Aflavin-3,3′-digallate / TumCI 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.


TumCI, Tumor Cell invasion: Click to Expand ⟱
Source:
Type:
Tumor cell invasion is a critical process in cancer progression and metastasis, where cancer cells spread from the primary tumor to surrounding tissues and distant organs. This process involves several key steps and mechanisms:

1.Epithelial-Mesenchymal Transition (EMT): Many tumors originate from epithelial cells, which are typically organized in layers. During EMT, these cells lose their epithelial characteristics (such as cell-cell adhesion) and gain mesenchymal traits (such as increased motility). This transition is crucial for invasion.

2.Degradation of Extracellular Matrix (ECM): Tumor cells secrete enzymes, such as matrix metalloproteinases (MMPs), that degrade the ECM, allowing cancer cells to invade surrounding tissues. This degradation facilitates the movement of cancer cells through the tissue.

3.Cell Migration: Once the ECM is degraded, cancer cells can migrate. They often use various mechanisms, including amoeboid movement and mesenchymal migration, to move through the tissue. This migration is influenced by various signaling pathways and the tumor microenvironment.

4.Angiogenesis: As tumors grow, they require a blood supply to provide nutrients and oxygen. Tumor cells can stimulate the formation of new blood vessels (angiogenesis) through the release of growth factors like vascular endothelial growth factor (VEGF). This not only supports tumor growth but also provides a route for cancer cells to enter the bloodstream.

5.Invasion into Blood Vessels (Intravasation): Cancer cells can invade nearby blood vessels, allowing them to enter the circulatory system. This step is crucial for metastasis, as it enables cancer cells to travel to distant sites in the body.

6.Survival in Circulation: Once in the bloodstream, cancer cells must survive the immune response and the shear stress of blood flow. They can form clusters with platelets or other cells to evade detection.

7.Extravasation and Colonization: After traveling through the bloodstream, cancer cells can exit the circulation (extravasation) and invade new tissues. They may then establish secondary tumors (metastases) in distant organs.

8.Tumor Microenvironment: The surrounding microenvironment plays a significant role in tumor invasion. Factors such as immune cells, fibroblasts, and signaling molecules can either promote or inhibit invasion and metastasis.
Scientific Papers found: Click to Expand⟱
5334- TFdiG,    Theaflavin inhibits the malignant phenotype of human anaplastic thyroid cancer 8305C cells by regulating lipid metabolism via PI3K/AKT signaling
- in-vitro, Thyroid, 8505C
TumCP↓, TumCMig↓, TumCI↓, Apoptosis↑, Casp3↑, Casp8↑, Casp9↑, survivin↓, SREBP1↓, toxicity↑,
5337- TFdiG,    Theaflavin 3,3'-digallate suppresses metastasis and reduces insulin-like growth factor-1-induced cancer stemness and invasiveness in human melanoma cells
- in-vitro, Melanoma, A375 - in-vitro, Melanoma, A2058
TumCMig↓, TumCI↓, MMPs↓, ALDH↓, CSCs↓, ABCG2↓, CD44↓, CXCR4↓, TumCG↓, angioG↓, TumMeta↓,

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:


Core Metabolism/Glycolysis ⓘ

SREBP1↓, 1,  

Cell Death ⓘ

Apoptosis↑, 1,   Casp3↑, 1,   Casp8↑, 1,   Casp9↑, 1,   survivin↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

ALDH↓, 1,   CD44↓, 1,   CSCs↓, 1,   TumCG↓, 1,  

Migration ⓘ

MMPs↓, 1,   TumCI↓, 2,   TumCMig↓, 2,   TumCP↓, 1,   TumMeta↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,  

Immune & Inflammatory Signaling ⓘ

CXCR4↓, 1,  

Drug Metabolism & Resistance ⓘ

ABCG2↓, 1,  

Functional Outcomes ⓘ

toxicity↑, 1,  
Total Targets: 19

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: TumCI, Tumor Cell invasion
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#:324  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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