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| "Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals." For example Vitamin C (normally Antioxidant), Vitamin e, and Trolox are anti-oxidants. Berries: Blueberries, Strawberries, Raspberries, Blackberries Fruits: Grapes, Pomegranates, Oranges, Apples Vegetables: Spinach and other leafy greens, Kale, Broccoli, Brussels sprouts Nuts and Seeds: Walnuts, Almonds, Flaxseeds, Chia seeds Beverages: Green tea, Black tea Spices and Herbs: curcumin, Ginger, Garlic, Cinnamon Other: Dark chocolate (with high cocoa content), Beans and legumes, Tomatoes (rich in lycopene) Antioxidants are compounds that help neutralize free radicals—unstable molecules that can damage cells and contribute to the development of chronic diseases including cancer. Cancer Prevention: Mechanism: Antioxidants protect cells from oxidative damage caused by free radicals, which can lead to mutations in DNA. Over time, these mutations might initiate or promote the growth of cancer cells. Dietary Role: Eating a diet rich in antioxidants (fruits, vegetables, and other plant-based foods) has been associated with a lower risk of some cancers. Many epidemiological studies suggest that diets high in natural antioxidants are linked to a reduced risk of cancer. During Cancer Treatment: Controversy: There is debate about whether taking antioxidant supplements during chemotherapy or radiation therapy is beneficial or harmful. Many therapies such as Chemotherapy raise the ROS(Reactive oxygen Species) intentionally to kill cancer cells. Some theory applies that antioxidants might prevent the ROS from being raised, and hence reduce treatment effectiveness. Some laboratory and clinical studies indicate that antioxidants might protect not only healthy cells but also cancer cells against the oxidative damage intentionally induced by these treatments. This could potentially reduce the effectiveness of cancer therapies. Another theory is there is a differential effect from taking antioxidants. Meaning the antioxidants help protect normal cells, but not the cancer cells. Recommendation: Many oncologists recommend caution with high-dose antioxidant supplements during active cancer treatment. Instead, a balanced diet with naturally occurring antioxidants is typically advised. thiol-containing antioxidants: -Contain a functional –SH (sulfhydryl) group -Can undergo oxidation to form disulfide bonds. This reversible redox behavior allows these molecules to neutralize reactive oxygen species (ROS). -Thiol antioxidants (like N‑acetylcysteine or glutathione) are potent because the –SH group can directly scavenge ROS. -There is concern that supplementation with thiol antioxidants during chemotherapy could neutralize some of the ROS generated by the treatment, potentially reducing the intended cytotoxic effects on cancer cells. Examples: -NAC -GSH -NMPG -dihydrolipoic acid (reduced form of ALA) -Cysteamine -Ergothioneine -Thioredoxin Non-thiol ROS scavengers: -Act by donating electrons or hydrogen atoms to free radicals, thereby stabilizing them or converting them into less reactive species. -Non‑thiol antioxidants (like vitamin C, vitamin E, flavonoids, etc.) have different mechanisms of action and may not interact as directly with ROS in the specific context of chemotherapy-induced cell death. -That said, even non‑thiol antioxidants could potentially interfere with chemotherapy in some cases. For example, high doses of vitamin C or vitamin E might also diminish the oxidative stress essential for the efficacy of some chemotherapeutics. Examples -Ascorbic Acid(VitC) -Vitamin E -Flavoniods (Quercetin) -Carotenoids(beta-carotene) -Resveratrol -Coenzyme Q10 (ubiquinone) -Curcumin (indirectly disrupt thiol systems) -Polyphenols (ferulic acid and caffeic acid) -manganese(III) -tetrakis( (4-benzoic acid) -porphyrin chloride (MnTBAP) -SOD *** NOTE: Thiol AntiOxidants could block ROS generation caused by Gambogic Acid, but not NON-Thiol AntiOxidants. -Thiol-based antioxidants directly support glutathione and thioredoxin buffering and are most likely to protect cancer cells from ROS- or thiol-dependent therapies. Non-thiol antioxidants may act as radical scavengers, redox modulators, or—under certain tumor-specific conditions—pro-oxidants. Therefore, the likelihood that an antioxidant interferes with cancer therapy depends less on whether it ‘scavenges ROS’ and more on whether it restores thiol redox homeostasis or activates cytoprotective signaling pathways such as NRF2. OTHER CLASSES of antioxidants 1. Enzymatics Antioxidants (SOD, Catalase, GPXs) -proteins that catalyze reactions to detoxify reactive oxygen species (ROS). 2. Non-Enzymatic (Small-Molecule) Antioxidants. Further divided to Thiol-Based Antioxidants, vs Non-Thiol Based Antioxidants. 3. Metal-Binding Proteins and Chelators (Ferritin, Transferrin) These compounds limit oxidative damage indirectly by sequestering transition metals (like iron and copper) that catalyze reactive oxygen species formation via the Fenton reaction. 4. Indirect Antioxidants (Nrf2 Activators): (Sulforaphane, Curcumin) enhance the body’s own antioxidant defenses by upregulating the expression of antioxidant enzymes. Cancer-Relevant Antioxidant Matrix (Oral/achievable doses)
Compatible – No known interference at oral doses Cond. (Conditional) – Timing, dose, or regimen dependent Caution – Likely to interfere with ROS-dependent therapies [T] = Timing-sensitive (avoid peri-infusion / ROS-dependent window) [D] = Dose-dependent (low vs high dose behave differently) [M] = Mechanism-dependent (NRF2, ETC, thiol buffering, metal chelation) [H] = Hormone- or receptor-dependent [F] = Form-dependent (chemical form matters)(organic vs nano) *NRF2 Explanation not necessarily reflected in ratings (example Quercetin) -NRF2↑ in normal cells is the dominant pattern -In cancer cells, NRF2 upregulation is possible, but not dominant, and often context-suppressed by stronger pro-oxidant mechanisms. Smaller <50 nm SeNPs generate ROS more efficiently; may interfere with ROS-dependent chemo if given concurrently Chemo compatibility assumes ROS-dependent cytotoxic modalities (e.g., anthracyclines, platinum agents, radiation). Non-ROS-dependent therapies may not share these constraints. *β-carotene is incompatible primarily in smokers / high-oxygen tissues (RCT harm signal in smokers/asbestos-exposed groups) Arrows show whether ROS increases (↑), decreases (↓), or neutral/variable (↔) Thiol Buffering Index (0–4): | TBI Score | Meaning | | --------- | ------------------------------------------------------------------------------------------------------ | | 0 | No effect on thiol pools; does not buffer redox stress (mostly non-thiol antioxidants) | | 1 | Minimal indirect thiol effect; may slightly modulate thiol-dependent enzymes | | 2 | Moderate indirect thiol effect; may perturb thiols or partially modulate GSH/Trx system | | 3 | Significant thiol buffering; contributes to redox stabilization in cancer cells | | 4 | Strong direct thiol donor; substantially increases GSH/thioredoxin pools; higher chemo interference risk | Note the table is very general, and database searches and details should be researched for each compound of interest. Example: Luteolin can show NRF2 down in cancer cells |
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| 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. -mitochondria is the main source of reactive oxygen species (ROS) (and the ETC is heavily related) "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 inhibition: 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 inhibition: 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 inhibition:regulates the expression of antioxidant genes. Inhibiting SIRT1 can increase ROS levels • AMPK activation: regulates energy metabolism and can increase ROS levels when activated. • mTOR inhibition: regulates cell growth and metabolism. Inhibiting mTOR can increase ROS levels • HSP90 inhibition: 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 Mevalonate 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 Combined effect research -Lycopene typically 100mg/day range (note debatable as it mainly lowers NRF2) Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy ROS-Inducing Interventions in Cancer — Canonical + Mechanistic Reference -generated from AI and Cancer database ROS rating: +++ strong | ++ moderate | + weak | ± mixed | 0 none NRF2: ↓ suppressed | ↑ activated | ± mixed | 0 none Conditions: [D] dose [Fe] metal [M] metabolic [O₂] oxygen [L] light [F] formulation [T] tumor-type [C] combination
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| 4759- | antiOx, | Chemo, | Potential Contributions of Antioxidants to Cancer Therapy: Immunomodulation and Radiosensitization |
| - | Review, | Var, | NA |
Query results interpretion may depend on "conditions" listed in the research papers. Such Conditions may include : -low or high Dose -format for product, such as nano of lipid formations -different cell line effects -synergies with other products -if effect was for normal or cancerous cells
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