Alpha-Lipoic-Acid / CSCs 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.

CSCs, Cancer Stem Cells: Click to Expand ⟱

Source:

Type:

Cancer Stem Cells

Phytochemicals (natural plant-derived compounds) that may affect CSCs:
Curcumin
— suppresses self-renewal and pathways (Wnt/Notch/Hedgehog).
Resveratrol
— shown to reduce CSC populations and sphere formation in multiple models.
Sulforaphane (from broccoli sprouts)
— reported to inhibit CSC properties and pathways; active in vitro and in vivo.
EGCG (epigallocatechin-3-gallate, green tea)
— reduces CSC markers and sphere formation in several cancer types.
Quercetin
— reported to inhibit CSC proliferation, self-renewal and invasiveness (breast, endometrial, others).
Berberine
— shown to suppress CSC “stemness” and reduce tumorigenic properties in multiple models.
Genistein (soy isoflavone)
— decreases CSC markers, sphere formation and stemness signaling in prostate/breast/other models.
Honokiol (Magnolia bark)
— shown to eliminate or suppress CSC-like populations in oral, colon, glioma models.
Luteolin
— inhibits stemness/EMT and reduces CSC markers and self-renewal in breast, prostate and other models.
Withaferin A (from Withania somnifera / ashwagandha)
— multiple preclinical reports show WA targets CSCs and reduces tumor growth/metastasis in models.

Circadian disruption in cancer and regulation of cancer stem cells by circadian clock genes: An updated review
Potential Role of the Circadian Clock in the Regulation of Cancer Stem Cells and Cancer Therapy
Can we utilise the circadian clock to target cancer stem cells?

Scientific Papers found: Click to Expand⟱

3436-

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 Author links open overlay panel

in-vitro,

BC,

MCF7

ChemoSen↑, LA also enhanced the sensitivity of breast cancer spheroids to doxorubicin (Dox), demonstrating a synergistic effect.
PI3K↓, LA inhibits PI3K/AKT signaling in breast cancer spheroids
Akt↓,
ATP↓, found that LA markedly reduced both ATP levels and glucose uptake
GlucoseCon↓,
ROS↑, LA also induced ROS generation in both MCF-7 and MDA-MB231 spheroids
PKM2↓, LA downregulated the expression of PKM2 and LDHA in the spheroids, indicating an inhibition of glycolysis in BCSCs
Glycolysis↓,
CSCs↓,
IGF-1R↓, LA inhibits IGF-1R via furin downregulation, synergizes with other anticancer drugs like paclitaxel and cisplatin, and enhances radiosensitivity in breast cancer
Furin↓,
RadioS↑,

3454-

ALA,

Lipoic acid blocks autophagic flux and impairs cellular bioenergetics in breast cancer and reduces stemness

in-vitro,

BC,

MCF7

(0.5 mM, 1 mM, 2.5 mM, and 5 mM)

in-vitro,

BC,

MDA-MB-231

TumCG↑, Lipoic acid inhibits breast cancer cell growth via accumulation of autophagosomes.
Glycolysis↓, Lipoic acid inhibits glycolysis in breast cancer cells.
ROS↑, Lipoic acid induces ROS production in breast cancer cells/BCSC.
CSCs↓, Here, we demonstrate that LA inhibits mammosphere formation and subpopulation of BCSCs
selectivity↑, In contrast, LA at similar doses. had no significant effect on the cell viability of the human embryonic kidney cell line (HEK-293)
LC3B-II↑, LA treatment (0.5 mM and 1.0 mM) increased the expression level of LC3B-I to LC3B-II in both MCF-7 and MDA-MB231cells at 48 h
MMP↓, LA induced mitochondrial ROS levels, decreased mitochondria complex I activity, and MMP in both MCF-7 and MDA-MB231 cells
mitResp↓, In MCF-7 cells, we found a substantial reduction in maximal respiration and ATP production at 0.5 mM and 1 mM of LA treatment after 48 h
ATP↓,
OCR↓, LA at 2.5 mM decreased OCR
NAD↓, we found that LA (0.5 mM and 1 mM) significantly reduced ATP production and NAD levels in MCF-7 and MDA-MB231 cells
p‑AMPK↑, LA treatment (0.5 mM and 1.0 mM) increased p-AMPK levels;
GlucoseCon↓, LA (0.5 mM and 1 mM) significantly decreased glucose uptake and lactate production in MCF-7, whereas LA at 1 mM significantly reduced glucose uptake and lactate production in MDA-MB231 cells but it had no effect at 0.5 mM
lactateProd↓,
HK2↓, LA reduced hexokinase 2 (HK2), phosphofructokinase (PFK), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) expression in MCF-7 and MDA-MB231 cells
PFK↓,
LDHA↓,
eff↓, Moreover, we found that LA-mediated inhibition of cellular bioenergetics including OCR (maximal respiration and ATP production) and glycolysis were restored by NAC treatment (Fig. 6E and F) which indicates that LA-induced ROS production is responsibl
mTOR↓, LA inhibits mTOR signaling and thereby decreased the p-TFEB levels in breast cancer cells
ECAR↓, LA also inhibits glycolysis as evidenced by decreased glucose uptake, lactate production, and ECAR.
ALDH↓, LA decreased ALDH1 activity, CD44+/CD24-subpopulation, and increased accumulation of autophagosomes possibly due to inhibition of autophagic flux of breast cancer.
CD44↓,
CD24↓,

Showing Research Papers: 1 to 2 of 2

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 2

Pathway results for Effect on Cancer / Diseased Cells:

Pathway results for Effect on Normal Cells:

Total Targets: 0

Scientific Paper Hit Count for: CSCs, Cancer Stem Cells

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#:795  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

Alpha-Lipoic-Acid / CSCs Cancer Research Results

Lipoic Acid Cancer Mechanisms

Lipoic Acid in Alzheimer’s Disease

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress(tgid=1) ⓘ

Mitochondria & Bioenergetics(tgid=3) ⓘ

Core Metabolism/Glycolysis(tgid=4) ⓘ

Cell Death(tgid=5) ⓘ

Autophagy & Lysosomes(tgid=9) ⓘ

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

Migration(tgid=13) ⓘ

Drug Metabolism & Resistance(tgid=21) ⓘ

Pathway results for Effect on Normal Cells:

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