| Features: antioxidant, energy production in cell mitochondria |
| Alpha-Lipoic-Acid: also known as lipoic acid or thioctic acid (reduced form is dihydrolipoic acid). "Universal antioxidant" because it is both water- and fat-soluble and can neutralize free radicals. -Treatment sometimes as ALA/N (alpha-lipoic acid/low-dose naltresone) -Also done in IV -Decreases ROS production, but also has pro-oxidant role. Normal adult can take 300 milligrams twice a day with food, but they should always take a B-complex vitamin with it. Because B complex vitamins, especially thiamine, and biotin, and riboflavin, are depleted during this metabolic process. α-Lipoic acid acts as a chelating agent for metal ions, a quenching agent for reactive oxygen species, and a reducing agent for the oxidized form of glutathione and vitamins C and E. -It seems a paradox that LA functions as both antioxidant and prooxidant. LA functions the pro-oxidant only in special cancer cells, such as A549 and PC9 cells which should show high-level NRF2 expression and high glycolytic level. Through inhibiting PDK1 to further prohibit NRF2; LA functions as anticancer prooxidant. α-lipoic acid possesses excellent silver chelating properties. - ALA acts as pro-Oxidant only in cancer cells:#278 - Pro-Oxidant Dose margin >100uM:#304 - Bioavailability: 80-90%, but conversion to EPA/DHA is 5-10% (and takes longer time). - AI (Adequate Intake): 1.1-1.6g/day. - human studies have shown that ALA levels decline significantly with age - 1g of ALA might achieve 500uM in the blood. - ALA is poorly soluble, lecithin has been used as an amphiphilic matrix to enhance its bioavailability. - Pilot studies or observational interventions have used flaxseed supplementation (rich in ALA) in doses providing roughly 3–4 g of ALA daily. - Flaxseed oil is even more concentrated in ALA – typical 50–60% ALA by weight. - single walnut may contain 300mg of ALA - chia oil contains 55-65% ALA. - α-LA can also be obtained from the diet through the consumption of dark green leafy vegetables and meats - ALA is more stable in chia seeds, (2grams of ALA per tablespoon) - ALA degrades when exposed to heat, light, and air. (prone to oxidation) -Note half-life 1-2 hrs. BioAv 30-40% from walnuts, 60-80% from supplements. Co-ingestion with fat improves absorption. Both fat and water soluble Pathways: - induce ROS production - ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Cyt‑c↑, Caspases↑, DNA damage↑, - Lowers AntiOxidant defense in Cancer Cells: NRF2↓, SOD↓, GSH↓ Catalase↓ HO1↓ GPx↓ - Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑, - lowers Inflammation : NF-kB↓, COX2↓, Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓, IL-8↓ - inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, IGF-1↓, VEGF↓, FAK↓, NF-κB↓, TGF-β↓, α-SMA↓, ERK↓ - cause Cell cycle arrest : TumCCA↑, cyclin D1↓, - inhibits Migration/Invasion : TumCMig↓, TumCI↓, TNF-α↓, FAK↓, ERK↓, EMT↓, - inhibits glycolysis and ATP depletion : HIF-1α↓, PKM2↓, GLUT1↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, ECAR↓, OXPHOS↓, GRP78↑, Glucose↓, GlucoseCon↓ - inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓, Integrins↓, - small indication of inhibiting Cancer Stem Cells : CSC↓, CD24↓, β-catenin↓, - Others: PI3K↓, AKT↓, JAK↓, STAT↓, β-catenin↓, AMPK, ERK↓, JNK, - Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective, - Selectivity: Cancer Cells vs Normal Cells |
| Source: |
| Type: |
| Oxidative phosphorylation (or phosphorylation) is the fourth and final step in cellular respiration. Alterations in phosphorylation pathways result in serious outcomes in cancer. Many signalling pathways including Tyrosine kinase, MAP kinase, Cadherin-catenin complex, Cyclin-dependent kinase etc. are major players of the cell cycle and deregulation in their phosphorylation-dephosphorylation cascade has been shown to be manifested in the form of various types of cancers. Many tumors exhibit a well-known metabolic shift known as the Warburg effect, where glycolysis is favored over OxPhos even in the presence of oxygen. However, this is not universal. Many cancers, including certain subpopulations like cancer stem cells, still rely on OXPHOS for energy production, biosynthesis, and survival. – In several cancers, especially during metastasis or in tumors with high metabolic plasticity, OxPhos can remain active or even be upregulated to meet energy demands. In some cancers, high OxPhos activity correlates with aggressive features, resistance to standard therapies, and poor outcomes, particularly when tumor cells exploit mitochondrial metabolism for survival and metastasis. – Conversely, low OxPhos activity can be associated with a reliance on glycolysis, which is also linked with rapid tumor growth and certain adverse prognostic features. Inhibiting oxidative phosphorylation is not a universal strategy against all cancers. Targeting OXPHOS can potentially disrupt the metabolic flexibility of cancer cells, leading to their death or making them more susceptible to other treatments. Since normal cells also rely on OXPHOS, inhibitors must be carefully targeted to avoid significant toxicity to healthy tissues. Not all tumors are the same. Some may be more glycolytic, while others depend more on mitochondrial metabolism. Therefore, metabolic profiling of tumors is crucial before adopting this strategy. Inhibiting OXPHOS is being explored in combination with other treatments (such as chemo- or immunotherapies) to improve efficacy and overcome resistance. In cancer cells, metabolic reprogramming is a hallmark where cells often rely on glycolysis (known as the Warburg effect); however, many cancer types also depend on OXPHOS for energy production and survival. Targeting OXPHOS(using inhibitor) to increase the production of reactive oxygen species (ROS) can selectively induce oxidative stress and cell death in cancer cells. -One side effect of increased OXPHOS is the production of reactive oxygen species (ROS). -Many cancer cells therefore simultaneously upregulate antioxidant systems to mitigate the damaging effects of elevated ROS. -Increase in oxidative phosphorylation can inhibit cancer growth. |
| 3447- | ALA, | Redox Active α-Lipoic Acid Differentially Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer and Its Control Cells |
| - | in-vitro, | AD, | SH-SY5Y |
Filter Conditions: Pro/AntiFlg:% IllCat:% CanType:% Cells:% prod#:29 Target#:230 State#:% Dir#:%
wNotes=on sortOrder:rid,rpid