Alpha-Lipoic-Acid / mTOR Cancer Research Results

ALA, Alpha-Lipoic-Acid: Click to Expand ⟱
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 → ROS ↑ (cancer cells; high dose / stressed mitochondria)
ALA → ROS ↓ (normal cells; low–moderate dose)
same pattern seen with: Vitamin C, Menadione, Quercetin, EGCG, Resveratrol
- 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

Cancer-Relevant Pathways
Rank Pathway / Axis Cancer Cells Normal Cells Label Interpretation Notes
1 Reactive oxygen species (ROS) ↑ ROS (dose- & stress-dependent) ↓ ROS Conditional Driver Biphasic redox behavior ALA/DHLA redox cycling can push already stressed cancer mitochondria past tolerance while buffering ROS in normal cells
2 Glutathione (GSH) system ↓ functional buffering ↑ GSH regeneration Secondary Redox amplification vs protection In cancer cells, GSH consumption accompanies ROS escalation; in normal cells DHLA supports GSH recycling
3 Mitochondrial function (ΔΨm) ↓ ΔΨm (stress-induced) ↔ stabilized Secondary Mitochondrial selectivity Cancer cells with unstable ETC show depolarization; normal cells tolerate or benefit metabolically
4 NF-κB signaling ↓ survival signaling ↓ inflammatory tone Secondary Redox-sensitive transcription NF-κB suppression reduces cancer cell survival programs but is anti-inflammatory in normal tissue
5 Cell proliferation ↓ proliferation ↔ spared Phenotypic Cytostatic selectivity ALA slows cancer cell cycling without universal apoptosis
6 Apoptosis ↑ apoptosis (conditional) ↓ apoptosis Phenotypic Threshold-dependent death Occurs in cancer cells when redox stress exceeds buffering capacity
7 NRF2 antioxidant response ↑ NRF2 (adaptive, often insufficient) ↑ NRF2 (protective) Adaptive Stress compensation NRF2 reflects attempted redox recovery; not a kill mechanism


mTOR, mammalian target of rapamycin: Click to Expand ⟱
Source: HalifaxProj (inhibit)
Type:
mTOR (mechanistic target of rapamycin) is a central regulator of cell growth, proliferation, metabolism, and survival. It is a serine/threonine kinase that integrates signals from nutrients, growth factors, and cellular energy status.
mTOR promotes protein synthesis and cell growth by activating downstream targets such as S6 kinase and 4E-BP1. In cancer, this pathway can become hyperactivated, leading to uncontrolled cell proliferation.

mTor Inhibitors:
-rapamycin (Sirolimus): classic natural product mTOR inhibitor
-Curcumin
-Resveratrol
-Epigallocatechin Gallate (EGCG)
-Honokiol
Scientific Papers found: Click to Expand⟱
3434- ALA,    Alpha lipoic acid modulates metabolic reprogramming in breast cancer stem cells enriched 3D spheroids by targeting phosphoinositide 3-kinase: In silico and in vitro insights
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
tumCV↓, PI3K↓, p‑Akt↓, p‑P70S6K↓, mTOR↓, ATP↓, GlucoseCon↓, ROS↑, PKM2↓, LDHA↓, Glycolysis↓, ChemoSen↑,
3454- ALA,    Lipoic acid blocks autophagic flux and impairs cellular bioenergetics in breast cancer and reduces stemness
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
TumCG↑, Glycolysis↓, ROS↑, CSCs↓, selectivity↑, LC3B-II↑, MMP↓, mitResp↓, ATP↓, OCR↓, NAD↓, p‑AMPK↑, GlucoseCon↓, lactateProd↓, HK2↓, PFK↓, LDHA↓, eff↓, mTOR↓, ECAR↓, ALDH↓, CD44↓, CD24↓,
262- ALA,    Lipoic acid decreases breast cancer cell proliferation by inhibiting IGF-1R via furin downregulation
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
TumCP↓, Akt↓, ERK↓, IGF-1R↓, Furin↓, Ki-67↓, AMPK↑, mTOR↓,
1124- ALA,    Alpha lipoic acid inhibits proliferation and epithelial mesenchymal transition of thyroid cancer cells
- in-vitro, Thyroid, BCPAP - in-vitro, Thyroid, HTH-83 - in-vitro, Thyroid, CAL-62 - in-vitro, Thyroid, FTC-133 - in-vivo, NA, NA
TumCP↓, AMPK↑, mTOR↓, TumCMig↓, TumCI↓, EMT↓, E-cadherin↑, β-catenin/ZEB1↓, Vim↓, Snail↓, Twist↓, TGF-β↓, p‑SMAD2↓, TumCG↓,
297- ALA,    Insights on the Use of α-Lipoic Acid for Therapeutic Purposes
- Review, BC, SkBr3 - Review, neuroblastoma, SK-N-SH - Review, AD, NA
PDH↑, TumCG↓, ROS↑, AMPK↑, EGR4↓, Half-Life↓, BioAv↝, *GSH↑, *IronCh↑, *ROS↓, *antiOx↑, *neuroP↑, *Ach↑, *lipid-P↓, *IL1β↓, *IL6↓, TumCP↓, FDG↓, Apoptosis↑, AMPK↑, mTOR↓, EGFR↓, TumCI↓, TumCMig↓, *memory↑, *BioAv↑, *BioAv↝, *other↓, *other↝, *Half-Life↓, *BioAv↑, *ChAT↑, *GlucoseCon↑,

Showing Research Papers: 1 to 5 of 5

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 5

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

ROS↑, 3,  

Mitochondria & Bioenergetics ⓘ

ATP↓, 2,   mitResp↓, 1,   MMP↓, 1,   OCR↓, 1,  

Core Metabolism/Glycolysis ⓘ

AMPK↑, 4,   p‑AMPK↑, 1,   ECAR↓, 1,   FDG↓, 1,   GlucoseCon↓, 2,   Glycolysis↓, 2,   HK2↓, 1,   lactateProd↓, 1,   LDHA↓, 2,   NAD↓, 1,   PDH↑, 1,   PFK↓, 1,   PKM2↓, 1,  

Cell Death ⓘ

Akt↓, 1,   p‑Akt↓, 1,   Apoptosis↑, 1,  

Transcription & Epigenetics ⓘ

tumCV↓, 1,  

Autophagy & Lysosomes ⓘ

LC3B-II↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

ALDH↓, 1,   CD24↓, 1,   CD44↓, 1,   CSCs↓, 1,   EMT↓, 1,   ERK↓, 1,   IGF-1R↓, 1,   mTOR↓, 5,   p‑P70S6K↓, 1,   PI3K↓, 1,   TumCG↓, 2,   TumCG↑, 1,  

Migration ⓘ

E-cadherin↑, 1,   Furin↓, 1,   Ki-67↓, 1,   p‑SMAD2↓, 1,   Snail↓, 1,   TGF-β↓, 1,   TumCI↓, 2,   TumCMig↓, 2,   TumCP↓, 3,   Twist↓, 1,   Vim↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature ⓘ

EGFR↓, 1,   EGR4↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↝, 1,   ChemoSen↑, 1,   eff↓, 1,   Half-Life↓, 1,   selectivity↑, 1,  

Clinical Biomarkers ⓘ

EGFR↓, 1,   Ki-67↓, 1,  
Total Targets: 56

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 1,   GSH↑, 1,   lipid-P↓, 1,   ROS↓, 1,  

Metal & Cofactor Biology ⓘ

IronCh↑, 1,  

Core Metabolism/Glycolysis ⓘ

GlucoseCon↑, 1,  

Transcription & Epigenetics ⓘ

Ach↑, 1,   other↓, 1,   other↝, 1,  

Immune & Inflammatory Signaling ⓘ

IL1β↓, 1,   IL6↓, 1,  

Synaptic & Neurotransmission ⓘ

ChAT↑, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↑, 2,   BioAv↝, 1,   Half-Life↓, 1,  

Clinical Biomarkers ⓘ

IL6↓, 1,  

Functional Outcomes ⓘ

memory↑, 1,   neuroP↑, 1,  
Total Targets: 18

Scientific Paper Hit Count for: mTOR, mammalian target of rapamycin
5 Alpha-Lipoic-Acid
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

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:29  Target#:209  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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