Proanthocyanidins / Hif1a Cancer Research Results

PACs, Proanthocyanidins: Click to Expand ⟱
Features:

Proanthocyanidins (PACs; condensed tannins) = oligomeric/polymeric flavan-3-ols (e.g., catechin/epicatechin units); abundant in grape seed, cocoa, cranberry, apple skin, pine bark. Degree of polymerization (DP) influences bioactivity and absorption.
Primary mechanisms (conceptual rank):
1) Redox modulation → direct ROS scavenging + metal chelation (Fe²⁺/Cu²⁺).
2) NRF2 activation → endogenous antioxidant enzymes (HO-1, NQO1, GCLC).
3) Anti-inflammatory signaling → ↓ NF-κB / ↓ COX-2 / ↓ cytokines.
4) Anti-proliferative / pro-apoptotic signaling in cancer (MAPK, PI3K/Akt modulation; dose-dependent).
5) Anti-angiogenic / anti-metastatic effects (VEGF, MMPs; model-dependent).
PK / bioavailability: monomers/low-DP oligomers absorbed; higher-DP polymers poorly absorbed but metabolized by gut microbiota to phenolic acids; plasma parent PAC levels modest vs many in-vitro studies.
In-vitro vs systemic exposure: many cancer studies use ≥10–100 µM equivalents; achievable circulating levels typically lower and largely conjugated/metabolite-driven.
Clinical evidence status: strongest human data in vascular/cardiometabolic endpoints; oncology evidence largely preclinical/adjunct.

Polyphenols found in cranberry, blueberry, and grape seeds.

Proanthocyanidin B2 (PB2) is a type of dimer flavonoid that is found in grape seed, pine bark, wine, and tea leaves [17]. PB2 has been shown to possess various bioactivities, including anti-oxidant, anti-inflammation, and anti-obesity activities, and it has also shown efficacy in the treatment of cancer, cardiovascular disease, type 2 diabetes, ulcerative colitis, as well as acute liver injury. PKM2 is the target of proanthocyanidin B2

PB2 also suppressed glucose uptake and lactate levels via the direct inhibition of the key glycolytic enzyme, PKM2.

Proanthocyanidins (PACs) — Cancer-Relevant Pathways

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 ROS tone / redox balance ↓ (low–mod dose); ↑ (high concentration only) ↓ P→R Antioxidant; metal chelation Catechol-rich structure scavenges radicals; pro-oxidant shift reported at high doses in tumors (model-dependent).
2 NRF2 axis ↑ (context-dependent) ↑ R→G Endogenous antioxidant induction ↑ HO-1/NQO1; protective in normal tissue; may support tumor stress resistance (context-dependent).
3 NF-κB / inflammatory signaling ↓ ↓ R→G Anti-inflammatory Reduces cytokines, COX-2; anti-tumor microenvironment effect plausible.
4 PI3K/Akt / MAPK pathways ↓ proliferation (model-dependent) ↔ R→G Growth signaling attenuation Observed in breast, colon, prostate models; dose and DP dependent.
5 Apoptosis (caspase activation) ↑ (dose-dependent) ↔ / ↓ R→G Pro-apoptotic signaling Mitochondrial depolarization reported; often supra-physiologic exposure.
6 Angiogenesis (VEGF) ↓ (preclinical) ↔ G Anti-angiogenic ↓ VEGF expression in models; human oncologic data limited.
7 Ferroptosis axis ↓ (anti-lipid-ROS bias) ↓ P→R Lipid peroxidation inhibition Strong antioxidant property may counter ferroptotic strategies (context-dependent).
8 Clinical Translation Constraint — — — Bioavailability & dose gap High-DP PACs poorly absorbed; many in-vitro doses exceed realistic plasma exposure; adjunct role most plausible.

TSF Legend: P: 0–30 min | R: 30 min–3 hr | G: >3 hr


Proanthocyanidins (PACs) — Alzheimer’s Disease–Relevant Axes

Rank Pathway / Axis Cells (neurons/glia) TSF Primary Effect Notes / Interpretation
1 Lipid peroxidation / neuronal ROS ↓ P Neuroprotective antioxidant Reduces oxidative damage markers in models; aligns with AD oxidative stress hypothesis.
2 NRF2 activation ↑ R→G Endogenous antioxidant upregulation Supports neuronal resilience; mostly preclinical evidence.
3 Neuroinflammation (NF-κB) ↓ R→G Microglial modulation Reduced cytokine production in animal models.
4 Aβ aggregation / toxicity ↓ (preclinical) G Interference with amyloid aggregation Reported inhibition of Aβ fibrillization in vitro; human data limited.
5 BDNF / synaptic plasticity ↑ (model-dependent) G Neurotrophic signaling Observed in flavanol-rich cocoa/grape extract studies; translation to PAC isolates unclear.
6 Clinical Translation Constraint — — Dietary-level evidence Human trials mostly use flavanol-rich extracts; cognitive effects modest and stage-dependent.

TSF Legend: P: 0–30 min | R: 30 min–3 hr | G: >3 hr
Hif1a, HIF1α/HIF1a: Click to Expand ⟱
Source:
Type:
Hypoxia-Inducible-Factor 1A (HIF1A gene, HIF1α, HIF-1α protein product)
-Dominantly expressed under hypoxia(low oxygen levels) in solid tumor cells
-HIF1A induces the expression of vascular endothelial growth factor (VEGF)
-High HIF-1α expression is associated with Poor prognosis
-Low HIF-1α expression is associated with Better prognosis

-Functionally, HIF-1α is reported to regulate glycolysis, whilst HIF-2α regulates genes associated with lipoprotein metabolism.
-Cancer cells produce HIF in response to hypoxia in order to generate more VEGF that promote angiogenesis

Key mediators of aerobic glycolysis regulated by HIF-1α.
-GLUT-1 → regulation of the flux of glucose into cells.
-HK2 → catalysis of the first step of glucose metabolism.
-PKM2 → regulation of rate-limiting step of glycolysis.
-Phosphorylation of PDH complex by PDK → blockage of OXPHOS and promotion of aerobic glycolysis.
-LDH (LDHA): Rapid ATP production, conversion of pyruvate to lactate;

HIF-1α Inhibitors:
-Curcumin: disruption of signaling pathways that stabilize HIF-1α (ie downregulate).
-Resveratrol: downregulate HIF-1α protein accumulation under hypoxic conditions.
-EGCG: modulation of upstream signaling pathways, leading to decreased HIF-1α activity.
-Emodin: reduce HIF-1α expression. (under hypoxia).
-Apigenin: inhibit HIF-1α accumulation.
Scientific Papers found: Click to Expand⟱
959- PACs,    Grape seed extract inhibits VEGF expression via reducing HIF-1α protein expression
- in-vitro, GBM, U251 - in-vitro, BC, MDA-MB-231
Hif1a↓, p‑Akt↓, p‑S6K↓, p‑S6↓, VEGF↓,
2396- PACs,    PKM2 is the target of proanthocyanidin B2 during the inhibition of hepatocellular carcinoma
- in-vitro, HCC, HCCLM3 - in-vitro, HCC, SMMC-7721 cell - in-vitro, HCC, Bel-7402 - in-vitro, HCC, HUH7 - in-vitro, HCC, HepG2 - in-vitro, Nor, L02
TumCP↓, TumCCA↓, Apoptosis↑, GlucoseCon↓, lactateProd↓, PKM2↓, Glycolysis↓, HK2↓, PFK↓, OXPHOS↑, ChemoSen↑, HSP90↓, Hif1a↓,

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:


Redox & Oxidative Stress ⓘ

OXPHOS↑, 1,  

Core Metabolism/Glycolysis ⓘ

GlucoseCon↓, 1,   Glycolysis↓, 1,   HK2↓, 1,   lactateProd↓, 1,   PFK↓, 1,   PKM2↓, 1,   p‑S6↓, 1,   p‑S6K↓, 1,  

Cell Death ⓘ

p‑Akt↓, 1,   Apoptosis↑, 1,  

Protein Folding & ER Stress ⓘ

HSP90↓, 1,  

Cell Cycle & Senescence ⓘ

TumCCA↓, 1,  

Migration ⓘ

TumCP↓, 1,  

Angiogenesis & Vasculature ⓘ

Hif1a↓, 2,   VEGF↓, 1,  

Drug Metabolism & Resistance ⓘ

ChemoSen↑, 1,  
Total Targets: 17

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: Hif1a, HIF1α/HIF1a
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#:136  Target#:143  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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