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 |
|