Alpha-Lipoic-Acid / ERK 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

Lipoic Acid Cancer Mechanisms

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Mitochondrial redox and ROS ↑ mitochondrial ROS; ↔/↓ total ROS (context-dependent) ↓ ROS P/R Apoptosis and redox disruption Central but bidirectional mechanism. HT-29 and A549 models show pro-oxidant ROS-mediated death, whereas MCF-7 and some prostate models show ROS lowering with growth inhibition.
2 PI3K Akt survival signaling ↓ Akt; ↑ p27; ↓ proliferation ↔/↑ Akt (context-dependent) R/G Cell-cycle arrest and apoptosis Breast cancer studies demonstrate suppression of Akt with G1 arrest, Bax/Bcl-2 shift and apoptotic signaling.
3 Mitochondria and MPTP ↑ permeability transition; ↓ membrane potential; ↑ cytochrome c Generally protected from oxidative mitochondrial injury R Intrinsic apoptosis Provides a mechanistic bridge between altered mitochondrial metabolism, ROS production and caspase activation.
4 ER stress CHOP XBP1 ↑ GRP78; ↑ CHOP; ↑ XBP1; ↑ caspases Not established as a therapeutic effect R/G ER-stress-mediated apoptosis Demonstrated prominently in A549 lung cancer cells and substantially dependent on ROS.
5 Ca²⁺ and TRPV1 signaling ↑ Ca²⁺; ↑ TRPV1-dependent mitochondrial apoptosis Context-dependent P/R Apoptotic amplification Particularly evident with cisplatin; Ca²⁺ has also been implicated in ALA-induced lung-cancer apoptosis.
6 Bax Bcl-2 caspase axis ↑ Bax; ↓ Bcl-2/Bcl-XL; ↑ caspase-3/9; ↑ PARP cleavage Often ↓ inappropriate apoptosis during oxidative injury R/G Apoptosis Downstream convergence point for multiple ALA-responsive pathways.
7 KEAP1 NRF2 p62 ↓ NRF2/p62 in selected prostate models ↑ NRF2; ↑ HO-1/SOD antioxidant defense R/G Context-dependent redox regulation NRF2 should not be classified simply as increased or decreased. ALA activates protective NRF2 signaling in normal cells but can suppress NRF2 in some malignant cells.
8 Glutathione redox system ↑ GSH in some models; ↓ functional antioxidant defense during pro-oxidant killing (context-dependent) ↑ GSH; ↑ GSH/GSSG ratio; ↑ antioxidant protection R/G Redox buffering and context-dependent modulation of apoptosis ALA/DHLA can increase intracellular GSH and stimulate GSH synthesis, particularly in normal or oxidatively stressed cells. In cancer cells, however, increased GSH can oppose ROS-dependent ALA cytotoxicity; several anticancer models instead show ROS accumulation or suppression of antioxidant enzymes. Therefore GSH is mechanistically important but not uniformly anticancer.
9 Autophagy mTOR Beclin-1 LC3 ↓ Beclin-1; ↓ LC3; ↓ autophagy in prostate models Context-dependent G Reduced cancer-cell survival ALA-associated ↑ mTOR and inhibition of autophagy have been reported in LNCaP and DU-145 cells; not established as universal.
10 NF-κB IKK inflammatory signaling ↓ NF-κB (model-dependent) ↓ inflammatory NF-κB activation R/G Reduced survival and inflammatory signaling ALA can inhibit IKK/NF-κB independently of its antioxidant activity, but much of the evidence is from non-malignant experimental systems.
11 Integrin FAK EMT invasion ↓ β1-integrin/FAK; ↓ MMP-2/MMP-9; ↓ EMT Not established G Reduced migration and invasion Preclinical evidence supports antimetastatic effects, but systemic clinical relevance has not been established.
12 Chemosensitization ↑ cisplatin-associated ROS, Ca²⁺ and apoptosis (model-dependent) ↓ chemotherapy-associated oxidative injury in several normal tissues R/G Potential selective treatment modulation ALA can enhance cisplatin cytotoxicity in cultured cancer cells while protecting normal tissue in other models. Clinical net effect on antitumor efficacy is unresolved.
13 Radiosensitivity and radioprotection ↔ antitumor radiosensitization not established ↓ radiation-induced ROS and tissue injury R/G Predominantly radioprotection Human and preclinical literature is oriented toward mitigation of normal-tissue radiation toxicity rather than tumor radiosensitization.
14 Clinical Translation Constraint Common experimental concentrations exceed oral systemic exposure Systemic antioxidant effects occur at clinically used doses G Limits direct anticancer translation Oral bioavailability is approximately 30%, elimination is rapid, and many cancer experiments use 250–1000 µM compared with transient human plasma concentrations typically in the low tens of micromolar.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr

Lipoic acid and Alzheimer’s disease — ALA has sufficient AD-specific mechanistic and human evidence to justify a separate database section, although efficacy remains unproven. Its rationale includes mitochondrial cofactor activity, reduction of oxidative stress, regeneration of endogenous antioxidants, modulation of inflammatory signaling and potential improvement of neuronal glucose/energy metabolism. Small open-label studies using 600 mg/day reported slower cognitive decline, while a small randomized trial of omega-3 plus 600 mg/day ALA found less decline in selected MMSE and instrumental-ADL outcomes but no benefit in its primary oxidative-stress endpoint or ADAS-cog. Another randomized antioxidant combination containing 900 mg/day ALA produced an unexpected greater MMSE decline, making the clinical evidence mixed and insufficient for therapeutic conclusions.

Clinical evidence status: Small human / pilot RCT / adjunct use. No adequately powered confirmatory trial establishes ALA as a disease-modifying treatment for Alzheimer’s disease.

Lipoic Acid in Alzheimer’s Disease

Rank Pathway / Axis Modulation Primary Effect Notes / Interpretation
1 Oxidative stress and glutathione redox cycling ↓ ROS; ↑ antioxidant capacity Neuroprotection ALA/DHLA can scavenge oxidants and regenerate endogenous antioxidant systems; biologically plausible but clinical disease modification is unproven.
2 Mitochondrial energy metabolism ↑ mitochondrial cofactor function Support of neuronal bioenergetics Lipoyl groups are essential cofactors for pyruvate and α-ketoglutarate dehydrogenase complexes.
3 NRF2 antioxidant response ↑ NRF2-associated antioxidant defense Reduced oxidative injury Well supported mechanistically in non-cancer tissues but direct AD clinical validation is limited.
4 NF-κB inflammatory signaling ↓ NF-κB Reduced neuroinflammatory signaling Mechanistically plausible; much supporting evidence is indirect rather than from human AD brain studies.
5 Cognitive and functional decline ↔/↓ decline (study-dependent) Possible clinical neuroprotection Small open-label and omega-3 plus ALA studies produced signals of benefit, but larger confirmatory evidence is lacking and antioxidant-combination data include a possible adverse cognitive signal.


ERK, ERK signaling: Click to Expand ⟱
Source:
Type:
MAPK3 (ERK1)
ERK proteins are kinases that activate other proteins by adding a phosphate group. An overactivation of these proteins causes the cell cycle to stop.
The extracellular signal-regulated kinase (ERK) signaling pathway is a crucial component of the mitogen-activated protein kinase (MAPK) signaling cascade, which plays a significant role in regulating various cellular processes, including proliferation, differentiation, and survival. high levels of phosphorylated ERK (p-ERK) in tumor samples may indicate active ERK signaling and could correlate with aggressive tumor behavior

EEk singaling is frequently activated and is often associated with aggressive tumor behavior, treatment resistance, and poor outcomes.
Scientific Papers found: Click to Expand⟱
3272- ALA,    Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential
- Review, AD, NA
*antiOx↑, LA has long been touted as an antioxidant,
*glucose↑, improve glucose and ascorbate handling,
*eNOS↑, increase eNOS activity, activate Phase II detoxification via the transcription factor Nrf2, and lower expression of MMP-9 and VCAM-1 through repression of NF-kappa-B.
*NRF2↑,
*MMP9↓,
*VCAM-1↓,
*NF-kB↓,
*cardioP↑, used to improve age-associated cardiovascular, cognitive, and neuromuscular deficits,
*cognitive↑,
*eff↓, The efficiency of LA uptake was also lowered by its administration in food,
*BBB↑, LA has been shown to cross the blood-brain barrier in a limited number of studies;
*IronCh↑, LA preferentially binds to Cu2+, Zn2+ and Pb2+, but cannot chelate Fe3+, while DHLA forms complexes with Cu2+, Zn2+, Pb2+, Hg2+ and Fe3+
*GSH↑, LA markedly increases intracellular glutathione (GSH),
*PKCδ↑, PKCδ, LA activates Erk1/2 [92,93], p38 MAPK [94], PI3 kinase [94], and Akt
*ERK↑,
*p38↑,
*MAPK↑,
*PI3K↑,
*Akt↑,
*PTEN↓, LA decreases the activities of Protein Tyrosine Phosphatase 1B [99], Protein Phosphatase 2A [95], and the phosphatase and tensin homolog PTEN [95],
*AMPK↑, LA activates peripheral AMPK
*GLUT4↑, stimulate GLUT4 translocation
*GLUT1↑, LA-stimulated translocation of GLUT1 and GLUT4.
*Inflam↓, LA as an anti-inflammatory agent

3549- ALA,    Important roles of linoleic acid and α-linolenic acid in regulating cognitive impairment and neuropsychiatric issues in metabolic-related dementia
- Review, AD, NA
*Inflam↓, LA and ALA attenuate neuroinflammation by modulating inflammatory signaling.
*other↝, ratio of LA to ALA in typical Western diets is reportedly 8–10:1 or higher, which is rather higher than the ideal ratio of LA to ALA (1–2:1) required to reach the maximal conversion of ALA to its longer chain PUFAs
*other↝, LA and ALA are essential PUFAs that must be obtained from dietary intake because they cannot be synthesized de novo
*neuroP↑, several studies have also suggested that lower dietary intake of LA influences AA metabolism in brain and subsequently causes progressive neurodegenerative disorders
*BioAv↝, LA cannot be synthesized in the human body
*adiP↑, study suggested that LA-rich oil consumption leads to the high levels of adiponectin in the blood [114], which could stimulate mitochondrial function in the liver and skeletal muscles for energy thermogenesis
*BBB↑, Although LA can penetrate the BBB, most of the LA that enters the brain cannot be changed into AA [48,49], and 59 % of the LA that enters the brain is broken down by fatty acid β-oxidation
*Casp6↓, In neurons, LA and ALA attenuate the activation of cleaved caspase-3/-9, p-NF-Kb and the production of TNF-a, IL-6, IL-1b, and ROS by binding GPR40 and GPR120.
*Casp9↓,
*TNF-α↓,
*IL6↓,
*IL1β↓,
*ROS↓,
*NO↓, LA reduces NO production and inducible nitric oxide synthases (iNOS) protein expression in BV-2 microglia
*iNOS↓,
*COX2/PTGS2↓, ALA increases antioxidant enzyme activities in the brain [182] and inhibits the activation of COX-2 in AD models
*JNK↓, ALA has also been shown to suppress the activation of c-Jun N-terminal kinases (JNKs) and p-NF-kB p65 (Ser536), which is involved in inflammatory signaling
*p‑NF-kB↓,
*Aβ↓, and to inhibit Aβ aggregation and neuronal cell necrosis
*BP↓, LA also improves blood pressure, blood triglyceride and cholesterol levels, and vascular inflammation
*memory↑, One study suggested that long-term intake of ALA enhances memory function by increasing hippocampal neuronal function through activation of cAMP response element-binding protein (CREB) [192], extracellular signal-regulated kinase (ERK), and Akt signa
*cAMP↑,
*ERK↑,
*Akt↑,
cognitive?, Furthermore, ALA administration inhibits Aβ induced neuroinflammation in the cortex and hippocampus and enhances cognitive function

3539- ALA,    Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential
- Review, AD, NA
*ROS↓, scavenges free radicals, chelates metals, and restores intracellular glutathione levels which otherwise decline with age.
*IronCh↑, LA preferentially binds to Cu2+, Zn2+ and Pb2+, but cannot chelate Fe3+, while DHLA forms complexes with Cu2+, Zn2+, Pb2+, Hg2+ and Fe3+
*GSH↑,
*antiOx↑, LA has long been touted as an antioxidant
*NRF2↑, activate Phase II detoxification via the transcription factor Nrf2
*MMP9↓, lower expression of MMP-9 and VCAM-1 through repression of NF-kappa-B.
*VCAM-1↓,
*NF-kB↓,
*cognitive↑, it has been used to improve age-associated cardiovascular, cognitive, and neuromuscular deficits, and has been implicated as a modulator of various inflammatory signaling pathways
*Inflam↓,
*BioAv↝, LA bioavailability may be dependent on multiple carrier proteins.
*BioAv↝, observed that approximately 20-40% was absorbed [
*BBB↑, LA has been shown to cross the blood-brain barrier in a limited number of studies
*H2O2∅, Neither species is active against hydrogen peroxide
*neuroP↑, chelation of iron and copper in the brain had a positive effect in the pathobiology of Alzheimer’s Disease by lowering free radical damage
*PKCδ↑, In addition to PKCδ, LA activates Erk1/2 [92, 93], p38 MAPK [94], PI3 kinase [94], and Akt [94-97].
*ERK↑,
*MAPK↑,
*PI3K↑,
*Akt↑,
*PTEN↓, LA decreases the activities of Protein Tyrosine Phosphatase 1B [99], Protein Phosphatase 2A [95], and the phosphatase and tensin homolog PTEN
*AMPK↑, LA activates peripheral AMPK
*GLUT4↑, In skeletal muscle, LA is proposed to recruit GLUT4 from its storage site in the Golgi to the sarcolemma, so that glucose uptake is stimulated by the local increase in transporter abundance.
*GlucoseCon↑,
*BP↝, Feeding LA to hypertensive rats normalized systolic blood pressure and cytosolic free Ca2+
*eff↑, Clinically, LA administration (in combination with acetyl-L-carnitine) showed some promise as an antihypertensive therapy by decreasing systolic pressure in high blood pressure patients and subjects with the metabolic syndrome
*ICAM-1↓, decreased demyelination and spinal cord expression of adhesion molecules (ICAM-1 and VCAM-1)
*VCAM-1↓,
*Dose↝, Considering the transient cellular accumulation of LA following an oral dose, which does not exceed low micromolar levels, it is entirely possible that some of the cellular effects of LA when given at supraphysiological concentrations may be not be c

262- ALA,    Lipoic acid decreases breast cancer cell proliferation by inhibiting IGF-1R via furin downregulation
- in-vitro, BC, MCF7 - in-vitro, BC, MDA-MB-231
TumCP↓,
Akt↓,
ERK↓,
IGF-1R↓,
Furin↓,
Ki-67↓,
AMPK↑,
mTOR↓,

295- ALA,    α-Lipoic acid suppresses migration and invasion via downregulation of cell surface β1-integrin expression in bladder cancer cells
- in-vitro, Bladder, T24/HTB-9
ITGB1↓,
TumCMig↓,
ERK↓,
Akt↓,


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:


Core Metabolism/Glycolysis(tgid=4) ⓘ

AMPK↑, 1,  

Cell Death(tgid=5) ⓘ

Akt↓, 2,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

ERK↓, 2,   IGF-1R↓, 1,   mTOR↓, 1,  

Migration(tgid=13) ⓘ

Furin↓, 1,   ITGB1↓, 1,   Ki-67↓, 1,   TumCMig↓, 1,   TumCP↓, 1,  

Clinical Biomarkers(tgid=22) ⓘ

Ki-67↓, 1,  

Functional Outcomes(tgid=23) ⓘ

cognitive?, 1,  
Total Targets: 12

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

antiOx↑, 2,   GSH↑, 2,   H2O2∅, 1,   NRF2↑, 2,   ROS↓, 2,  

Metal & Cofactor Biology(tgid=2) ⓘ

IronCh↑, 2,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

adiP↑, 1,   AMPK↑, 2,   cAMP↑, 1,   glucose↑, 1,   GlucoseCon↑, 1,  

Cell Death(tgid=5) ⓘ

Akt↑, 3,   Casp6↓, 1,   Casp9↓, 1,   iNOS↓, 1,   JNK↓, 1,   MAPK↑, 2,   p38↑, 1,  

Transcription & Epigenetics(tgid=7) ⓘ

other↝, 2,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

ERK↑, 3,   PI3K↑, 2,   PTEN↓, 2,  

Migration(tgid=13) ⓘ

MMP9↓, 2,   PKCδ↑, 2,   VCAM-1↓, 3,  

Angiogenesis & Vasculature(tgid=14) ⓘ

eNOS↑, 1,   NO↓, 1,  

Barriers & Transport(tgid=15) ⓘ

BBB↑, 3,   GLUT1↑, 1,   GLUT4↑, 2,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

COX2/PTGS2↓, 1,   ICAM-1↓, 1,   IL1β↓, 1,   IL6↓, 1,   Inflam↓, 3,   NF-kB↓, 2,   p‑NF-kB↓, 1,   TNF-α↓, 1,  

Protein Aggregation(tgid=19) ⓘ

Aβ↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↝, 3,   Dose↝, 1,   eff↓, 1,   eff↑, 1,  

Clinical Biomarkers(tgid=22) ⓘ

BP↓, 1,   BP↝, 1,   IL6↓, 1,  

Functional Outcomes(tgid=23) ⓘ

cardioP↑, 1,   cognitive↑, 2,   memory↑, 1,   neuroP↑, 2,  
Total Targets: 50

Scientific Paper Hit Count for: ERK, ERK signaling
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#:105  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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