PDH Cancer Research Results

PDH, mitochondrial pyruvate dehydrogenase (PDH): Click to Expand ⟱
Source:
Type:
-An enzyme complex that plays a crucial role in cellular metabolism, particularly in the conversion of pyruvate to acetyl-CoA, which is then used to produce energy in the form of ATP. -Key enzyme in cellular metabolism that catalyzes the conversion of pyruvate (produced during glycolysis) into acetyl-CoA, which then enters the tricarboxylic acid (TCA) cycle in the mitochondria.
The phosphorylation state of PDH (p-PDH) broadly exists in the cancer cells.
Some cancer cells have been found to inhibit PDH activity, which can lead to increased lactate production and a shift towards glycolysis, even in the presence of oxygen. This is known as the Warburg effect.
-In cancer cells, PDH has been shown to be inhibited.
PDH expression is regulated by various transcription factors, including HIF-1α, c-Myc, and p53.
Scientific Papers found: Click to Expand⟱
5257- 3BP,    Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment
- Review, Var, NA
Glycolysis↓, In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug.
mt-OXPHOS↓, Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells.
HK2↓, The direct inhibition of mitochondrial HK-II isolated from the rabbit liver implanted VX2 tumor via 3-BrPA was demonstrated by Ko et al. [17].
Cyt‑c↑, -BrPA treatment resulted in an increase of cytochrome c release [59,60], along with an elevated expression of active proapoptotic caspase-3 and a decrease of antiapoptotic Bcl-2 and Mcl-1 [59]
Casp3↓,
Bcl-2↓,
Mcl-1↓,
GAPDH↓, Additionally, GAPDH was found to be inhibited by 3-BrPA in several studies
LDH↓, Recent reports showed 3-BrPA had ability to inhibit post glycolysis targets and other metabolic pathways, such as LDH, PDH, TCA cycle, and glutaminolysis
PDH↓, 3-BrPA was proven to be an inhibitor of PDH [72,73,74],
TCA↓,
GlutaM↓, this inhibition of TCA cycle can lead to the impairment of glutaminolysis due to α-KG generated from glutamine is incorporated into the TCA cycle by IDH and αKD activities
GSH↓, Indeed, a remarkable decrease of reduced glutathione (GSH) level was observed after 3-BrPA treatment in both microorganisms and various tumor cells [53,61,65].
ATP↓, 3-BrPA successfully killed AS-30D hepatocellular carcinoma (HCC) cells via the inhibition of both ATP-producing glycolysis and mitochondrial respiration [17].
mitResp↓,
ROS↑, the increase of ROS and concomitant decrease of GSH were commonly found in 3-BrPA-mediated antitumor studies [53,59,61,64,65,76,77,86,89].
ChemoSen↑, When 3-BrPA was combined with cisplatin or oxaliplatin with non-toxic low-dose, 3-BrPA strikingly enhanced the antiproliferative effects of both platinum drugs in HCT116 cells and resistant p53-deficient HCT116 cells [89].
toxicity↝, Finally, two years after the first diagnosis, the patient died due to an overload of liver function rather than the tumor itself [118].

5266- 3BP,    3-bromopyruvate-based agent KAT-101
- Review, Var, NA
eff↑, Upon oral administration of 3-BP-based agent KAT-101, the 3-BP derivative, being structurally similar to lactic acid, specifically binds to and enters cancer cells through monocarboxylic acid transporters (MCTs)
Glycolysis↓, KAT-101 interferes with both glycolysis and mitochondrial oxidative phosphorylation (OxPhos), thereby depleting adenosine triphosphate (ATP) levels and thus limits energy supply needed by cancer cells to proliferate.
OXPHOS↓,
ATP↓,
TumCP↓,
Apoptosis↑, This induces cancer cell apoptosis and prevents cancer cell proliferation.
HK2↓, In addition, KAT-101 is able to release mitochondrial-bound hexokinase (HK) II (HK2)
MPT↑, increases the formation of mitochondrial permeability transition pores (MPTPs), which induces apoptosis.
LDH↓, KAT-101 also inhibits a variety of enzymes, including lactate dehydrogenase (LDH), pyruvate dehydrogenase (PDH) and pyruvate dehydrogenase kinase (PDHK).
PDH↓,

1640- CA,  MET,    Caffeic Acid Targets AMPK Signaling and Regulates Tricarboxylic Acid Cycle Anaplerosis while Metformin Downregulates HIF-1α-Induced Glycolytic Enzymes in Human Cervical Squamous Cell Carcinoma Lines
- in-vitro, Cerv, SiHa
GLS↓, downregulation of Glutaminase (GLS) and Malic Enzyme 1 (ME1)
NADPH↓, CA alone and co-treated with Met caused significant reduction of NADPH
ROS↑, increased ROS formation and enhanced cell death
TumCD↑,
AMPK↑, activation of AMPK
Hif1a↓, Met inhibited Hypoxia-inducible Factor 1 (HIF-1α). CA treatment at 100 μM for 24 h also inhibited HIF-1α
GLUT1↓,
GLUT3↓,
HK2↓,
PFK↓, PFKFB4
PKM2↓,
LDH↓,
cMyc↓, Met suppressed the expression of c-Myc, BAX and cyclin-D1 (CCND1) a
BAX↓,
cycD1/CCND1↓,
PDH↓, CA at a concentration of 100 µM caused inhibition of PDK activity
ROS↑, CA Regulates TCA Cycle Supply via Pyruvate Dehydrogenase Complex (PDH), Induces Mitochondrial ROS Generation and Evokes Apoptosis
Apoptosis↑,
eff↑, both drugs inhibited the expression of ACLY and FAS, but the greatest effect was detected after co-treatment
ACLY↓,
FASN↓,
Bcl-2↓,
Glycolysis↓, Met acts as a glycolytic inhibitor under normoxic and hypoxic conditions

1593- Citrate,    Citrate Induces Apoptotic Cell Death: A Promising Way to Treat Gastric Carcinoma?
- in-vitro, GC, BGC-823 - in-vitro, GC, SGC-7901
PFK↓, citrate, a strong physiological inhibitor of phosphofructokinase (PFK)
Glycolysis↓, citrate is a strong inhibitor of glycolysis
tumCV↓, 10 mM citrate led to a nearly complete disappearance of cancer cells, and after 72 h, no cells remained viable whatever the concentration used
cl‑Casp3↑,
cl‑PARP↑,
Apoptosis↑,
ATP↓, depletion of ATP generated by citrate
ChemoSen↑, In the previous study, citrate sensitized the cells to cisplatin, a drug which was poorly efficient by itself on such cells
Mcl-1↓, In the current study, citrate reduced MCL-1 expression in both the gastric cancer lines in a dose-dependent manner, in agreement with previous observations in mesothelioma cells
glucoNG↑, citrate activates neoglucogenesis by enhancing fructose 1,6-bisphosphatase activity
FBPase↑,
OXPHOS↓, When citrate is abundant in cells, this usually means that energy production (ATP) is sufficient, so oxidative phosphorylation (OXPHOS) and the Krebs cycle are slowed down or stopped.
TCA↓, Krebs cycle are slowed down or stopped.
β-oxidation↓, concomitantly inhibits β-oxidation
HK2↓, It may inhibit HK, at least indirectly, by the physiological retroaction of glucose-6-phosphate (G6P) on HK
PDH↓, citrate may inhibit pyruvate dehydrogenase (PDH) (39), the enzyme of the Krebs cycle which links glycolysis and the tricarboxylic cycle
ROS↑, citrate could also promote the formation of reactive oxygen species (ROS) since a sudden elevation of citrate concentration inside the cell might immediately stimulate the Krebs cycle.

1576- Citrate,    Targeting citrate as a novel therapeutic strategy in cancer treatment
- Review, Var, NA
TCA↓, Citrate serves as a key metabolite in the tricarboxylic acid cycle (TCA cycle, also referred to as the Krebs cycle)
T-Cell↝, modulation of T cell differentiation
Glycolysis↓, Citrate directly suppresses both cell glycolysis and TCA.
PKM2↓, citrate also inhibits glycolysis via its indirect inhibition of PK
PFK2?, In addition, citrate can inhibit PFK2,
SDH↓, citrate can inhibit enzymes, such as succinate dehydrogenase (SDH) and pyruvate dehydrogenase (PDH), in the TCA cycle
PDH↓,
β-oxidation↓, Citrate also inhibits β-oxidation as it promotes the formation of malonyl-CoA, which decreases the mitochondrial transport of fatty acids by inhibiting carnitine palmitoyl transferase I (CPT I)
CPT1A↓,
FASN↑, citrate has a positive role in promoting fatty acid synthesis
Casp3↑,
Casp2↑,
Casp8↑,
Casp9↑,
cl‑PARP↑,
Hif1a↓, Notably, in AML cell line U937, citrate induces apoptosis in a dose- and time-dependent manner by regulating the expression of HIF-1α and its downstream target GLUT-1
GLUT1↓,
angioG↓, citrate can also inhibit angiogenesis
Ca+2↓, chelate calcium ions in tumor cells
ROS↓, The other potential mechanism involved in citrate-mediated promotion of cancer growth and proliferation may be through its ability to decrease the levels of reactive oxygen species (ROS) in tumor cells
eff↓, dual effects of citrate in tumors may depend on the concentrations of citrate treatment, and different concentrations may bring out completely opposite effects even in the same tumor.
Dose↓, citrate concentration (<5 mM) appears to boost tumor growth and expansion in lung cancer A549 cells. 10mM and higher inhibited cell growth.
eff↑, citrate combined with ultraviolet (UV) radiation caused activation of caspase-3 and -9 in tumor cells (
Mcl-1↓, citrate has also been found to downregulate Mcl-1
HK2↓, Citrate also inhibits the enzymes PFK1 and hexokinase II (HK II) in glycolysis in tumor cells
IGF-1R↓,
PTEN↑, citrate may exert its effect via activating PTEN pathway
citrate↓, In addition to prostate cancer, citrate levels are significantly decreased in blood of patients with lung, bladder, pancreas and esophagus cancers
Dose∅, daily oral administration of citrate for 7 weeks at dose of 4 g/kg/day reduces tumor growth of several xenograft tumors and increases significantly the numbers of tumor-infiltrating T cells with no significant side effects in mouse models
eff↑, combining citrate with other compounds such as celecoxib, cisplatin, and 3-bromo-pyruvate, and have generated promising results
eff↑, combination of low effective doses of 3-bromo-pyruvate (3BP) (15uM), an inhibitor of glycolysis, and citrate (3 mM) significantly depleted the proliferation capability and migratory power of the C6 glioma
eff↑, Zinc treatment could lead to citrate accumulation in malignant prostate cells, which could have therapeutic potential in clinical therapy of prostate cancer.
eff↑, synergistic efficacy mediated by citrate combined with current checkpoint blockade therapies with anti-CTLA4 and/or anti-PD1/PDL1 will develop alternative novel strategies for future immunotherapy.

5195- DCA,  Rad,    Dichloroacetate Radiosensitizes Hypoxic Breast Cancer Cells
- in-vitro, BC, 4T1 - in-vitro, BC, EMT6
PDKs↑, Dichloroacetate (DCA) is a specific inhibitor of the pyruvate dehydrogenase kinase (PDK), which leads to enhanced reactive oxygen species (ROS) production.
ROS↑, Remarkably, DCA treatment led to a significant increase in ROS production (up to 15-fold) in hypoxic cancer cells but not in aerobic cells
p‑PDH↓, hypoxic conditions. As expected, DCA treatment decreased phosphorylated pyruvate dehydrogenase (PDH) and lowered both extracellular acidification rate (ECAR) and lactate production.
ECAR↓,
lactateProd↓,
selectivity↓, Remarkably, DCA treatment led to a significant increase in ROS production (up to 15-fold) in hypoxic cancer cells but not in aerobic cells
RadioS↑, Consistently, DCA radiosensitized hypoxic tumor cells and 3D spheroids while leaving the intrinsic radiosensitivity of the tumor cells unchanged.

995- MEL,    Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma
- vitro+vivo, GBM, NA
LDHA↓,
MCT4↓,
lactateProd↓,
i-pH↓, decrease in intracellular pH: melatonin treatment induced a pH reversal with intracellular acidosis parallel to a downregulation in glycolysis in GBM.
ROS↑,
ATP↓,
TumCD↑, cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation
TumCCA↑, cell cycle arrest at G0/G1 in both GBM1A and QNS120 and G2/M in GBM1A
PDH↓, decrease in pyruvate dehydrogenase (PDH) expression for both cell lines at aMT 3.0 mM
Glycolysis↓,
GlucoseCon↓,
TumCG↓, in vivo

998- PB,    Phenyl butyrate inhibits pyruvate dehydrogenase kinase 1 and contributes to its anti-cancer effect
- in-vivo, NA, NA
p‑PDH↓,
PDH↑,
PDK1↓,
HDAC↓,
Glycolysis↓, decreased glycolysis in cytoplasm
MMP↓,
Apoptosis↑,

3195- SFN,    AKT1/HK2 Axis-mediated Glucose Metabolism: A Novel Therapeutic Target of Sulforaphane in Bladder Cancer
- in-vitro, Bladder, UMUC3
ATP↓, SFN strongly downregulates ATP production by inhibiting glycolysis and mitochondrial oxidative phosphorylation (OXPHOS).
Glycolysis↓,
OXPHOS↓,
HK2↓, SFN weaken the glycolytic flux by suppressing multiple metabolic enzymes, including hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH).
PDH↓,
AKT1↓, SFN decreases the level of AKT1 and p-AKT ser473 , especially in low-invasive UMUC3 cells.
p‑Akt↓,

1888- VitB1/Thiamine,  DCA,    High Dose Vitamin B1 Reduces Proliferation in Cancer Cell Lines Analogous to Dichloroacetate
- in-vitro, PC, SK-N-BE - NA, PC, PANC1
p‑PDH↓, Both thiamine and DCA reduced the extent of PDH phosphorylation, reduced glucose consumption, lactate production, and mitochondrial membrane potential.
GlucoseCon↓, High dose thiamine reduces glucose consumption and lactate production
lactateProd↓,
MMP↓,
Casp3↑, High dose thiamine and DCA did not increase ROS but increased caspase-3 activity
eff↑, Our findings suggest that high dose thiamine reduces cancer cell proliferation by a mechanism similar to that described for dichloroacetate
PDKs↓,
selectivity↑, An advantage to targeting PDK activity is that overexpression of PDKs and extensive phosphorylation of PDH is found in cancer cells and not in normal tissue [14]. This may provide for selective targeting towards malignant tissue
TumCG↓, thiamine suppressed tumor growth at doses greater than 75 times the recommended daily intake
Dose∅, IC50 of thiamine was lower than DCA for both cell lines with values of 4.9 for SK-N-BE and 5.4 mM for Panc-1.
MMP↓, decrease in mitochondrial membrane potential
ROS∅, cells treated with thiamine or DCA were assayed for peroxide following 30 min, 1 h, and 2 h of treatment. No significant change in ROS was observed over all time
toxicity↑, Smithline et al. reported no adverse effects in healthy patients who were given 1.5g/day of thiamine [34]. Only minor side effects, such as nausea and indigestion were reported in patients given doses as high as 7.5 g/day
antiOx↑, Free thiamine has direct antioxidant properties

1214- VitK2,    Vitamin K2 promotes PI3K/AKT/HIF-1α-mediated glycolysis that leads to AMPK-dependent autophagic cell death in bladder cancer cells
- in-vitro, Bladder, T24/HTB-9 - in-vitro, Bladder, J82
Glycolysis↑, Vitamin K2 renders bladder cancer cells more dependence on glycolysis than TCA cycle
GlucoseCon↑, results suggest that Vitamin K2 is able to induce metabolic stress, including glucose starvation and energy shortage, in bladder cancer cells, upon glucose limitation.
lactateProd↑,
TCA↓, Vitamin K2 promotes glycolysis and inhibits TCA cycle in bladder cancer cells
PI3K↑,
Akt↑,
AMPK↑, Vitamin K2 remarkably activated AMPK pathway
mTORC1↓,
TumAuto↑,
GLUT1↑, Vitamin K2 stepwise elevated the expression of some glycolytic proteins or enzymes, such as GLUT-1, Hexokinase II (HK2), PFKFB2, LDHA and PDHK1, in bladder cancer T24
HK2↑,
LDHA↑, Vitamin K2 stepwise elevated the expression of some glycolytic proteins or enzymes, such as GLUT-1, Hexokinase II (HK2), PFKFB2, LDHA and PDHK1, in bladder cancer T24
ACC↓, Vitamin K2 remarkably decreased the amounts of Acetyl coenzyme A (Acetyl-CoA) in T24 cells
PDH↓, suggesting that Vitamin K2 inactivates PDH
eff↓, Intriguingly, glucose supplementation profoundly abrogated AMPK activation and rescued bladder cancer cells from Vitamin K2-triggered autophagic cell death.
cMyc↓, c-MYC protein level was also significantly reduced in T24 cells following treatment with Vitamin K2 for 18 hours
Hif1a↑, Besides, the increased expression of GLUT-1, HIF-1α, p-AKT and p-AMPK were also detected in Vitamin K2-treated tumor group
p‑Akt↑,
eff↓, 2-DG, 3BP and DCA-induced glycolysis attenuation significantly prevented metabolic stress and rescued bladder cancer cells from Vitamin K2-triggered AMPK-dependent autophagic cell death
eff↓, inhibition of PI3K/AKT and HIF-1α notably attenuated Vitamin K2-upregulated glycolysis, indicating that Vitamin K2 promotes glycolysis in bladder cancer cells via PI3K/AKT and HIF-1α signal pathways.
eff↓, (NAC, a ROS scavenger) not only alleviated Vitamin K2-induced AKT activation and glycolysis promotion, but also significantly suppressed the subsequent AMPK-dependent autophagic cell death.
eff↓, glucose supplementation not only restored c-MYC expression, but also rescued bladder cancer cells from Vitamin K2-triggered AMPK-dependent autophagic cell death
ROS↑, under glucose limited condition, the increased glycolysis inevitably resulted in metabolic stress, which augments ROS accumulation due to lack of glucose for sustained glycolysis.


Showing Research Papers: 1 to 11 of 11

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 11

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 1,   GSH↓, 1,   OXPHOS↓, 3,   mt-OXPHOS↓, 1,   ROS↓, 1,   ROS↑, 7,   ROS∅, 1,  

Mitochondria & Bioenergetics ⓘ

ATP↓, 5,   mitResp↓, 1,   MMP↓, 3,   MPT↑, 1,   SDH↓, 1,  

Core Metabolism/Glycolysis ⓘ

ACC↓, 1,   ACLY↓, 1,   AKT1↓, 1,   AMPK↑, 2,   citrate↓, 1,   cMyc↓, 2,   CPT1A↓, 1,   ECAR↓, 1,   FASN↓, 1,   FASN↑, 1,   FBPase↑, 1,   GAPDH↓, 1,   GLS↓, 1,   glucoNG↑, 1,   GlucoseCon↓, 2,   GlucoseCon↑, 1,   GlutaM↓, 1,   Glycolysis↓, 8,   Glycolysis↑, 1,   HK2↓, 6,   HK2↑, 1,   lactateProd↓, 3,   lactateProd↑, 1,   LDH↓, 3,   LDHA↓, 1,   LDHA↑, 1,   MCT4↓, 1,   NADPH↓, 1,   PDH↓, 8,   PDH↑, 1,   p‑PDH↓, 3,   PDK1↓, 1,   PDKs↓, 1,   PDKs↑, 1,   PFK↓, 2,   PFK2?, 1,   PKM2↓, 2,   TCA↓, 4,   β-oxidation↓, 2,  

Cell Death ⓘ

Akt↑, 1,   p‑Akt↓, 1,   p‑Akt↑, 1,   Apoptosis↑, 4,   BAX↓, 1,   Bcl-2↓, 2,   Casp2↑, 1,   Casp3↓, 1,   Casp3↑, 2,   cl‑Casp3↑, 1,   Casp8↑, 1,   Casp9↑, 1,   Cyt‑c↑, 1,   Mcl-1↓, 3,   TumCD↑, 2,  

Transcription & Epigenetics ⓘ

tumCV↓, 1,  

Autophagy & Lysosomes ⓘ

TumAuto↑, 1,  

DNA Damage & Repair ⓘ

cl‑PARP↑, 2,  

Cell Cycle & Senescence ⓘ

cycD1/CCND1↓, 1,   TumCCA↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

HDAC↓, 1,   IGF-1R↓, 1,   mTORC1↓, 1,   PI3K↑, 1,   PTEN↑, 1,   TumCG↓, 2,  

Migration ⓘ

Ca+2↓, 1,   TumCP↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   Hif1a↓, 2,   Hif1a↑, 1,  

Barriers & Transport ⓘ

GLUT1↓, 2,   GLUT1↑, 1,   GLUT3↓, 1,  

Immune & Inflammatory Signaling ⓘ

T-Cell↝, 1,  

Cellular Microenvironment ⓘ

i-pH↓, 1,  

Drug Metabolism & Resistance ⓘ

ChemoSen↑, 2,   Dose↓, 1,   Dose∅, 2,   eff↓, 6,   eff↑, 8,   RadioS↑, 1,   selectivity↓, 1,   selectivity↑, 1,  

Clinical Biomarkers ⓘ

LDH↓, 3,  

Functional Outcomes ⓘ

toxicity↑, 1,   toxicity↝, 1,  
Total Targets: 98

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: PDH, mitochondrial pyruvate dehydrogenase (PDH)
2 3-bromopyruvate
2 Citric Acid
2 Dichloroacetate
1 Caffeic acid
1 Metformin
1 Radiotherapy/Radiation
1 Melatonin
1 Phenylbutyrate
1 Sulforaphane (mainly Broccoli)
1 Vitamin B1/Thiamine
1 Vitamin K2
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

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