Galloflavin / ER-α36 Cancer Research Results

Gallo, Galloflavin: Click to Expand ⟱
Features:
Galloflavin is a flavonoid compound found in certain plants, such as the Galphimia gracilis. Studies have demonstrated that galloflavin can inhibit the growth of cancer cells and induce apoptosis (cell death) in various types of cancer, including breast, lung, and colon cancer. Galloflavin's anti-cancer effects are thought to be due to its ability to modulate various cellular signaling pathways, including the PI3K/Akt and NF-κB pathways, which are involved in cell survival and proliferation. Additionally, galloflavin has been shown to have antioxidant and anti-inflammatory properties, which may also contribute to its anti-cancer effects.

Galloflavin has been reported to be a lactate dehydrogenase (LDH) inhibitor. LDH is an enzyme that plays a crucial role in the metabolism of cancer cells, particularly in the process of glycolysis, which is the breakdown of glucose to produce energy.
Galloflavin's LDH inhibitory activity has been demonstrated in various studies, which have shown that it can inhibit LDH activity in cancer cells, leading to a decrease in lactate production and an increase in the production of reactive oxygen species (ROS). The increase in ROS can lead to cell death, making galloflavin a potential therapeutic agent for the treatment of cancer.
Galloflavin is unusually clean mechanistically:
-LDH-A inhibition is the primary molecular target
-Everything else (↓ lactate, NAD⁺ stress, ROS, mitochondrial dependence) is downstream
-Apoptosis and tumor suppression are consequences, not drivers
This makes galloflavin one of the best-defined Warburg-effect inhibitors.

Not use if antitumor effect extends to in vivo?

Galloflavin — a synthetic polyphenolic small molecule and non-substrate-competitive inhibitor of human lactate dehydrogenase A and B. It is classified as an experimental metabolic anticancer agent and Warburg-effect inhibitor; the standard abbreviation is GF. Galloflavin, CAS 568-80-9, was originally characterized as an oxidation-derived dimeric product related to gallic acid rather than as a clinically established plant flavonoid. It remains a research compound with no approved therapeutic indication.

Primary mechanisms (ranked):

  1. Direct inhibition of LDH-A and LDH-B, preferentially through binding to the free enzyme.
  2. Suppression of pyruvate-to-lactate conversion, aerobic glycolysis, lactate secretion and glycolysis-dependent ATP production.
  3. Disruption of NADH/NAD+ redox recycling and induction of metabolic stress in highly glycolytic cancer cells.
  4. Induction of apoptosis through context-dependent mitochondrial, caspase and survival-signalling changes.
  5. Suppression of MYC-associated metabolic and proliferative signalling in susceptible cancer models.
  6. Reduction of inflammation-associated epithelial–mesenchymal transition, migration and invasive behaviour through decreased lactate production.
  7. Inhibition of noncanonical LDH-A binding to single-stranded DNA and suppression of cellular RNA synthesis.
  8. Context-dependent elevation of ROS, mitochondrial DNA damage and oxidative stress downstream of metabolic disruption.
  9. Context-dependent inhibition of NLRP3-associated inflammatory and malignant signalling in colorectal cancer models.

Bioavailability / PK relevance: No validated human pharmacokinetic, oral-bioavailability or therapeutic-exposure data are available. Galloflavin has been described as having poor physicochemical and drug-development properties, prompting development of galloflavin mimetics and alternative LDH inhibitors. Systemic exposure, metabolic stability, tissue distribution, protein binding and dose-limiting toxicity remain insufficiently characterized.

In-vitro vs systemic exposure relevance: Most anticancer studies use approximately 10–100 µM galloflavin, commonly around 25–50 µM over 24–72 hours. Whether these concentrations can be safely and continuously achieved in human tumors is unknown. Consequently, direct translation of cell-culture efficacy to oral or systemic treatment is not currently justified.

Clinical evidence status: Preclinical only. Evidence consists predominantly of enzyme assays and cultured cancer-cell studies, including breast, lymphoma, endometrial, pancreatic and colorectal models. Some animal or mechanistic studies may exist, but there is no established human cancer trial, approved formulation, clinical dose, demonstrated response rate or regulatory authorization for galloflavin.

Safety and interpretation: Galloflavin inhibits both LDH-A and LDH-B rather than being strictly LDH-A selective. Because LDH is required in normal erythrocytes, skeletal muscle, heart and other tissues during high glycolytic demand, systemic LDH inhibition could produce on-target toxicity. Normal-cell selectivity, hemolytic risk, exercise intolerance, hepatic effects, drug interactions and chronic safety have not been adequately established.

Galloflavin Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Lactate dehydrogenase A and B ↓ LDH-A and LDH-B activity ↓ LDH activity expected P Direct metabolic enzyme inhibition Galloflavin preferentially binds the free enzymes without directly competing with pyruvate or NADH. Reported inhibition constants are in the low micromolar range, with greater potency toward LDH-A than LDH-B.
2 Pyruvate to lactate conversion ↓ lactate production
↑ pyruvate		 ↓ lactate production possible P–R Warburg-effect suppression The most direct cellular consequence of LDH inhibition. Effects are expected to be strongest in tumors that depend heavily on aerobic glycolysis.
3 Glycolysis and ATP production ↓ glycolytic flux
↓ ATP		 ↓ glycolytic reserve possible R Cellular energy stress Galloflavin may spare mitochondrial respiration initially, but cells unable to compensate through oxidative phosphorylation are particularly vulnerable.
4 NADH and NAD+ redox balance ↓ NAD+ regeneration
↑ reductive stress		 Potential impairment during anaerobic demand R Redox and biosynthetic disruption Reduced LDH-mediated NAD+ recycling can constrain glycolysis and indirectly disturb multiple NAD-dependent reactions.
5 MYC metabolic signalling ↓ MYC
↓ proliferation		 Insufficient evidence G Metabolic and transcriptional growth suppression Demonstrated particularly in Burkitt lymphoma cells; the direction and magnitude are model-dependent.
6 Mitochondrial apoptosis ↓ BCL-2
↓ MCL-1
↑ cleaved caspase-3
↑ apoptosis		 Insufficient selectivity data G Programmed cell death Likely a downstream consequence of prolonged metabolic stress rather than a primary direct molecular target.
7 Reactive oxygen species and mitochondrial damage ↑ ROS
↑ mitochondrial DNA damage		 Unknown
potential ↑ oxidative injury		 R–G Secondary oxidative cytotoxicity ROS elevation is not consistently demonstrated across all models and should be considered secondary and context-dependent.
8 Cell-cycle regulation ↑ cell-cycle arrest Insufficient evidence G Reduced proliferation G2 or other checkpoint changes have been reported depending on the cancer-cell model and exposure duration.
9 Epithelial–mesenchymal transition and migration ↑ E-cadherin
↓ Slug
↓ migration		 Insufficient evidence G Reduced invasive phenotype May result partly from reduced extracellular lactate and reversal of inflammation-driven metabolic reprogramming.
10 NLRP3 inflammatory signalling ↓ NLRP3-associated activity
↓ malignant behaviour		 Potential ↓ inflammation
insufficient evidence		 G Contextual anti-inflammatory and antitumor effect Reported in colorectal cancer models. It is uncertain whether NLRP3 is directly bound by galloflavin or altered downstream of metabolic effects.
11 LDH-A single-stranded DNA binding and RNA synthesis ↓ LDH-A DNA binding
↓ RNA synthesis		 ↓ RNA synthesis possible R–G Noncanonical transcriptional inhibition Mechanistically distinct from inhibition of lactate production, but its contribution to selective tumor killing remains uncertain.
12 Chemosensitization and combination metabolic therapy ↑ response to metformin and selected metabolic inhibitors (model-dependent) Combination toxicity unknown G Enhanced metabolic collapse Combination activity is preclinical and may depend on hypoxia, mitochondrial reserve, glucose availability and tumor genotype.
13 Clinical Translation Constraint Effective concentrations commonly in the micromolar range Normal-tissue LDH inhibition and therapeutic window unresolved G Limits clinical deployment Poorly defined PK, formulation limitations, lack of human safety data, dual LDH-A and LDH-B inhibition, metabolic heterogeneity and absence of clinical trials prevent therapeutic interpretation.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr
ER-α36, estrogen receptor alpha (ERα) protein variant: Click to Expand ⟱
Source:
Type:
ER-α36 is a variant of the estrogen receptor alpha (ERα) protein. It is a truncated form of the full-length ERα protein.
ER-α36 is overexpressed in certain types of breast cancer, including triple-negative breast cancer (TNBC) and tamoxifen-resistant breast cancer. ER-α36 has been found to promote cell proliferation, migration, and invasion in breast cancer cells, contributing to tumor progression and metastasis. The expression of ERα is a significant factor in the prognosis of various cancers, particularly in breast and endometrial cancers, where it is a key target for therapy. The relationship between ERα expression and prognosis can vary widely among different cancer types, and ongoing research is essential to fully understand its role in cancer biology and treatment response.
Scientific Papers found: Click to Expand⟱
935- Gallo,    Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways
- in-vitro, BC, MCF7 - in-vitro, BC, MDA-MB-231
LDH↓, ROS↑, TumCP↓, Glycolysis↓, ATP↓, ER-α36↓, Apoptosis?,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

ROS↑, 1,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

ATP↓, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

Glycolysis↓, 1,   LDH↓, 1,  

Cell Death(tgid=5) ⓘ

Apoptosis?, 1,  

Migration(tgid=13) ⓘ

ER-α36↓, 1,   TumCP↓, 1,  

Clinical Biomarkers(tgid=22) ⓘ

LDH↓, 1,  
Total Targets: 8

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: ER-α36, estrogen receptor alpha (ERα) protein variant
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#:177  Target#:843  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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