Graviola / Cyt‑c 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)


Cyt‑c, cyt-c Release into Cytosol: Click to Expand ⟱
Source:
Type:
Cytochrome c
** The term "release of cytochrome c" ** an increase in level for the cytosol.
Small hemeprotein found loosely associated with the inner membrane of the mitochondrion where it plays a critical role in cellular respiration. Cytochrome c is highly water-soluble, unlike other cytochromes. It is capable of undergoing oxidation and reduction as its iron atom converts between the ferrous and ferric forms, but does not bind oxygen. It also plays a major role in cell apoptosis.

The term "release of cytochrome c" refers to a critical step in the process of programmed cell death, also known as apoptosis.
In its new location—the cytosol—cytochrome c participates in the apoptotic signaling pathway by helping to form the apoptosome, which activates caspases that execute cell death.
Cytochrome c is a small protein normally located in the mitochondrial intermembrane space. Its primary role in healthy cells is to participate in the electron transport chain, a process that helps produce energy (ATP) through oxidative phosphorylation.
Mitochondrial outer membrane permeability leads to the release of cytochrome c from the mitochondria into the cytosol.
The release of cytochrome c is a pivotal event in apoptosis where cytochrome c moves from the mitochondria to the cytosol, initiating a chain reaction that leads to programmed cell death.

On the one hand, cytochrome c can promote cancer cell survival and proliferation by regulating the activity of various signaling pathways, such as the PI3K/AKT pathway. This can lead to increased cell growth and resistance to apoptosis, which are hallmarks of cancer.
On the other hand, cytochrome c can also induce apoptosis in cancer cells by interacting with other proteins, such as Apaf-1 and caspase-9. This can lead to the activation of the intrinsic apoptotic pathway, which can result in the death of cancer cells.
Overexpressed in Breast, Lung, Colon, and Prostrate.
Underexpressed in Ovarian, and Pancreatic.


Scientific Papers found: Click to Expand⟱
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↓,
858- Gra,    Annona muricata leaves induce G₁ cell cycle arrest and apoptosis through mitochondria-mediated pathway in human HCT-116 and HT-29 colon cancer cells
- in-vitro, CRC, HT-29 - in-vitro, CRC, HCT116
TumCCA↑, Apoptosis↑, ROS↑, MMP↓, Cyt‑c↑, Casp↑, BAX↑, Bcl-2↓, TumCMig↓, TumCI↓,
841- Gra,    The Chemopotential Effect of Annona muricata Leaves against Azoxymethane-Induced Colonic Aberrant Crypt Foci in Rats and the Apoptotic Effect of Acetogenin Annomuricin E in HT-29 Cells: A Bioassay-Guided Approach
- in-vitro, CRC, HT-29 - in-vitro, Nor, CCD841
PCNA↓, Bcl-2↓, BAX↑, *MDA↓, lipid-P↓, TumCG↓, MMP↓, Cyt‑c↑, Casp3↑, Casp7↑, Casp9↑, *ROS↓, LDH↓, *toxicity↓, selectivity↑,
835- Gra,    Annona muricata leaves induced apoptosis in A549 cells through mitochondrial-mediated pathway and involvement of NF-κB
- in-vitro, Lung, A549
ROS↑, MMP↓, BAX↑, Bcl-2↓, Cyt‑c↑, Casp9↑, Casp3↑, Apoptosis↑, TumCCA↑,

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

lipid-P↓, 1,   ROS↑, 3,  

Mitochondria & Bioenergetics

ATP↓, 1,   MMP↓, 4,  

Core Metabolism/Glycolysis

HK2↓, 1,   LDH↓, 1,   LDHA↓, 1,  

Cell Death

Apoptosis↑, 3,   BAX↑, 4,   Bcl-2↓, 4,   Casp↑, 1,   Casp3↑, 2,   Casp7↑, 1,   Casp9↑, 2,   Cyt‑c↑, 4,  

DNA Damage & Repair

PCNA↓, 1,  

Cell Cycle & Senescence

cycD1/CCND1↓, 1,   TumCCA↑, 3,  

Proliferation, Differentiation & Cell State

TumCG↓, 1,  

Migration

TumCI↓, 1,   TumCMig↓, 1,  

Angiogenesis & Vasculature

EGFR↓, 1,   Hif1a↓, 1,  

Barriers & Transport

GLUT1↓, 1,   GLUT4↓, 1,  

Immune & Inflammatory Signaling

NF-kB↓, 1,  

Drug Metabolism & Resistance

selectivity↑, 1,  

Clinical Biomarkers

EGFR↓, 1,   LDH↓, 1,  
Total Targets: 29

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress

MDA↓, 1,   ROS↓, 1,  

Functional Outcomes

toxicity↓, 1,  
Total Targets: 3

Scientific Paper Hit Count for: Cyt‑c, cyt-c Release into Cytosol
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#:77  State#:%  Dir#:2
wNotes=0 sortOrder:rid,rpid

 

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