condition found tbRes List
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 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


TumCG, Tumor cell growth: Click to Expand ⟱
Source:
Type:
Normal cells grow and divide in a regulated manner through the cell cycle, which consists of phases (G1, S, G2, and M).
Cancer cells often bypass these regulatory mechanisms, leading to uncontrolled proliferation. This can result from mutations in genes that control the cell cycle, such as oncogenes (which promote cell division) and tumor suppressor genes (which inhibit cell division).
Scientific Papers found: Click to Expand⟱
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↑, 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↓,

280- ALA,    Alpha‐lipoic acid inhibits lung cancer growth via mTOR‐mediated autophagy inhibition
- in-vivo, Lung, A549
p‑mTOR↑, significantly increased mTOR phosphorylation level by 76.9%
TumCG↓, LA suppressed lung cancer growth in mice.
NA↑,
TumAuto↓, (note this research paper takes the approach of wanting to reduce autophagy)
p‑P70S6K↑, phosphorylation level of p70S6K, a downstream target of mTOR, was increased by 83.2% when compared with controls

285- ALA,  HCA,    Tolerance of oral lipoid acid and hydroxycitrate combination in cancer patients: first approach of the cancer metabolism research group
- Human, Var, NA
PI3K↝,
AMPK↝,
TumCG↓,
*toxicity↓, No hepatic toxicity found, no weight loss, no hypoglycemia
Weight∅,

258- ALA,    Effects of α-lipoic acid on cell proliferation and apoptosis in MDA-MB-231 human breast cells
- in-vitro, BC, MDA-MB-231
TumCG↓, inhibited growth
p‑Akt↓,
Akt↓,
HER2/EBBR2↓, ErbB2 and ErbB3 protein and mRNA expressions
Bcl-2↓,
BAX↑,
Casp3↑,

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↑, ALA is capable of activating pyruvate dehydrogenase in tumor cells.
TumCG↓, ALA also significantly inhibited tumor growth in mouse xenograft model using BCPAP and FTC-133 cells
ROS↑, ALA is able to generate ROS, which promote ALA-dependent cell death in lung cancer [75], breast cancer [76] and colon cancer
AMPK↑,
EGR4↓,
Half-Life↓, Data suggests that ALA has a short half-life and bioavailability (about 30%)
BioAv↝,
*GSH↑, Moreover, it is able to increase the glutathione levels inside the cells, that chelate and excrete a wide variety of toxins, especially toxic metals from the body
*IronCh↑, The existence of thiol groups in ALA is responsible for its metal chelating abilities [14,35].
*ROS↓, ALA exerts a direct impact in oxidative stress reduction
*antiOx↑, ALA is being referred as the universal antioxidant
*neuroP↑, ALA has neuroprotective effects on Aβ-mediated cytotoxicity
*Ach↑, ALA show anti-dementia or anti-AD properties by increasing acetylcholine (ACh) production through activation of choline acetyltransferase, which increases glucose absorption
*lipid-P↓, ALA has multiple and complex effects in this way, namely scavenging ROS, transition metal ions, increasing the levels of reduced glutathione [59,63], scavenging of lipid peroxidation products
*IL1β↓, ALA downregulated the levels of the inflammatory cytokines IL-1B and IL-6 in SK-N-BE human neuroblastoma cells
*IL6↓,
TumCP↓, ALA inhibited cell proliferation, [18F]-FDG uptake and lactate formation and increased apoptosis in neuroblastoma cell lines Kelly, SK-N-SH, Neuro-2a and in the breast cancer cell line SkBr3.
FDG↓,
Apoptosis↑,
AMPK↑, ALA suppressed thyroid cancer cell proliferation and growth through activation of AMPK and subsequent down-regulation of mTOR-S6 signaling pathway in BCPAP, HTH-83, CAL-62 and FTC-133 cells lines.
mTOR↓,
EGFR↓, ALA inhibited cell proliferation through Grb2-mediated EGFR down-regulation
TumCI↓, ALA inhibited metastatic breast cancer cells migration and invasion, partly through ERK1/2 and AKT signaling
TumCMig↓,
*memory↑, Alzheimer’s Disease: ALA led to a marked improvement in learning and memory retention
*BioAv↑, Since ALA is poorly soluble, lecithin has been used as an amphiphilic matrix to enhance its bioavailability.
*BioAv↝, ALA were found to be considerably higher in adults with mean age greater than 75 years as compared to young adults between the ages of 18 and 45 years.
*other↓, ALA treatment has been recently studied by some clinical trials to explain its efficacy in preventing miscarriage
*other↝, 1800 mg of ALA or placebo were administrated orally every day, except during the period 2 days before to 4 days after administration of each dose of platinum to avoid potential interference with platinum’s antitumor effects
*Half-Life↓, Data shows a short half-life and bioavailability of about 30% of ALA due to mechanisms involving hepatic degradation, reduced ALA solubility as well as instability in the stomach.
*BioAv↑, ALA bioavailability is greatly reduced after food intake and it has been recommended that ALA should be admitted at least 2 h after eating or if taken before; meal should be taken at least 30 min after ALA administration
*ChAT↑, ALA show anti-dementia or anti-AD properties by increasing acetylcholine (ACh) production through activation of choline acetyltransferase, which increases glucose absorption
*GlucoseCon↑,

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↓, mouse model

296- ALA,    Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo
- vitro+vivo, neuroblastoma, SK-N-SH - vitro+vivo, BC, SkBr3
TumCG↓,
Casp3↑,

291- ALA,  HCA,  MET,  Dicl,    Metabolic therapies inhibit tumor growth in vivo and in silico
- in-vivo, Melanoma, B16-F10 - in-vivo, Lung, LL/2 (LLC1) - in-vivo, Bladder, MBT-2
TumCG↓,

290- ALA,  HCA,    A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: preliminary results
- vitro+vivo, Melanoma, B16-F10
TumCG↓,
OS↑,

288- ALA,  HCA,  CAP,  Octr,    Tumor regression with a combination of drugs interfering with the tumor metabolism: efficacy of hydroxycitrate, lipoic acid and capsaicin
TumCG↓, delays tumor growth in mice

300- VitC,  ALA,    Combination of High-Dose Parenteral Ascorbate (Vitamin C) and Alpha-Lipoic Acid Failed to Enhance Tumor-Inhibitory Effect But Increased Toxicity in Preclinical Cancer Models
- in-vitro, BC, MDA-MB-231 - in-vitro, Colon, HCT116 - in-vitro, Ovarian, PANC1 - in-vitro, Pca, PC3
TumCG∅,


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 11

Results for Effect on Cancer/Diseased Cells:
Akt↓,1,   p‑Akt↓,1,   ALDH↓,1,   AMPK↑,3,   AMPK↝,1,   p‑AMPK↑,1,   Apoptosis↑,1,   ATP↓,1,   BAX↑,1,   Bcl-2↓,1,   BioAv↝,1,   Casp3↑,2,   CD24↓,1,   CD44↓,1,   CSCs↓,1,   E-cadherin↑,1,   ECAR↓,1,   eff↓,1,   EGFR↓,1,   EGR4↓,1,   EMT↓,1,   FDG↓,1,   GlucoseCon↓,1,   Glycolysis↓,1,   Half-Life↓,1,   HER2/EBBR2↓,1,   HK2↓,1,   lactateProd↓,1,   LC3B-II↑,1,   LDHA↓,1,   mitResp↓,1,   MMP↓,1,   mTOR↓,3,   p‑mTOR↑,1,   NA↑,1,   NAD↓,1,   OCR↓,1,   OS↑,1,   p‑P70S6K↑,1,   PDH↑,1,   PFK↓,1,   PI3K↝,1,   ROS↑,2,   selectivity↑,1,   p‑SMAD2↓,1,   Snail↓,1,   TGF-β↓,1,   TumAuto↓,1,   TumCG↓,9,   TumCG↑,1,   TumCG∅,1,   TumCI↓,2,   TumCMig↓,2,   TumCP↓,2,   Twist↓,1,   Vim↓,1,   Weight∅,1,   β-catenin/ZEB1↓,1,  
Total Targets: 58

Results for Effect on Normal Cells:
Ach↑,1,   antiOx↑,1,   BioAv↑,2,   BioAv↝,1,   ChAT↑,1,   GlucoseCon↑,1,   GSH↑,1,   Half-Life↓,1,   IL1β↓,1,   IL6↓,1,   IronCh↑,1,   lipid-P↓,1,   memory↑,1,   neuroP↑,1,   other↓,1,   other↝,1,   ROS↓,1,   toxicity↓,1,  
Total Targets: 18

Scientific Paper Hit Count for: TumCG, Tumor cell growth
11 Alpha-Lipoic-Acid
4 HydroxyCitric Acid
1 Metformin
1 Diclofenac
1 Capsaicin
1 octreotide
1 Vitamin C (Ascorbic Acid)
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:29  Target#:323  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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