Laetrile B17 Amygdalin / Bcl-2 Cancer Research Results

Lae, Laetrile B17 Amygdalin: Click to Expand ⟱
Features: Sourced from apricot kernels
Banned in some states. May cause cyanide poisoning.
Laetrile B17 (Amygdalin )
Summary:
-Activation of the caspase-3 protease and downregulating Bcl-2, upregulates BAX
-Bax-to-Bcl-2 ratio and caspase-3 activity were increased
-Inhibits NF-kβ and NLRP3 signaling pathways
-Release of cyanide through the decomposition of amygdalin by the gut microfloral B-glucosidase enzyme. (bad)
-IV might be better to avoid the digestive tract which could convert to hydrogen cyanide.????

Selective Toxicity (some challenges to this statement)
The amygdalin itself is not toxic, but the HCN released from it causes the amygdalin toxic effect [35]. Cancer cells are dominant in anaerobic glycolysis and β -glucosidase is at its highest activity in lactate-induced acidic conditions [36]. Therefore, cancer cells have a high level of the unlocking enzyme β -glucosidase activity that breaks down amygdalin, leading to the release of HCN On the other hand, normal cells are normo-oxygenated and contain low levels of the β -glucosidase enzyme as well as high levels of rhodanese enzyme which transforms hydrogen cyanide into harmless thiocyanate [46, 47]. Thiocyanate has positive effects on organisms such as lowering blood pressure and is also considered a precursor for vitamin B12.

It is poisonous when combined with plant-rich beta-glucosidase.
Upon ingestion, amygdalin is hydrolyzed to cyanide by beta-glucuronidase in the small intestine [2]. Oral intake of 500 mg of amygdalin may contain as much as 30 mg of cyanide [3]. Oral amygdalin is estimated to be 40 times more potent than intravenous form due to its enzymatic conversion to hydrogen cyanide in the gastrointestinal tract [4].

Laetrile / Amygdalin — Amygdalin is a naturally occurring cyanogenic diglucoside concentrated in bitter apricot kernels and other Prunus seeds; it can be enzymatically hydrolyzed to prunasin, benzaldehyde, glucose, and hydrogen cyanide. Amygdalin is commonly abbreviated AMY or AMG. “Laetrile” has historically referred to purified or semisynthetic cyanogenic preparations related to amygdalin and should not be treated as chemically synonymous in all contexts. “Vitamin B17” is a nonrecognized marketing designation and amygdalin is not a vitamin. It is best classified as a plant-derived cyanogenic natural product with experimental anticancer activity but substantial cyanide-toxicity liability. Neither amygdalin, Laetrile, nor “vitamin B17” is authorized by Health Canada as a cancer treatment, and Laetrile is not FDA-approved.

Primary mechanisms (ranked):

  1. Cyanogenic hydrolysis and hydrogen-cyanide generation: microbial or enzymatic β-glucosidase-mediated cleavage can release HCN, which inhibits mitochondrial cytochrome-c oxidase and cellular respiration. This mechanism is cytotoxic but has not been demonstrated to be selectively activated in human tumors.
  2. Intrinsic apoptosis: experimental cancer models report ↑ BAX, ↓ BCL-2 and ↑ caspase-3 activity, shifting the mitochondrial apoptotic balance toward cell death.
  3. Cell-cycle and proliferation suppression: ↓ CDK1 and cyclin B and context-dependent alterations in other cyclins/CDKs can produce G0/G1, G1, S or G2 arrest depending on cancer model.
  4. AKT/mTOR and adhesion/invasion signaling: experimental studies report ↓ AKT-mTOR activity, altered integrin/cadherin signaling and reduced clonogenic growth, adhesion or migration.
  5. Metabolic tumor targets: recent cervical-cancer studies identify CA9 and HK2 as candidate amygdalin-sensitive targets associated with altered glycolytic and metabolic signaling; this remains preclinical.
  6. Proteostasis: inhibition of 20S/26S proteasome activity has been reported in breast-cancer cells and may contribute to proteotoxic stress and apoptosis.

Bioavailability / PK relevance: Oral parent-amygdalin bioavailability is very low and highly dependent on gastrointestinal microbiota. In human pharmacokinetic studies, a 500-mg oral dose produced parent-drug plasma concentrations below approximately 0.525 µg/mL while substantially increasing blood cyanide; by contrast, intravenous dosing produced plasma amygdalin concentrations exceeding 1,000 µg/mL with much less immediate cyanide formation. Intravenous amygdalin showed an elimination half-life of approximately 2 hours. Oral exposure is therefore dominated by gut-dependent metabolism and carries substantially greater cyanide risk. Raw apricot kernels, other β-glucosidase-containing foods, and high-dose vitamin C may further increase toxicity.

In-vitro vs systemic exposure relevance: Common anticancer experiments often use approximately 1–10 mg/mL amygdalin, with several mechanistic studies using 10 mg/mL. These concentrations are orders of magnitude above the approximately 0.0005 mg/mL peak parent-amygdalin concentration reported after a 500-mg oral human dose. Consequently, direct parent-compound effects observed at millimolar in-vitro concentrations cannot be assumed to occur after conventional oral exposure. Oral administration instead creates a separate pharmacology dominated by local microbial conversion to cyanide, making simple concentration extrapolation particularly unreliable.

Clinical evidence status: Preclinical with negative human efficacy evidence. Multiple cell-culture studies demonstrate antiproliferative and pro-apoptotic activity, and mechanistic work continues, including recent CA9/HK2 findings. However, no randomized controlled trial has established anticancer efficacy. The principal prospective clinical study involving 178 cancer patients found no substantive benefit in tumor response, symptoms or survival and documented cyanide toxicity. Systematic reviews have concluded that the benefit-risk balance for Laetrile/amygdalin as a cancer treatment is negative. It should not be classified as an established anticancer therapy or adjunct.

Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells Primary Effect Notes / Interpretation
1 Cyanogenic metabolism and mitochondrial complex IV HCN ↑; complex IV ↓; oxidative phosphorylation ↓; ATP ↓ HCN ↑; complex IV ↓; oxidative phosphorylation ↓ Mitochondrial respiratory inhibition and cytotoxicity β-Glucosidase-mediated hydrolysis can release HCN, which inhibits cytochrome-c oxidase. Historically proposed tumor selectivity is not established; cyanide generation can also injure normal cells and is a major toxicity mechanism.
2 Mitochondrial intrinsic apoptosis BAX ↑; BCL-2 ↓; cytochrome c ↑; caspase-9 ↑; caspase-3 ↑; PARP cleavage ↑ Not established Apoptotic cell death One of the most reproducible direct anticancer effects of amygdalin. Reported in prostate, breast, hepatic and lung cancer models. Evidence remains predominantly preclinical and commonly involves high concentrations.
3 Cell-cycle and proliferation control CDK1 ↓; CDK2 modulation; cyclin A/B ↓; proliferation ↓; cell-cycle arrest ↑ Not established Growth arrest and reduced clonogenicity Cell-cycle phase is model-dependent. G0/G1, G1 and G2/M arrest have all been reported, indicating that a single universal arrest phase should not be assigned.
4 AKT mTOR growth signaling AKT signaling ↓; mTOR signaling ↓; Raptor/Rictor signaling altered Not established Reduced proliferative and survival signaling Supported particularly by prostate-cancer and adhesion studies. Changes in AKT-mTOR signaling may contribute to suppression of proliferation, adhesion and metastatic behavior.
5 Mitochondrial ROS and oxidative stress ROS ↑ (context-dependent); oxidative stress ↑ ROS ↑/↓ (context-dependent) Oxidative stress and amplification of apoptosis Secondary rather than universally established primary mechanism. ROS elevation is mechanistically compatible with mitochondrial respiratory disruption and has been reported in selected cancer and formulation studies, but amygdalin can suppress ROS in other experimental contexts.
6 Glycolysis and tumor acid adaptation HK2 ↓; CA9 ↓ (model-dependent); glycolytic signaling ↓ Not established Metabolic disruption and reduced tumor-cell proliferation Recent multi-omics work in cervical-cancer models identifies HK2 and CA9 as important candidate targets. This is promising but currently model-specific and preclinical.
7 NF-κB apoptotic signaling NF-κB signaling ↓; NF-κB1-related pro-apoptotic signaling ↑ (model-dependent) NF-κB ↓ (context-dependent) Reduced survival signaling and promotion of mitochondrial apoptosis Lung-cancer models link amygdalin-induced mitochondrial apoptosis to NF-κB1 activation with suppression of downstream NF-κB signaling. Direction depends on the specific NF-κB component measured.
8 p38 MAPK stress signaling p38 MAPK ↑ Not established Pro-apoptotic stress signaling Demonstrated in triple-negative breast-cancer cells together with BAX ↑, BCL-2 ↓, caspase-3 activation and PARP cleavage. Currently a secondary and model-dependent mechanism.
9 Adhesion migration and cytoskeletal signaling Integrin α5/β1 ↓ or altered; adhesion ↓; chemotaxis ↓; migration ↓ Not established Reduced invasive and metastatic phenotype Changes in integrins, catenins, cadherins, vimentin, ezrin and talin have been reported. Effects are generally moderate and primarily demonstrated in vitro.
10 Proteasome and proteostasis 20S proteasome ↓; 26S proteasome ↓; proteotoxic stress ↑ Not established Protein-homeostasis disruption and apoptosis Reported in breast-cancer cells. Mechanistically interesting but supported by fewer studies than apoptosis, cell-cycle or AKT-mTOR effects.
11 Inflammatory signaling COX-2 ↓; iNOS ↓; inflammatory signaling ↓ (context-dependent) NF-κB ↓; NLRP3 ↓; inflammatory mediators ↓ (context-dependent) Anti-inflammatory modulation Substantial evidence exists outside cancer models, but this appears secondary to the principal anticancer mechanisms and may occur independently of tumor cytotoxicity.
12 Clinical Translation Constraint Therapeutically relevant parent-drug exposure uncertain Cyanide exposure ↑ after oral administration Major limitation to clinical translation Many anticancer experiments use millimolar or mg/mL concentrations that greatly exceed circulating parent-amygdalin concentrations after oral dosing. Gut microbiota can convert oral amygdalin to cyanide, creating variable systemic toxicity. Clinical anticancer efficacy has not been demonstrated.


Bcl-2, B-cell CLL/lymphoma 2: Click to Expand ⟱
Source: HalifaxProj (inhibit) CGL-Driver Genes
Type: Antiapoptotic Oncogene
The proteins of BCL-2 family are classified into three subgroups, i.e., the anti-apoptotic/pro-survival proteins represented by BCL-2 and BCL-XL, the pro-apoptotic proteins represented by BAX and Bak, and the pro-apoptotic BH3-only proteins represented by BAD and BID.
Since the expression of Bcl-2 protein in tumor cells is much higher than that in normal cells, inhibitors targeting it have little effect on normal cells.
Scientific Papers found: Click to Expand⟱
860- Lae,    Amygdalin as a Promising Anticancer Agent: Molecular Mechanisms and Future Perspectives for the Development of New Nanoformulations for Its Delivery
- Review, NA, NA
eff↑, Casp3↑, Bcl-2↓,
862- Lae,    Molecular mechanism of amygdalin action in vitro: review of the latest research
- Review, NA, NA
BAX↑, Casp3↑, Bcl-2↓, Akt↓, mTOR↓, p19↑, TumCCA↑, other↓,
866- Lae,    Amygdalin from Apricot Kernels Induces Apoptosis and Causes Cell Cycle Arrest in Cancer Cells: An Updated Review
- Review, NA, NA
BAX↑, Casp3↑, Bcl-2↓, TumCCA↑,

Showing Research Papers: 1 to 3 of 3

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 3

Pathway results for Effect on Cancer / Diseased Cells:


Cell Death(tgid=5) ⓘ

Akt↓, 1,   BAX↑, 2,   Bcl-2↓, 3,   Casp3↑, 3,  

Transcription & Epigenetics(tgid=7) ⓘ

other↓, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

p19↑, 1,   TumCCA↑, 2,  

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

mTOR↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

eff↑, 1,  
Total Targets: 9

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: Bcl-2, B-cell CLL/lymphoma 2
3 Laetrile B17 Amygdalin
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#:112  Target#:27  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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