Aflavin-3,3′-digallate / GSH Cancer Research Results

TFdiG, Aflavin-3,3′-digallate: Click to Expand ⟱
Features:

Aflavin-3,3′-digallate — also known in the tea literature as theaflavin-3,3′-digallate (TF3; TFDG; Nestronics abbrev: TFdiG) — is a galloylated theaflavin dimer polyphenol formed during oxidation/“fermentation” of tea catechins in black tea (Camellia sinensis). It is a small-molecule phytochemical (flavonoid-derived polyphenol) with prominent redox-reactive and signaling-modulatory bioactivity that is largely supported by in-vitro and limited in-vivo oncology models, with no clear clinical development path as a standalone therapeutic.

Primary mechanisms (ranked):

  1. PI3K/Akt axis suppression with downstream p53 network engagement (Akt/MDM2/p53), producing growth inhibition, apoptosis, and G2 arrest (model-dependent).
  2. Redox stress modulation (often ROS↑ in cancer cells; context-dependent antioxidant vs pro-oxidant behavior) contributing to apoptosis and, in some models, ferroptosis signaling.
  3. Apoptosis pathway activation (intrinsic and extrinsic; caspase engagement) with cell-cycle checkpoint effects (e.g., cyclin B1–linked G2 arrest in some models).
  4. Anti-angiogenic signaling (reported via Akt and Notch-1 pathway modulation in ovarian cancer models).
  5. Chemosensitization to platinum therapy in ovarian cancer models (CTR1-mediated cisplatin uptake↑ and GSH depletion / thiol buffering↓; context-dependent).
  6. Metal/catalytic cofactor interactions (polyphenol chelation chemistry; may intersect with redox cycling and iron biology in specific settings).

Bioavailability / PK relevance: Oral systemic bioavailability is generally considered low for theaflavins; intestinal permeability is poor and efflux transporters contribute to limited absorption. Gallated theaflavins (including TFDG) can be unstable and are biotransformed during epithelial transport and by gut microbiota to theaflavin, mono-gallates, gallic acid, and related metabolites; therefore, local GI exposure and microbiome-derived metabolites may be more exposure-relevant than plasma parent compound.

In-vitro vs systemic exposure relevance: Many mechanistic cancer studies use micromolar concentrations; given poor absorption/efflux and biotransformation, direct translation of high in-vitro parent-compound concentrations to achievable systemic exposures is uncertain (likely exceeds plasma parent exposure in typical dietary contexts).

Clinical evidence status: Predominantly preclinical (cell culture + limited animal models). Human evidence is mainly for black tea/theaflavin-enriched extracts and related endpoints rather than purified TFDG as a therapeutic agent; no clear late-stage clinical program is evident for isolated TFDG.

TFdiG is a type of theaflavin, which is a class of flavonoids that are unique to tea plants. Theaflavins are formed during the fermentation process of tea production, and they are responsible for the characteristic astringent taste and dark color of black tea.

TFdiG is one of the most abundant theaflavins found in black tea, and it has been shown to have a range of biological activities, including anti-inflammatory, antioxidant, and anti-cancer effects. Other natural sources of TFdiG include:
Black tea: TFdiG is found in high amounts in black tea, particularly in the leaves and buds of the tea plant.
Green tea: TFdiG is also found in green tea, although in lower amounts than in black tea.
Oolong tea: TFdiG is found in oolong tea, which is a type of tea that is partially fermented.
Aflavin-3,3′-digallate is a naturally derived polyphenolic compound that has shown promise in preclinical studies through its antioxidant, apoptosis-inducing, and cell cycle-arresting effects. Its potential modulation of key oncogenic signaling pathways is an additional point of interest. However, the compound is still in the early phases of research, lacking extensive in vivo validation and clinical trial data.

Mechanistic pathway map for Aflavin-3,3′-digallate (TF3 / TFDG)

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 PI3K/Akt to MDM2 to p53 Akt signaling ↓; p53 activity ↑ (model-dependent); apoptosis ↑; growth ↓ Lower cytotoxicity reported vs matched ovarian epithelial model (context-dependent) R/G Pro-apoptotic tumor suppression In cisplatin-resistant ovarian cancer cells, TF3 linked to Akt/MDM2/p53 with apoptosis + G2 arrest (cyclin B1 implicated).
2 Redox stress signaling ROS ↑ (often); oxidative stress ↑; redox-sensitive death programs ↑ Can induce endogenous antioxidant responses (context-dependent) P/R Stress-lethal redox shift Tea polyphenols can act as antioxidants chemically yet trigger pro-oxidant biology under some conditions (metal/oxygen/pH dependent).
3 Apoptosis execution Apoptosis ↑ (intrinsic + extrinsic reported); caspase signaling ↑ ↔ (insufficient direct mapping for TF3; likely context-dependent) R/G Programmed cell death Apoptotic engagement is a consistent endpoint across theaflavin literature; TF3-specific ovarian model shows preferential apoptosis vs normal ovarian epithelial comparator.
4 Cell cycle checkpoint control G2 arrest ↑; cyclin B1 axis disruption (model-dependent) ↔ G Anti-proliferative arrest Often coupled to p53 network effects in ovarian cancer models.
5 Angiogenesis programs Angiogenesis ↓ ↔ G Anti-angiogenic signaling Reported in ovarian carcinoma–induced angiogenesis with involvement of Akt and Notch-1 (MAPK not the primary mediator in that report).
6 Chemosensitization to platinum therapy Cisplatin sensitivity ↑; CTR1 ↑; intracellular Pt accumulation ↑; GSH ↓ ↔ R/G Enhanced drug uptake and reduced thiol buffering In ovarian cancer cells, TF3 potentiated cisplatin via CTR1 upregulation and GSH depletion; effect attenuated by CTR1 knockdown.
7 Iron biology and ferroptosis interface (context-dependent) lipid peroxidation ↑; ferroptosis signaling ↑ (reported in some models) ↔ R/G Non-apoptotic death contribution Some reports describe TF3 engaging ROS/MAPK with concurrent apoptotic and ferroptotic phenotypes; iron handling may be involved indirectly via redox chemistry.
8 Clinical Translation Constraint Effective concentrations may be hard to achieve systemically; biotransformation and efflux limit parent exposure Same constraints — Delivery and exposure limitation Poor permeability (very low Papp range reported for theaflavins), efflux transporter involvement, instability of gallated forms, and microbiome-driven metabolism imply high uncertainty in systemic target engagement for purified TF3.


GSH, Glutathione: Click to Expand ⟱
Source:
Type:
Glutathione (GSH) is a thiol antioxidant that scavenges reactive oxygen species (ROS), resulting in the formation of oxidized glutathione (GSSG). Decreased amounts of GSH and a decreased GSH/GSSG ratio in tissues are biomarkers of oxidative stress.
Glutathione is a powerful antioxidant found in every cell of the body, composed of three amino acids: cysteine, glutamine, and glycine. It plays a crucial role in protecting cells from oxidative stress, detoxifying harmful substances, and supporting the immune system.
cancer cells can have elevated levels of glutathione, which may help them survive in the oxidative environment created by the immune response and chemotherapy. This can make cancer cells more resistant to treatment.
While glutathione can be obtained from certain foods (like fruits, vegetables, and meats), its absorption from supplements is debated. Some people take N-acetylcysteine (NAC) or other precursors to boost glutathione levels, but the effects on cancer prevention or treatment are still being studied.
Depleting glutathione (GSH) to raise reactive oxygen species (ROS) is a strategy that has been explored in cancer research and therapy.
Many cancer cells have altered redox states and may rely on GSH to survive. Increasing ROS levels can induce stress in these cells, potentially leading to cell death.
Certain drugs and compounds can deplete GSH levels. For example, agents like buthionine sulfoximine (BSO) inhibit the synthesis of GSH, leading to its depletion.
Cancer cells tend to exhibit higher levels of intracellular GSH, possibly as an adaptive response to a higher metabolism and thus higher steady-state levels of reactive oxygen species (ROS).

"...intracellular glutathione (GSH) exhibits an astounding antioxidant activity in scavenging reactive oxygen species (ROS)..."
"Cancer cells have a high level of GSH compared to normal cells."
"...cancer cells are affluent with high antioxidant levels, especially with GSH, whose appearance at an elevated concentration of ∼10 mM (10 times less in normal cells) detoxifies the cancer cells." "Therefore, GSH depletion can be assumed to be the key strategy to amplify the oxidative stress in cancer cells, enhancing the destruction of cancer cells by fruitful cancer therapy."

The loss of GSH is broadly known to be directly related to the apoptosis progression.
Scientific Papers found: Click to Expand⟱
5330- TFdiG,  Cisplatin,    Theaflavin-3,3′-Digallate Enhances the Inhibitory Effect of Cisplatin by Regulating the Copper Transporter 1 and Glutathione in Human Ovarian Cancer Cells
- in-vitro, Ovarian, A2780S - in-vitro, Ovarian, OVCAR-3
selectivity↑, ChemoSen↑, DNAdam↑, GSH↓, CTR1↑,
5331- TFdiG,    Anti-Cancer Properties of Theaflavins
- Review, Var, NA
AntiCan↑, TumCP↓, TumCMig↓, Apoptosis↑, cl‑PARP↑, cl‑Casp3↑, cl‑Casp7↑, cl‑Casp8↑, cl‑Casp9↑, BAX↑, Bcl-2↓, p‑Akt↓, p‑mTOR↓, PI3K↓, cMyc↓, P53↑, ROS↑, NF-kB↓, MMP9↓, MMP2↓, TumVol↓, PSA↓, TumCCA↑, VEGF↓, Hif1a↓, CDK2↓, CDK4↓, GSH↓, Dose↑, BioAv↓, BioAv↓, BioAv↑,
5333- TFdiG,    Theaflavin-3,3′-Digallate Plays a ROS-Mediated Dual Role in Ferroptosis and Apoptosis via the MAPK Pathway in Human Osteosarcoma Cell Lines and Xenografts
- vitro+vivo, OS, MG63
tumCV↓, TumCP↓, TumCCA↑, Iron↑, ROS↑, GSH↓, Fenton↑, Ferroptosis↑, Apoptosis↑, MAPK↑, ERK↑, JNK↑, p38↑, TumCG↓, Dose↝, FTH1↓, GPx4↓,

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:


Redox & Oxidative Stress ⓘ

Fenton↑, 1,   Ferroptosis↑, 1,   GPx4↓, 1,   GSH↓, 3,   Iron↑, 1,   ROS↑, 2,  

Metal & Cofactor Biology ⓘ

FTH1↓, 1,  

Core Metabolism/Glycolysis ⓘ

cMyc↓, 1,  

Cell Death ⓘ

p‑Akt↓, 1,   Apoptosis↑, 2,   BAX↑, 1,   Bcl-2↓, 1,   cl‑Casp3↑, 1,   cl‑Casp7↑, 1,   cl‑Casp8↑, 1,   cl‑Casp9↑, 1,   Ferroptosis↑, 1,   JNK↑, 1,   MAPK↑, 1,   p38↑, 1,  

Transcription & Epigenetics ⓘ

tumCV↓, 1,  

DNA Damage & Repair ⓘ

DNAdam↑, 1,   P53↑, 1,   cl‑PARP↑, 1,  

Cell Cycle & Senescence ⓘ

CDK2↓, 1,   CDK4↓, 1,   TumCCA↑, 2,  

Proliferation, Differentiation & Cell State ⓘ

ERK↑, 1,   p‑mTOR↓, 1,   PI3K↓, 1,   TumCG↓, 1,  

Migration ⓘ

MMP2↓, 1,   MMP9↓, 1,   TumCMig↓, 1,   TumCP↓, 2,  

Angiogenesis & Vasculature ⓘ

Hif1a↓, 1,   VEGF↓, 1,  

Barriers & Transport ⓘ

CTR1↑, 1,  

Immune & Inflammatory Signaling ⓘ

NF-kB↓, 1,   PSA↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 2,   BioAv↑, 1,   ChemoSen↑, 1,   Dose↑, 1,   Dose↝, 1,   selectivity↑, 1,  

Clinical Biomarkers ⓘ

PSA↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,   TumVol↓, 1,  
Total Targets: 49

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: GSH, Glutathione
3 Aflavin-3,3′-digallate
1 Cisplatin
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#:238  Target#:137  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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