Graviola / Hif1a Cancer Research Results

Gra, Graviola: Click to Expand ⟱
Features:
Soursop or Brazilian paw paw or guanabana. People use fruit, roots, seeds and leaves. Graviola, also known as Annona muricata, is a tropical fruit-bearing tree native to the Americas.
Graviola (Annona muricata; soursop) contains annonaceous acetogenins (e.g., annonacin, bullatacin-class compounds) that are widely described as mitochondrial complex I inhibitors, producing ATP depletion and downstream stress signaling that can lead to cell-cycle arrest and apoptosis in many in-vitro cancer models. A key real-world constraint is safety: epidemiology in the French Caribbean reports an association between high Annonaceae consumption and atypical parkinsonism, and animal data indicate annonacin can enter brain tissue and drive ATP depletion with neurodegenerative patterns under chronic exposure; therefore Graviola products should be treated as higher-risk than many polyphenols and should not be framed as a casual long-term supplement.

GLUT1 inhibitor?
The major pathways involved in Graviola's anti-cancer effects include:
-Reported reduction of glucose uptake (e.g., GLUT1 expression) in selected tumor models.: Graviola extracts have been shown to inhibit the activity of lactate dehydrogenase (LDH), a key enzyme involved in glycolysis, the process by which cancer cells produce energy. By inhibiting LDH, Graviola reduces the production of lactate, a key metabolite that fuels cancer cell growth.(likely secondary to mitochondrial ATP depletion)
-Inhibition of glucose uptake: Graviola extracts have also been shown to inhibit the uptake of glucose by cancer cells, further reducing their energy production.
-Inhibition of the PI3K/AKT pathway: The PI3K/AKT pathway is a key signaling pathway involved in cell survival and proliferation. Graviola extracts have been shown to inhibit this pathway, leading to reduced cancer cell growth and survival.
-Induction of apoptosis: Graviola extracts have been shown to induce apoptosis in cancer cells by activating pro-apoptotic proteins and inhibiting anti-apoptotic proteins.

The major compounds responsible for Graviola's anti-cancer effects are:
Annonaceous acetogenins: These are a group of compounds found in Graviola that have been shown to inhibit cancer cell growth and induce apoptosis.

Rank Pathway / Axis Cancer / Tumor Context Normal Tissue Context TSF Primary Effect Notes / Interpretation
1 Mitochondrial ETC Complex I inhibition → ATP depletion (acetogenins) Complex I ↓; ATP ↓; energetic crisis ↑ Risk of toxicity with sufficient exposure P, R, G Metabolic choke-point Core mechanistic theme: annonaceous acetogenins inhibit mitochondrial complex I, suppressing ATP generation (often framed as a basis for cytotoxicity in vitro).
2 ROS / mitochondrial stress (secondary to Complex I inhibition) ROS ↑ or redox destabilization (context); oxidative damage ↑ Oxidative injury risk depends on exposure P, R, G Stress amplification ROS direction varies by model/extract; best treated as secondary to energy failure rather than a universal primary ROS driver.
3 Intrinsic apoptosis (mitochondrial; caspases; PARP) Apoptosis ↑; caspase activation ↑; cl-PARP ↑ (reported) ↔ / toxicity risk at higher exposures G Cell death execution Common endpoint in cancer cell studies; often downstream of energetic collapse and stress signaling.
4 Cell-cycle control / proliferation Proliferation ↓; cell-cycle arrest ↑ (reported; phase varies) ↔ G Cytostasis Frequently reported phenotype-level effect across models; checkpoint phase depends on tumor type and extract composition.
5 NF-κB inflammatory transcription NF-κB ↓; pro-inflammatory/survival outputs ↓ (reported) Anti-inflammatory effects reported R, G Anti-inflammatory / anti-survival transcription Many extracts/constituents are reported to reduce NF-κB signaling, contributing to reduced cytokines and survival programs.
6 PI3K → AKT (± mTOR) and other survival kinases Survival kinase tone ↓ (reported; model-dependent) ↔ R, G Growth/survival suppression Often listed in reviews; keep “reported/model-dependent” because extracts vary substantially.
7 MAPK re-wiring (ERK / JNK / p38) Stress-MAPK modulation (context-dependent) ↔ P, R, G Signal reprogramming MAPK directions are heterogeneous across studies; avoid fixed arrows unless tied to a specific paper/extract.
8 Invasion / metastasis programs (MMPs / EMT) Migration/invasion ↓; MMPs/EMT markers ↓ (reported) ↔ G Anti-invasive phenotype Downstream phenotype-level outcomes reported in some tumor systems; not universal.
9 Angiogenesis signaling (VEGF & related outputs) VEGF/angiogenic outputs ↓ (reported) ↔ G Anti-angiogenic support Usually observed as later gene-expression/assay outcomes, often linked to NF-κB and survival-pathway suppression.
10 Safety constraint: neurotoxicity signal (annonacin; atypical parkinsonism association) — Long-term/high exposure concern: neurotoxicity & atypical parkinsonism association reported — Translation constraint Evidence links Annonaceae consumption (including soursop) with atypical parkinsonism in the French Caribbean; annonacin crosses BBB in animal studies and causes ATP depletion and neurodegenerative patterns with chronic exposure.

Time-Scale Flag (TSF): P / R / G

  • P: 0–30 min (primary/rapid effects; early mitochondrial/kinase shifts)
  • R: 30 min–3 hr (acute stress-response + inflammatory transcription signaling shifts)
  • G: >3 hr (gene-regulatory adaptation and phenotype-level outcomes)
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⟱
2438- Gra,    Emerging therapeutic potential of graviola and its constituents in cancers
- Review, Var, NA
Hif1a↓, GLUT1↓, GLUT4↓, HK2↓, LDHA↓, MUC4↓, TumCCA↑, MMP↓, NF-kB↓, ROS↓, Bax:Bcl2↑, ER(estro)↓, cycD1/CCND1↓, chemoPv↑, hepatoP↑,
1232- Gra,    Graviola: A Systematic Review on Its Anticancer Properties
- Review, NA, NA
EGFR↓, cycD1/CCND1↓, Bcl-2↓, TumCCA↑, Apoptosis↑, ROS↑, MMP↓, BAX↑, Cyt‑c↑, Hif1a↓, NF-kB↓, GLUT1↓, GLUT4↓, HK2↓, LDHA↓, ATP↓,
836- Gra,    Graviola: A Novel Promising Natural-Derived Drug That Inhibits Tumorigenicity and Metastasis of Pancreatic Cancer Cells In Vitro and In Vivo Through Altering Cell Metabolism
- vitro+vivo, PC, NA
Hif1a↓, NF-kB↓, GLUT1↓, GLUT4↓, HK2↓, LDHA↓, TumCCA↑, TumMeta↓, GlucoseCon↓, ATP↓, necrosis↑, Casp∅, p‑FAK↓, MMP9↓, MUC4↓,
834- Gra,    Anticancer Properties of Graviola (Annona muricata): A Comprehensive Mechanistic Review
- Review, NA, NA
EGFR↓, PI3K/Akt↓, NF-kB↓, JAK↓, STAT↓, Hif1a↓, GLUT1↓, GLUT4↓, ROS↑, Catalase↑, SOD↑, HO-1↑,

Showing Research Papers: 1 to 4 of 4

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 4

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Catalase↑, 1,   HO-1↑, 1,   ROS↓, 1,   ROS↑, 2,   SOD↑, 1,  

Mitochondria & Bioenergetics ⓘ

ATP↓, 2,   MMP↓, 2,  

Core Metabolism/Glycolysis ⓘ

GlucoseCon↓, 1,   HK2↓, 3,   LDHA↓, 3,   PI3K/Akt↓, 1,  

Cell Death ⓘ

Apoptosis↑, 1,   BAX↑, 1,   Bax:Bcl2↑, 1,   Bcl-2↓, 1,   Casp∅, 1,   Cyt‑c↑, 1,   necrosis↑, 1,  

Cell Cycle & Senescence ⓘ

cycD1/CCND1↓, 2,   TumCCA↑, 3,  

Proliferation, Differentiation & Cell State ⓘ

STAT↓, 1,  

Migration ⓘ

p‑FAK↓, 1,   MMP9↓, 1,   MUC4↓, 2,   TumMeta↓, 1,  

Angiogenesis & Vasculature ⓘ

EGFR↓, 2,   Hif1a↓, 4,  

Barriers & Transport ⓘ

GLUT1↓, 4,   GLUT4↓, 4,  

Immune & Inflammatory Signaling ⓘ

JAK↓, 1,   NF-kB↓, 4,  

Hormonal & Nuclear Receptors ⓘ

ER(estro)↓, 1,  

Clinical Biomarkers ⓘ

EGFR↓, 2,  

Functional Outcomes ⓘ

chemoPv↑, 1,   hepatoP↑, 1,  
Total Targets: 35

Pathway results for Effect on Normal Cells:


Total Targets: 0

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

 

Home Page