeutic roles via antioxidant and prooxidant mechanisms, respectively
ChemoSen↑,
TET2↑, activating ten-eleven translocation proteins (TETs)
eff↑, A regular supplement of vitamin C during pregnancy was found to reduce the risk of the fetus in developing pediatric brain tumors
OS↑, ascorbate demonstrated safety and chemotherapeutic efficacy in prolonging life span and improving quality of life
QoL↑,
eff↑, Vitamin C has been found to enhance the chemotherapeutic effects of methotrexate on glioblastoma cells

3138- VitC,    The Hypoxia-inducible Factor Renders Cancer Cells More Sensitive to Vitamin C-induced Toxicity
- in-vitro, RCC, RCC4 - in-vitro, CRC, HCT116 - in-vitro, BC, MDA-MB-435 - in-vitro, Ovarian, SKOV3 - in-vitro, Colon, SW48 - in-vitro, GBM, U251
eff↑, Here, we show that a Warburg effect triggered by activation of the hypoxia-inducible factor (HIF) pathway greatly enhances Vc-induced toxicity in multiple cancer cell lines
Warburg↓,
BioAv↑, HIF increases the intracellular uptake of oxidized Vc through its transcriptional target glucose transporter 1 (GLUT1),
ROS↑, resulting high levels of intracellular Vc induce oxidative stress and massive DNA damage, which then causes metabolic exhaustion by depleting cellular ATP reserves.
DNAdam↑,
ATP↓,
eff↑, Activation of HIF increases the susceptibility to Vc-induced cell toxicity
necrosis↑, High intracellular levels of Vc increase ROS and trigger necrosis in VHL-defective renal cancer cells.
PARP↑, Activation of the PARP Pathway by Vc Depletes Intracellular ATP Reserves in VHL-defective Renal Cancer Cells

3136- VitC,    Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer
- in-vitro, Colon, SW48 - in-vitro, Colon, LoVo
ERK↓, Vitamin C induces RAS detachment from the cell membrane inhibiting ERK 1/2 and PKM2 phosphorylation.
p‑PKM2↓,
GLUT1↓, As a consequence of this activity, strong downregulation of the glucose transporter (GLUT-1) and pyruvate kinase M2 (PKM2)
Warburg↓, causing a major blockage of the Warburg effect and therefore energetic stress.
TumCD↑, Vitamin C selectively kills KRAS mutant colon cancer cells alone or in combination with cetuximab
eff↑, Remarkably, treatment of HT29, SW480 and LoVo cells with cetuximab (0,4 μM) and vitamin C (5mM) abolished cell growth in the three lines tested.
ROS↓, Interestingly, we detected that vitamin C treatment dramatically reduced intracellular ROS levels in SW480 and LoVo cells (Figure 2D),
cMyc↓, strong inhibition of c-Myc oncogene in colonospheres treated at concentrations of vitamin C as low as 100 μM

3128- VitC,    Vitamin C Mitigates Oxidative Stress and Tumor Necrosis Factor-Alpha in Severe Community-Acquired Pneumonia and LPS-Induced Macrophages
- in-vitro, Nor, NA
*ROS↓, Vitamin C significantly decreased ROS, DNA damage, TNF-α, and IL-6. Vitamin C inhibited LPS-induced ROS, DNA damage, TNF-α, IL-6, and p38 in macrophages cells.
*DNAdam↓,
*TNF-α↓,
*IL6↓,
*p38↓,

3127- VitC,    ROS">Vitamin C inhibits the activation of the NLRP3 inflammasome by scavenging mitochondrial ROS
- in-vitro, Nor, NA - in-vivo, Nor, NA
*NLRP3↓, Here we report that vitamin C has an inhibitory effect on the activation of the NLRP3 inflammasome in vitro and in vivo.
*AIM2↓, Vitamin C also inhibits AIM2 and NLRC4 inflammasomes
*mt-ROS↓, Vitamin C inhibits mitochondrial ROS production
*IL1β↓, Vitamin C inhibits LPS -induced IL-1β production in vivo

3126- VitC,    Safety of High-Dose Vitamin C in Non-Intensive Care Hospitalized Patients with COVID-19: An Open-Label Clinical Study
- Study, NA, NA
*NLRP3↓, ascorbic acid may directly inhibit the NLRP3 inflammasome.
*ROS↓, Ascorbic acid, with its potent antioxidant properties, can scavenge R.O.S., thereby reducing oxidative stress
*antiOx↑,

606- VitC,    Understanding the Therapeutic Potential of Ascorbic Acid in the Battle to Overcome Cancer
- Review, NA, NA
ROS↑, millimolar (mM) concentrations, also functions as a pro-oxidant
H2O2↑,
Fenton↑, elevated copper concentrations ... made cancer cells vulnerable to the ROS-generated selective cytotoxicity of copper and ascorbic acid

605- VitC,    Therapeutic Use of Vitamin C in Cancer: Physiological Considerations
- Review, NA, NA
ROS↑,
ChemoSideEff↓,

599- VitC,    Generation of Hydrogen Peroxide in Cancer Cells: Advancing Therapeutic Approaches for Cancer Treatment
- Review, NA, NA
H2O2↑,
DNAdam↑,
ROS↑,
Fenton↑,
Apoptosis↑, Moderate concentrations of H2O2 typically induce apoptosis
necrosis↑, higher H2O2 concentrations induce necrosis

598- VitC,    Ascorbic Acid in Cancer Treatment: Let the Phoenix Fly
- Review, NA, NA
H2O2↑,
ROS↑,
TET1↑, DNA demethylation mediated by ten-eleven translocation enzyme activation
DNAdam↑,
G6PD∅, **** patients who receive intravenous ascorbate must be prescreened for glucose 6 phosphate dehydrogenase deficiency

597- VitC,  STF,  GlucDep,    The Result of Vitamin C Treatment of Patients with Cancer: Conditions Influencing the Effectiveness
other↝, action as an electron donor
H2O2↑, ascorbate readily undergoes pH-dependent autoxidation creating hydrogen peroxide (H2O2).
ROS↑, high concentration is pro-oxidant (IV 25–30 mmol/L are safely achieved)

596- VitC,    High-Dose Vitamin C in Advanced-Stage Cancer Patients
- Review, NA, NA
ChemoSideEff↓, reducing cancer-related symptoms, such as fatigue and bone pain
ROS↑, is able to reduce catalytic metals such as Fe3+ to Fe2+ and Cu2+ to Cu+, increasing the pro-oxidant chemistry of these metals and facilitating the generation of reactive oxygen species
H2O2↑, Reactions of ascorbate with oxygen or with free transition metal ions lead to the generation of superoxide, H2O2 and highly reactive oxidants, such as the hydroxyl radical by promoting the Fenton chemistry
Fenton↑,
Hif1a↝, Ascorbate regulates the transcription of hypoxia inducible factor-1α (HIF-1α)
Dose↑, Results obtained from in vitro studies revealed that millimolar ascorbate plasma concentrations, achievable only after intravenous vitamin C administration, are cytotoxic to fast-growing malignant cells.
BioAv↓, For this reason, ascorbate concentration in plasma does not exceed 100 μmol/L when it is supplied orally with food; even with oral supplementation approaching maximum tolerated doses, it is always <250 μmol/L
Dose↝, 100 mg, the concentration of ascorbate in daily fasting plasma reaches a plateau between 50–60 µmol/L [24]. Whereas increasing the daily dose ten times to 1000 mg gives only a slight increase in plasma concentration to 70–85 μmol/L
Half-Life↝, high concentrations are relatively transient due to the rapid clearance by the kidneys resulting in a half-life of about 2 h in circulation
IL1β↓, IVC (15–50 g up to three times a week) resulted in reduced CRP levels (in 76 ± 13% of study participants) and reduced concentration of pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, IL-8, tumor necrosis factor TNF-α)
IL2↓,
IL8↓,
TNF-α↓,

623- VitC,    The Involvement of Ascorbic Acid in Cancer Treatment
- Review, NA, NA
ROS↑,
GLUT1↓, VC may impede glucose transport and adenosine triphosphate (ATP) production
ATP↓,

1819- VitC,  VitK3,    The association of vitamins C and K3 kills cancer cells mainly by autoschizis, a novel form of cell death. Basis for their potential use as coadjuvants in anticancer therapy
- Review, Var, NA
Dose?, coadministration of these vitamins (in a ratio of 100:1, for C and K(3), respectively) produced selective cancer cell death.
TumCD↑,
selectivity↑,
H2O2↑, formation of H(2)O(2) during vitamins redox cycling, oxidative stress, DNA fragmentation
ROS↑,
DNAdam↑,

1216- VitC,    Ascorbic acid induces ferroptosis via STAT3/GPX4 signaling in oropharyngeal cancer
- in-vitro, Laryn, FaDu - in-vitro, SCC, SCC-154
Iron↝, impairing iron metabolism
ROS↑,
tumCV↓,
Ki-67↓,
TumCCA↑, accumulation in the G0/G1 phase
Ferroptosis↑,
GSH↓,
ROS↑,
MDA↑,
STAT3↓,
GPx4↓,
p‑STAT3↓,

635- VitC,  VitK3,    The combination of ascorbate and menadione causes cancer cell death by oxidative stress and replicative stress
- in-vitro, NA, NA
RNR↓, VC/VK3 inhibited RNR mainly by targeting its R2 subunit
GSH↓,
Trx1↓, increased highly oxidized Trx1 (oxidized (and generally less active) means effectively less)
GPx↓, VC/VK3 inhibited glutathione peroxidase activity and led to an elevated level of lipid peroxidation, which triggered apoptosis-inducing factor (AIF) mediated cell death pathway.
lipid-P↑,
AIF↑, which triggered apoptosis-inducing factor (AIF) mediated cell death pathway
ROS↑,

633- VitC,    Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment
- Analysis, NA, NA
Fenton↑,
ROS↑,
EMT↓, Ascorbic acid is also known to inhibit EMT of tumor cells
DNAdam↑,
PARP↑, DNA damage increases PARP activity, thereby decreasing NAD+ levels
NAD↓, NAD+
ATP↓,
Apoptosis↑,

632- VitC,    High-Dose Vitamin C: Preclinical Evidence for Tailoring Treatment in Cancer Patients
- Review, NA, NA
SVCT-2∅, vitamin C entry into cells is tightly regulated by SVCT
ROS↑, well-recognized pro-oxidant effects
Hif1a↓, HIF-1α proteasomal degradation
PARP∅, Moreover, vitamin C action at DNA levels may provide the rationale basis for combination therapies with PARP inhibitors and hypomethylating agents.
TET2↑, However, the ability of vitamin C to restore TET2 activity seems to depend on N- and C-terminal lysine acetylation and type of TET2 mutations

631- VitC,    Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2
- vitro+vivo, Liver, NA
SVCT-2∅, response to VC was correlated with sodium-dependent vitamin C transporter 2 (SVCT-2) expressions. Most importantly, SVCT-2 was highly expressed in liver CSCs
ROS↑,
DNAdam↑,
ATP↓,
TumCCA↑,
Apoptosis↑,
OS↑, VC use was linked to improved disease-free survival (DFS) in HCC patients
CD133↓, CD133+
EpCAM↓, EpCAM+
OV6↓, OV6+
γH2AX↑, p-H2AX induced by VC

629- VitC,  Cu,  Fe,    The antioxidant ascorbic acid mobilizes nuclear copper leading to a prooxidant breakage of cellular DNA: implications for chemotherapeutic action against cancer
- in-vitro, NA, NA
ROS↑,
DNAdam↑,
NAD↓,

628- VitC,  Mg,    Enhanced Anticancer Effect of Adding Magnesium to Vitamin C Therapy: Inhibition of Hormetic Response by SVCT-2 Activation
- in-vivo, Colon, CT26 - in-vitro, NA, MCF-7 - in-vitro, NA, SkBr3
AntiCan↑, combined vit c and Mg
SVCT-2↝, Cancer cells that showed high SVCT-2 expression levels were more sensitive to AA treatment (SVCT-2 expression was not changed)
TumCD↑, MgSO4 and MgCl2 significantly increased the cell deaths caused by vitamin C treatment
ROS↑,
P21↑,
proCasp3↑,
TumVol↓, cotreating with vitamin C and magnesium ions inhibited tumor growth more effectively than treating with only vitamin C (mouse)
DNAdam↑,
NAD↓,

627- VitC,    High-Dose Vitamin C for Cancer Therapy
- Review, NA, NA
ROS↑,
PARP↑, ROS activates poly (ADP-ribose) polymerase (PARP), which depletes NAD+
GAPDH↓, Hindering GAPDH can result in an “energy crisis”, due to the decrease in ATP production
DNAdam↑,
ATP↓,

2278- VitK2,  VitK3,  VitC,    Vitamin K: Redox-modulation, prevention of mitochondrial dysfunction and anticancer effect
- Review, Var, NA
ChemoSen↑, The analyzed data suggest that vitamin C&K can sensitize cancer cells to conventional chemotherapy, which allows achievement of a lower effective dose of the drug and minimizing the harmful side-effects.
ROS↑, modulation of redox-balance and induction of oxidative stress in cancer cells due to quinone structure of vitamin K.
eff↑, Vitamin C plus K3: A powerful redox-system to sensitize cancer cells towards chemotherapeutics

1828- VitK3,  VitC,    Pankiller effect of prolonged exposure to menadione on glioma cells: potentiation by vitamin C
- in-vivo, GBM, NA
eff↑, menadione:vitamin C at a ratio 1:100 showed higher anti-proliferative activity when compared to each drug alone and allowed to reduce each drug concentration between 2.5 to 5-fold.
ROS↑, cytotoxic effect of menadione is related to the generation of reactive oxygen species
Dose∅, When used in combination at relatively low doses (M:VC at 10 μM:1 mM) for one week M:VC was able to prevent regrowth

1832- VitK3,  VitC,    Vitamin K3 and vitamin C alone or in combination induced apoptosis in leukemia cells by a similar oxidative stress signalling mechanism
- in-vitro, AML, K562
ROS↑, vitamin K3- or vitamin C- induced apoptosis in leukemia cells by oxidative stress
H2O2↑, hydrogen peroxide generation,
NF-kB↑, activation of NF-κB,
P53↑, p53, c-Jun, protease caspase-3 activation
cJun↑,
Casp3↑,
MMP↓, mitochondria depolarization leading to nuclei fragmentation
DNAdam↑,
Dose?, Jurkat and K562 cells are exposed to VC and VK3 in a ratio 1000:1 (10 mM: 10 μM) or 100:1 (300 μM: 3 μM), respectively

1835- VitK3,  VitC,    Potential therapeutic application of the association of vitamins C and K3 in cancer treatment
- Review, Var, NA
ROS↑, A large body of evidence supports the idea that oxidative stress induced by redox cycling of vitamins C and K(3) in association surpasses cancer cellular defense systems and results in cell death
TumCD↑,
TumCG↓, Combined vitamin C and K(3) administration in vitro and in vivo produced tumor growth inhibition and increased the life-span of tumor-bearing mice.
OS↑,

1837- VitK3,  VitC,    Alpha-Tocopheryl Succinate Inhibits Autophagic Survival of Prostate Cancer Cells Induced by Vitamin K3 and Ascorbate to Trigger Cell Death
- in-vivo, Pca, NA
eff↑, the combination of α-TOS, VK3 and AA was more efficient in tumor suppression than when the drugs were given separately, without deleterious side effects.
ROS↑, The generation of ROS, cellular response to oxidative stress, and autophagy were investigated in PC3 prostate cancer cells by using drugs at sub-toxic doses.
TumAuto↑, ROS can induce autophagy


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 48

Results for Effect on Cancer/Diseased Cells:
AIF↑,1,   AntiCan↑,1,   Apoptosis↑,4,   ATP↓,5,   BioAv↓,1,   BioAv↑,2,   Casp3↑,1,   proCasp3↑,1,   CD133↓,1,   chemoP↑,1,   ChemoSen↑,4,   ChemoSideEff↓,3,   CHOP↑,1,   cJun↑,1,   cMyc↓,1,   COX2↓,1,   CSCs↓,1,   DNAdam↑,11,   Dose?,2,   Dose↑,1,   Dose↝,3,   Dose∅,1,   eff↓,5,   eff↑,16,   EMT↓,1,   EpCAM↓,1,   ER Stress↑,1,   ERK↓,1,   Fenton↑,7,   Ferritin↓,1,   Ferroptosis↑,2,   G6PD∅,1,   GAPDH↓,1,   GLUT1↓,2,   Glycolysis↓,1,   GPx↓,2,   GPx4↓,2,   GSH↓,2,   GSR↓,1,   H2O2↑,8,   Half-Life↝,1,   HIF-1↓,1,   Hif1a↓,3,   Hif1a↝,1,   HO-1↓,3,   IFN-γ↓,1,   IGF-1↓,1,   IL1β↓,1,   IL2↓,1,   IL8↓,1,   IRE1↑,1,   Iron↑,2,   Iron↝,1,   JNK↑,1,   Ki-67↓,1,   lipid-P↑,1,   MDA↑,1,   MMP↓,1,   MMPs↓,1,   NAD↓,3,   necrosis↑,2,   NF-kB↑,1,   NQO1↓,1,   NRF2↓,2,   NRF2⇅,1,   OS↑,3,   other↓,2,   other↝,2,   OV6↓,1,   P21↑,1,   P53↑,1,   PARP↑,3,   PARP∅,1,   p‑PKM2↓,1,   QoL↑,1,   Remission↑,1,   Risk↓,2,   RNR↓,1,   ROS↓,1,   ROS↑,40,   selectivity↑,2,   SOD↓,1,   STAT3↓,1,   STAT3⇅,1,   p‑STAT3↓,1,   SVCT-2↝,1,   SVCT-2∅,2,   TET1↑,3,   TET2↑,3,   TNF-α↓,1,   Trx1↓,1,   TumAuto↑,1,   TumCCA↑,2,   TumCD↑,5,   TumCG↓,6,   tumCV↓,1,   TumMeta↓,1,   TumVol↓,1,   VEGF↓,1,   Warburg↓,2,   YAP/TEAD↓,1,   γH2AX↑,1,  
Total Targets: 102

Results for Effect on Normal Cells:
AIM2↓,1,   antiOx↑,6,   AP-1↑,1,   BG↓,1,   Catalase↑,1,   CRP↓,1,   DNAdam↓,2,   Dose↝,1,   glucose↓,1,   GPx↑,1,   IL1β↓,1,   IL6↓,1,   Inflam↓,1,   MMP↑,1,   neuroP↑,1,   NLRP3↓,2,   NRF2↑,1,   p38↓,1,   pH↝,1,   radioP↑,1,   RNS↓,1,   ROS↓,12,   mt-ROS↓,1,   SOD↑,1,   TNF-α↓,1,   VitD↑,1,  
Total Targets: 26

Scientific Paper Hit Count for: ROS, Reactive Oxygen Species
48 Vitamin C (Ascorbic Acid)
7 VitK3,menadione
3 Quercetin
2 diet FMD Fasting Mimicking Diet
2 Magnetic Fields
2 Magnesium
1 Artemisinin
1 Lycopene
1 Resveratrol
1 immunotherapy
1 Piperine
1 Curcumin
1 Transarterial Chemoembolization
1 Short Term Fasting
1 glucose deprivation
1 Copper and Cu NanoParticlex
1 Iron
1 Vitamin K2
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:166  Target#:275  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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