lactateProd Cancer Research Results

lactateProd, lactate production: Click to Expand ⟱

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Type:

Lactate production has been linked to cancer development and progression. In normal conditions, lactate is produced in cells through a process called glycolysis, which breaks down glucose to generate energy. However, in cancer cells, this process is often upregulated, leading to increased lactate production, even in the presence of oxygen. This phenomenon is known as the Warburg effect.

-Lactate is the end product of glycolysis and induces TGFβ1 upregulation and the acidic microenvironment.

Scientific Papers found: Click to Expand⟱

5277-

3BP,

3-Bromopyruvate inhibits pancreatic tumor growth by stalling glycolysis, and dismantling mitochondria in a syngeneic mouse model

in-vivo,

PC,

Panc02

mouse model

HK2↓, It exerts potent anticancer effects by inhibiting hexokinase II enzyme (HK2) of the glycolytic pathway in cancer cells while not affecting the normal cells.
selectivity↑, it doesn’t affect the normal cells but strongly toxic to cancer cells
ATP↓, 3-BP killed 95% of Panc-2 cells at 15 μM concentration and severely inhibited ATP production by disrupting the interaction between HK2 and mitochondrial Voltage Dependent Anion Channel-1 (VDAC1) protein.
mtDam↑, Electron microscopy data revealed that 3-BP severely damaged mitochondrial membrane in cancer cells.
Dose↝, We further examined therapeutic effect of 3-BP in syngeneic mouse pancreatic cancer model by treating animals with 10, 15 and 20 mg/kg dose. 3-BP at 15 & 20 mg/kg dose level significantly reduced tumor growth by approximately 75-80% in C57BL/6 female
TumCG↓, 3-BP inhibit in vivo pancreatic tumor growth in C57BL/6 mouse model
Casp3↑, observed enhanced expression of active caspase-3 in tumor tissues exhibited apoptotic death.
Glycolysis↓, Notably, metabolomic data also revealed severe inhibition in glycolysis, NADP, ATP and lactic acid production in cancer cells treated with 40 μM 3-BP.
NADPH↓,
ATP↓,
ROS↑, 3-BP treatment produces increased levels of reactive oxygen species (ROS), which causes DNA damage with reduction of free glutathione levels [11].
DNAdam↑,
GSH↓,
Bcl-2↓, Further, treatment with 40 µM of 3-BP suppressed BCL2L1 expression and causing activation of mitochondrial caspases
Casp↑,
lactateProd↓, Metabolic inhibition of glucose consumption and lactic acid production in cancer cells treated with 3-BP

944-

AG,

Astragalus saponins inhibit cell growth, aerobic glycolysis and attenuate the inflammatory response in a DSS-induced colitis model

vitro+vivo,

CRC,

Glycolysis↓,
lactateProd↓,
TumCG↓,

3454-

ALA,

Lipoic acid blocks autophagic flux and impairs cellular bioenergetics in breast cancer and reduces stemness

in-vitro,

BC,

MCF7

(0.5 mM, 1 mM, 2.5 mM, and 5 mM)

in-vitro,

BC,

MDA-MB-231

TumCG↑, Lipoic acid inhibits breast cancer cell growth via accumulation of autophagosomes.
Glycolysis↓, Lipoic acid inhibits glycolysis in breast cancer cells.
ROS↑, Lipoic acid induces ROS production in breast cancer cells/BCSC.
CSCs↓, Here, we demonstrate that LA inhibits mammosphere formation and subpopulation of BCSCs
selectivity↑, In contrast, LA at similar doses. had no significant effect on the cell viability of the human embryonic kidney cell line (HEK-293)
LC3B-II↑, LA treatment (0.5 mM and 1.0 mM) increased the expression level of LC3B-I to LC3B-II in both MCF-7 and MDA-MB231cells at 48 h
MMP↓, LA induced mitochondrial ROS levels, decreased mitochondria complex I activity, and MMP in both MCF-7 and MDA-MB231 cells
mitResp↓, In MCF-7 cells, we found a substantial reduction in maximal respiration and ATP production at 0.5 mM and 1 mM of LA treatment after 48 h
ATP↓,
OCR↓, LA at 2.5 mM decreased OCR
NAD↓, we found that LA (0.5 mM and 1 mM) significantly reduced ATP production and NAD levels in MCF-7 and MDA-MB231 cells
p‑AMPK↑, LA treatment (0.5 mM and 1.0 mM) increased p-AMPK levels;
GlucoseCon↓, LA (0.5 mM and 1 mM) significantly decreased glucose uptake and lactate production in MCF-7, whereas LA at 1 mM significantly reduced glucose uptake and lactate production in MDA-MB231 cells but it had no effect at 0.5 mM
lactateProd↓,
HK2↓, LA reduced hexokinase 2 (HK2), phosphofructokinase (PFK), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) expression in MCF-7 and MDA-MB231 cells
PFK↓,
LDHA↓,
eff↓, Moreover, we found that LA-mediated inhibition of cellular bioenergetics including OCR (maximal respiration and ATP production) and glycolysis were restored by NAC treatment (Fig. 6E and F) which indicates that LA-induced ROS production is responsibl
mTOR↓, LA inhibits mTOR signaling and thereby decreased the p-TFEB levels in breast cancer cells
ECAR↓, LA also inhibits glycolysis as evidenced by decreased glucose uptake, lactate production, and ECAR.
ALDH↓, LA decreased ALDH1 activity, CD44+/CD24-subpopulation, and increased accumulation of autophagosomes possibly due to inhibition of autophagic flux of breast cancer.
CD44↓,
CD24↓,

6596-

Anamu,

Effect of Petiveria alliacea Extracts on Metabolism of K562 Myeloid Leukemia Cells

in-vitro,

AML,

K562

TumCP↓, P. alliacea reduces K562 cell proliferation
OCR↓, P. Alliacea extract decreased the oxygen consumption rate and intracellular ATP.
ATP↓,
TumCCA↑, leading to cell cycle arrest.
ECAR↑, Esperanza extract induced a significant reduction in the OCR (Figure 4A) and a slight increase in the ECAR
Glycolysis↓, P. alliacea induces changes in the cellular expression of several glycolytic enzymes, a decrease in glycolysis, lactate production, and mitochondrial respiration, and a reduction in β-F1-ATPase, ultimately leading to ATP deficiency
lactateProd↓,
mitResp↓,

206-

Api,

Inhibition of glutamine utilization sensitizes lung cancer cells to apigenin-induced apoptosis resulting from metabolic and oxidative stress

in-vitro,

Lung,

H1299

 20 uM

in-vitro,

Lung,

H460

in-vitro,

Lung,

A549

 40 uM

in-vitro,

CRC,

HCT116

in-vitro,

Melanoma,

A375

in-vitro,

Lung,

H2030

in-vitro,

CRC,

SW480

Glycolysis↓, glucose consumption, lactate production, and ATP production were all strongly decreased by apigenin
lactateProd↓,
PGK1↓,
ALDOA↓,
GLUT1↓, Apigenin reduces GLUT1 expression levels.
ENO1↓,
ATP↓,
Casp9↑,
Casp3↑,
cl‑PARP↑, cleavage
PI3K/Akt↓,
HK1↓, HK1, HK2
HK2↓,
ROS↑, Apigenin causes oxidative stress leading to apoptosis. Because apoptotic signal transduction cascades involving caspase-9, -3 and PARP cleavage can be activated by increased ROS levels
Apoptosis↑,
eff↓, Cancer cells expressing high levels of GLUT1 are resistant to apigenin-induced apoptosis through metabolic compensation of glucose utilization.
NADPH↓, apigenin significantly decreased glucose utilization through suppression of GLUT1 expression, and consequently decreased NADPH production, which led to increased ROS levels.
PPP↓, inhibition of the PPP

3383-

ART/DHA,

Dihydroartemisinin: A Potential Natural Anticancer Drug

Review,

Var,

TumCP↓, DHA exerts anticancer effects through various molecular mechanisms, such as inhibiting proliferation, inducing apoptosis, inhibiting tumor metastasis and angiogenesis, promoting immune function, inducing autophagy and endoplasmic reticulum (ER) stres
Apoptosis↑,
TumMeta↓,
angioG↓,
TumAuto↑,
ER Stress↑,
ROS↑, DHA could increase the level of ROS in cells, thereby exerting a cytotoxic effect in cancer cells
Ca+2↑, activation of Ca2+ and p38 was also observed in DHA-induced apoptosis of PC14 lung cancer cells
p38↑,
HSP70/HSPA5↓, down-regulation of heat-shock protein 70 (HSP70) might participate in the apoptosis of PC3 prostate cancer cells induced by DHA
PPARγ↑, DHA inhibited the growth of colon tumor by inducing apoptosis and increasing the expression of peroxisome proliferator-activated receptor γ (PPARγ)
GLUT1↓, DHA was shown to inhibit the activity of glucose transporter-1 (GLUT1) and glycolytic pathway by inhibiting phosphatidyl-inositol-3-kinase (PI3K)/AKT pathway and downregulating the expression of hypoxia inducible factor-1α (HIF-1α)
Glycolysis↓, Inhibited glycolysis
PI3K↓,
Akt↓,
Hif1a↓,
PKM2↓, DHA could inhibit the expression of PKM2 as well as inhibit lactic acid production and glucose uptake, thereby promoting the apoptosis of esophageal cancer cells
lactateProd↓,
GlucoseCon↓,
EMT↓, regulating the EMT-related genes (Slug, ZEB1, ZEB2 and Twist)
Slug↓, Downregulated Slug, ZEB1, ZEB2 and Twist in mRNA level
Zeb1↓,
ZEB2↓,
Twist↓,
Snail?, downregulated the expression of Snail and PI3K/AKT signaling pathway, thereby inhibiting metastasis
CAFs/TAFs↓, DHA suppressed the activation of cancer-associated fibroblasts (CAFs) and mouse cancer-associated fibroblasts (L-929-CAFs) by inhibiting transforming growth factor-β (TGF-β signaling
TGF-β↓,
p‑STAT3↓, blocking the phosphorylation of STAT3 and polarization of M2 macrophages
M2 MC↓,
uPA↓, DHA could inhibit the growth and migration of breast cancer cells by inhibiting the expression of uPA
HH↓, via inhibiting the hedgehog signaling pathway
AXL↓, DHA acted as an Axl inhibitor in prostate cancer, blocking the expression of Axl through the miR-34a/miR-7/JARID2 pathway, thereby inhibiting the proliferation, migration and invasion of prostate cancer cells.
VEGFR2↓, inhibition of VEGFR2-mediated angiogenesis
JNK↑, JNK pathway activated and Beclin 1 expression upregulated.
Beclin-1↑,
GRP78/BiP↑, Glucose regulatory protein 78 (GRP78, an ER stress-related molecule) was upregulated after DHA treatment.
eff↑, results demonstrated that DHA-induced ER stress required iron
eff↑, DHA was used in combination with PDGFRα inhibitors (sunitinib and sorafenib), it could sensitize ovarian cancer cells to PDGFR inhibitors and achieved effective therapeutic efficacy
eff↑, DHA combined with 2DG (a glycolysis inhibitor) synergistically induced apoptosis through both exogenous and endogenous apoptotic pathways
eff↑, histone deacetylase inhibitors (HDACis) enhanced the anti-tumor effect of DHA by inducing apoptosis.
eff↑, DHA enhanced PDT-induced cell growth inhibition and apoptosis, increased the sensitivity of esophageal cancer cells to PDT by inhibiting the NF-κB/HIF-1α/VEGF pathway
eff↑, DHA was added to magnetic nanoparticles (MNP), and the MNP-DHA has shown an effect in the treatment of intractable breast cancer
IL4↓, downregulated IL-4;
DR5↑, Upregulated DR5 in protein, Increased DR5 promoter activity
Cyt‑c↑, Released cytochrome c from the mitochondria to the cytosol
Fas↑, Upregulated fas, FADD, Bax, cleaved-PARP
FADD↑,
cl‑PARP↑,
cycE/CCNE↓, Downregulated Bcl-2, Bcl-xL, procaspase-3, Cyclin E, CDK2 and CDK4
CDK2↓,
CDK4↓,
Mcl-1↓, Downregulated Mcl-1
Ki-67↓, Downregulated Ki-67 and Bcl-2
Bcl-2↓,
CDK6↓, Downregulated of Cyclin E, CDK2, CDK4 and CDK6
VEGF↓, Downregulated VEGF, COX-2 and MMP-9
COX2↓,
MMP9↓,

566-

ART/DHA,

2DG,

Dihydroartemisinin inhibits glucose uptake and cooperates with glycolysis inhibitor to induce apoptosis in non-small cell lung carcinoma cells

in-vitro,

Lung,

A549

in-vitro,

Lung,

PC9

GlucoseCon↓,
ATP↓,
lactateProd↓,
p‑S6↓,
mTOR↓,
GLUT1↓,
Casp9↑,
Casp8↑,
Casp3↑,
Cyt‑c↑,
AIF↑,
ROS↑, generation of ROS is critical for the toxic effects of DHA

2323-

ART/DHA,

Dihydroartemisinin represses esophageal cancer glycolysis by down-regulating pyruvate kinase M2

in-vitro,

ESCC,

Eca109

10, 40, 80, 120 umol/L)

in-vitro,

ESCC,

EC9706

PKM2↓, DHA treatment cells, PKM2 was down-regulated and lactate product and glucose uptake were inhibited.
lactateProd↓,
GlucoseCon↓,
cycD1/CCND1↓, DHA treatment resulted in the down-regulation of the expression of PKM2, cyclin D1, Bcl-2, matrix metalloproteinase-2 (MMP2), vascular endothelial growth factor A (VEGF-A) and the up-regulation of caspase 3, cleaved-PARP and Bax
Bcl-2↓,
MMP2↓,
VEGF↓,
Casp3↑,
cl‑PARP↑,
BAX↑,
DNAdam↑, The specific mechanism of DHA towards cancer cells include inducing DNA damage and repair (Li et al., 2008), oxidative stress response by reactive oxygen species
ROS↑,

2320-

ART/DHA,

Dihydroartemisinin Inhibits the Proliferation of Leukemia Cells K562 by Suppressing PKM2 and GLUT1 Mediated Aerobic Glycolysis

in-vitro,

AML,

K562

1.1–2.6 μM

in-vitro,

Liver,

HepG2

Glycolysis↓, DHA prevented cell proliferation in K562 cells through inhibiting aerobic glycolysis.
GlucoseCon↓, Lactate product and glucose uptake were inhibited after DHA treatment.
lactateProd↓,
GLUT1↓, DHA modulates glucose uptake through downregulating glucose transporter 1 (GLUT1) in both gene and protein levels.
PKM2↓, DHA treatment, decreased expression of PKM2 was confirmed in situ.
ECAR↓, ECAR parameters including the glycolytic activity and capacity decreased in a concentration-dependent manner in K562 cells following DHA administration
LDHA↓, DHA treatment downregulated the relative expression of GLUT1, PKM2, LDH-A and c-Myc
cMyc↓,
other↝, The relative changes of PDK1, P53, HIF-1α, HK2, and PFK1 expression were modest, with most genes being altered by less than 2-fold

2388-

Ash,

Withaferin A decreases glycolytic reprogramming in breast cancer

in-vitro,

BC,

MDA-MB-231

5 μM WA

in-vitro,

BC,

MDA-MB-468

in-vitro,

BC,

MCF7

in-vitro,

BC,

MDA-MB-453

GlucoseCon↓, WA decreases the glucose uptake, lactate production and ATP generation by inhibiting the expression of key glycolytic enzymes i.e., GLUT1, HK2 and PKM2.
lactateProd↓,
ATP↓,
Glycolysis↓,
GLUT1↓,
HK2↓,
PKM2↓,
cMyc↓, WA decreases the protein expression of key glycolytic enzymes via downregulation of c-myc expression
Warburg↓, WA decreases protein expression of key glycolytic enzymes and Warburg effect via c-myc inhibition
cMyc↓,

3156-

Ash,

Withaferin A: From ayurvedic folk medicine to preclinical anti-cancer drug

Review,

Var,

MAPK↑, Figure 3
p38↑,
BAX↑,
BIM↑,
CHOP↑,
ROS↑,
DR5↑,
Apoptosis↑,
Ferroptosis↑,
GPx4↓,
BioAv↝, WA has a rapid oral absorption and reaches to peak plasma concentration of around 16.69 Â± 4.02 ng/ml within 10 min after oral administration of Withania somnifera aqueous extract at dose of 1000 mg/kg, which is equivalent to 0.458 mg/kg of WA
HSP90↓, table 1 10uM) were found to inhibit the chaperone activity of HSP90
RET↓,
E6↓,
E7↓,
Akt↓,
cMET↓,
Glycolysis↓, by suppressing the glycolysis and tricarboxylic (TCA) cycle
TCA↓,
NOTCH1↓,
STAT3↓,
AP-1↓,
PI3K↓,
eIF2α↓,
HO-1↑,
TumCCA↑, WA (1--3 uM) have been reported to inhibit cell proliferation by inducing G2 and M phase cycle arrest inovarian, breast, prostate, gastric and myelodysplastic/leukemic cancer cells and osteosarcoma
CDK1↓, WA is able to decrease the cyclin-dependent kinase 1 (Cdk1) activity and prevent Cdk1/cyclin B1 complex formation, which are key steps in cell cycle progression
*hepatoP↑, A treatment (40 mg/kg) reduces acetaminophen-induced liver injury (AILI) in mouse models and decreases H 2O 2-induced glutathione (GSH) depletion and necrosis in hepatocyte
*GSH↑,
*NRF2↑, WA triggers an anti-oxidant response after acetaminophen overdose by enhancing hepatic transcription of the nuclear factor erythroid 2ârelated factor 2 (NRF2)-responsive gene
Wnt↓, indirectly inhibit Wnt
EMT↓, WA can also block tumor metastasis through reduced expression of epithelial mesenchymal transition (EMT) markers.
uPA↓, WA (700 nM) exert anti-meta-static activities in breast cancer cells through inhibition of the urokinase-type plasminogen activator (uPA) protease
CSCs↓, s WA (125-500 nM) suppress tumor sphere formation indicating that the self-renewal of CSC is abolished
Nanog↓, loss of these CSC-specific characteristics is reflected in the loss of typical stem cell markers such as ALDH1A, Nanog, Sox2, CD44 and CD24
SOX2↓,
CD44↓,
lactateProd↓, drop in lactate levels compared to control mice.
Iron↑, Furthermore, we found that WA elevates the levels of intracellular labile ferrous iron (Fe +2 ) through excessive activation of heme oxygenase-1 (HMOX1), which independently causes accumulation of toxic lipid radicals and ensuing ferroptosis
NF-kB↓, nhibition of NF-kB kinase signaling pathway

996-

Ba,

Tam,

Baicalein resensitizes tamoxifen‐resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia‐inducible factor‐1α

Hif1a↓,
Glycolysis↓,
GlucoseCon↓,
lactateProd↓,
lact/pyru↓,
ROS↑, baicalein significantly increased mitochondrial ROS.
Apoptosis↑,

2620-

Ba,

Natural compounds targeting glycolysis as promising therapeutics for gastric cancer: A review

Review,

GC,

Hif1a↓, Baicalein reduces the levels of HIF-1α in AGS gastric cancer cells in a dose-dependent manner (10, 20, and 40 µM)
HK2↓, down-regulates the levels of HK2, LDHA, and PDK1
LDHA↓,
PDK1↓,
p‑Akt↓, inhibits Akt phosphorylation under hypoxic conditions
PTEN↑, promotes the expression of PTEN protein
GlucoseCon↓, gradually restores glucose uptake and lactic acid production in hypoxic AGS cells to those observed under normoxic conditions
lactateProd↓,
Glycolysis↓, Baicalein and other compounds could directly regulate glycolysis-related enzymes

2335-

BBR,

Chemoproteomics reveals berberine directly binds to PKM2 to inhibit the progression of colorectal cancer

in-vitro,

CRC,

HT29

EC50 of 4.62 μM

in-vitro,

CRC,

HCT116

and 9.39 μM

in-vivo,

NA,

mice

PKM2↓, berberine is directly bound to pyruvate kinase isozyme type M2 (PKM2) in colorectal cancer cells. Berberine inhibited PKM2 activity
Glycolysis↓, berberine was shown to inhibit the reprogramming of glucose metabolism and the phosphorylation of STAT3, down regulate the expression of Bcl-2 and Cyclin D1 genes
p‑STAT3↓,
Bcl-2↓,
cycD1/CCND1↓,
TumCG↓, n vivo experiments showed that tumor growth was inhibited in HT29 cell-bearing mice injected intraperitoneally with berberine (5 or 10 mg/kg body weight)
Ki-67↓, Berberine inhibited the proliferation index (Ki67 expression)
lactateProd↓, Berberine inhibited lactate production, glucose uptake, pyruvate production, and PKM2 activity in HWT tumor tissues, but no apparent effects were observed in both F244A mutant cells and I199S mutant tumor tissues
glucose↓,

940-

BBR,

Functional inhibition of lactate dehydrogenase suppresses pancreatic adenocarcinoma progression

vitro+vivo,

PC,

PANC1

33uM-62uM

253 patients who were treatment‐naive and pathologically diagnosed with pancreatic adenocarcinoma

in-vivo,

PC,

MIA PaCa-2

mouse

LDHA↓, berberine was selected as functional inhibitor of LDHA
lactateProd↓, berberine treatment significantly suppressed intracellular lactate content at 5 μΜ and 10 μΜ
AMPKα↓, suppressed AMPKa activation
TumVol↓,
Ki-67↓,

2738-

BetA,

Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway

in-vitro,

BC,

MDA-MB-231

in-vitro,

BC,

BT549

in-vivo,

NA,

mice

TumCI↓, BA inhibited invasion and migration of highly aggressive breast cancer cells.
TumCMig↓,
Glycolysis↓, Moreover, BA could suppress aerobic glycolysis of breast cancer cells presenting as a reduction of lactate production, quiescent energy phenotype transition, and downregulation of aerobic glycolysis-related proteins.
lactateProd↓, lactate production in both MDA-MB-231 and BT-549 cells was significantly reduced following BA administration
GRP78/BiP↑, (GRP78) was also identified as the molecular target of BA in inhibiting aerobic glycolysis. BA treatment led to GRP78 overexpression, and GRP78 knockdown abrogated the inhibitory effect of BA on glycolysis.
ER Stress↑, Further studies demonstrated that overexpressed GRP78 activated the endoplasmic reticulum (ER) stress sensor PERK.
PERK↑,
p‑eIF2α↑, Subsequent phosphorylation of eIF2α led to the inhibition of β-catenin expression, which resulted in the inhibition of c-Myc-mediated glycolysis.
β-catenin/ZEB1↓,
cMyc↓, These findings suggested that BA inhibited the β-catenin/c-Myc pathway by interrupting the binding between GRP78 and PERK and ultimately suppressed the glycolysis of breast cancer cells.
ROS↑, (i) the induction of cancer cell apoptosis via the mitochondrial pathway induced by the release of soluble factors or generation of reactive oxygen species (ROS)
angioG↓, (ii) the inhibition of angiogenesis [24];
Sp1/3/4↓, (iii) the degradation of transcription factor specificity protein 1 (Sp1)
DNAdam↑, (iv) the induction of DNA damage by suppressing topoisomerase I
TOP1↓,
TumMeta↓, BA Inhibits Metastasis of Highly Aggressive Breast Cancer Cells
MMP2↓, BA significantly decreased the expression of MMP-2 and MMP-9 secreted by breast cancer cells
MMP9↓,
N-cadherin↓, BA downregulated the levels of N-cadherin and vimentin as the mesenchymal markers, while increased E-cadherin which is an epithelial marker (Figure 2(c)), validating the EMT inhibition effects of BA in breast cancer cells.
Vim↓,
E-cadherin↑,
EMT↓,
LDHA↓, the levels of glycolytic enzymes, including LDHA and p-PDK1/PDK1, were all decreased in a dose-dependent manner by BA
p‑PDK1↓,
PDK1↓,
ECAR↓, extracellular acidification rate (ECAR), which reflects the glycolysis activity, was retarded following BA administration.
OCR↓, oxygen consumption rate (OCR), which is a marker of mitochondrial respiration, was also decreased simultaneously
Hif1a↓, BA could reduce prostate cancer angiogenesis via inhibiting the HIF-1α/stat3 pathway [39]
STAT3↓,

2740-

BetA,

Effects and mechanisms of fatty acid metabolism-mediated glycolysis regulated by betulinic acid-loaded nanoliposomes in colorectal cancer

in-vitro,

CRC,

HCT116

TumCP↓, BA-NLs significantly suppressed the proliferation and glucose uptake of CRC cells by regulating potential glycolysis and fatty acid metabolism targets and pathways, which forms the basis of the anti-CRC function of BA-NLs.
Glycolysis↓,
HK2↓, HK2, PFK-1, PEP and PK isoenzyme M2 (PKM2) in glycolysis, and of ACSL1, CPT1a and PEP in fatty acid metabolism, were blocked by BA-NLs, which play key roles in the inhibition of glycolysis and fatty acid-mediated production of pyruvate and lactate.
PFK1↓,
PKM2↓,
ACSL1↓,
CPT1A↓,
FASN↓,
FAO↓, Significant reduction of FAO was detected in BA-NL-treated HCT116 cells
GlucoseCon↓, glucose uptake in HCT116 cells was significantly decreased by BA-NLs
lactateProd↓, lactic acid secretion was significantly suppressed in HCT116 cells treated with BA-NLs

943-

BetA,

Betulinic acid suppresses breast cancer aerobic glycolysis via caveolin-1/NF-κB/c-Myc pathway

in-vitro,

BC,

MCF7

in-vitro,

BC,

MDA-MB-231

in-vivo,

NA,

mouse model

Glycolysis↓,
lactateProd↓,
GlucoseCon↓,
ECAR↓,
cMyc↓,
LDHA↓,
p‑PDK1↓,
PDK1↓,
Cav1↑, Cav-1) as one of key targets of BA in suppressing aerobic glycolysis, as BA administration resulted in Cav-1 upregulation
*Glycolysis↑, BA could lead to increased glycolysis in mouse embryonic fibroblasts by activating LKB1/AMPK pathway, whereas we found that BA inhibited aerobic glycolysis in breast cancer cells by modulating Cav-1/NF-ÎºB/c-Myc signaling
selectivity↑,
OCR↓, OCR parameters including the basal respiration, maximal respiration and spare respiratory capacity were also simultaneously inhibited
OXPHOS↓, implying that the activity of mitochondrial oxidative phosphorylation (OXPHOS) chain was also suppressed by BA

1261-

CAP,

Capsaicin inhibits glycolysis in esophageal squamous cell carcinoma by regulating hexokinase‑2 expression

in-vitro,

ESCC,

KYSE150

GlucoseCon↓,
lactateProd↓,
HK2↓,
Glycolysis↓,
PTEN↑,
AKT1↓, RAC‑α serine threonine‑protein kinase signaling pathway was downregulated

939-

Catechins,

5-FU,

Targeting Lactate Dehydrogenase A with Catechin Resensitizes SNU620/5FU Gastric Cancer Cells to 5-Fluorouracil

vitro+vivo,

GC,

SNU620

lactateProd↓, Catechin, the simplest compound among them, had the highest inhibitory effect on lactate production and LDHA activity
ROS↑, induced reactive oxygen species (ROS)-mediated apoptosis in SNU620/5FU cells.
tumCV↓,
LDHA↓, CA better than EGCG
mt-ROS↑, CA and 5FU significantly enhanced mitochondrial ROS production
proApCas↑,

6128-

CHr,

Chrysin: A Comprehensive Review of Its Pharmacological Properties and Therapeutic Potential

Review,

Nor,

Review,

Var,

Review,

AD,

*antiOx↑, Chrysin exhibits a range of biological activities, including antioxidant, anti-inflammatory, anticancer, neuroprotective, and anxiolytic effects.
*Inflam↓,
AntiCan↑,
*neuroP↑, exhibits neuroprotective effects in neurological disorders such as epilepsy, neuronal apoptosis, neuroinflammation [80], anxiety [81], depression [82], multiple sclerosis [83], Parkinson’s disease, Alzheimer’s disease, cognitive deficits,
*ROS↓, facilitate the neutralization of free radicals
*BioAv↓, Despite its therapeutic potential, chrysin’s bioavailability is significantly limited due to poor aqueous solubility and rapid metabolism in the gastrointestinal tract and liver, which reduces its systemic efficacy.
*BioAv↑, Ongoing research aims to enhance chrysin’s bioavailability through the development of delivery systems such as lipid-based carriers and nanoparticles.
*cardioP↑, Chrysin exerts cardioprotective effects by modulating certain cellular signaling pathways involved in inflammation, oxidative stress [66]
*COX2↓, it suppresses cyclooxygenase-2 (COX-2), an enzyme involved in prostaglandin synthesis that promotes inflammation
*TNF-α↓, inhibits phosphorylation and degradation of IκB-α, as well as the translocation of NF-κB, and reduces levels of TNF-α and IL-1β by inhibiting NF-κB expression
*IL1β↓,
*NF-kB↓,
*lipid-P↓, Chrysin protects against ROS by reducing lipid peroxidation levels in the liver and increasing both enzymatic and non-enzymatic antioxidant levels
*Apoptosis↓, chrysin counteracted oxidative stress, reduced neuronal apoptosis, and increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) [80].
*NRF2↑,
*HO-1↑,
*MDA↓, In rat models, chrysin was shown to lower serum corticosterone and malondialdehyde (MDA) levels while increasing glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (Gpx), glutathione reductase (GR), and catalase (CAT).
*GSH↑,
*SOD↑,
*GPx↑,
*GSR↑,
*Catalase↑,
*5HT↑, Moreover, chrysin increased serotonin (5-HT) levels and reduced the activity of indoleamine 2,3-dioxygenase.
*Casp3↓, It also decreased the expression of caspases-3 and -9 [97,98].
*Casp9↓,
TumCCA↑, it causes cell cycle arrest in cancer cells, reduces expression of MAPK and PI3K/Akt signaling pathways, and disrupts overall cell proliferation
MAPK↓,
PI3K↓,
Akt↓,
TumCP↓,
TET1↑, chrysin promoted TET1 and 5-hydroxymethylcytosine expression, which stimulated apoptosis and disrupted the migration of gastric cancer cells
TLR4↓, Chrysin’s effects in lung cancer include decreasing the expression of TLR4 and Myd88 in the signaling cascade from activated receptor to the cell interior.
HER2/EBBR2↓, pyrotinib combined with chrysin, it was confirmed that adding chrysin positively enhanced the inhibition of HER2-positive breast cancer growth both in vitro and in vivo,
HK2↓, As HK-2 levels decreased, chrysin inhibited glycolysis (which impairs glucose uptake and lactate production) in the tumor and activated mitochondria-related apoptosis
Glycolysis↓,
glucose↓,
lactateProd↓,
ROS↑, chrysin was shown to promote the generation of reactive oxygen species (ROS) and reduce mTOR expression, thereby stimulating autophagy [127]
mTOR↓,
TumAuto↑,
tumCV↓, chrysin significantly reduces cell viability by inducing ER stress through stimulation of UPR, PERK, ATF4, and eIF2α
ER Stress↑,
UPR↑,
PERK↑,
ATF4↑,
eIF2α↑,
BioAv↑, Solid Lipid Nanoparticles (SLNs) High biocompatibility and low toxicity due to the use of physiological lipids.

2782-

CHr,

Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives

Review,

Var,

Review,

Stroke,

Review,

Park,

*antiOx↑, antioxidant, anti-inflammatory, hepatoprotective, neuroprotective
*Inflam↓, inhibitory effect of chrysin on inflammation and oxidative stress is also important in Parkinson’s disease
*hepatoP↑,
*neuroP↑,
*BioAv↓, Accumulating data demonstrates that poor absorption, rapid metabolism, and systemic elimination are responsible for poor bioavailability of chrysin in humans that, subsequently, restrict its therapeutic effects
*cardioP↑, cardioprotective [69], lipid-lowering effect [70]
*lipidLev↓,
*RenoP↑, Renoprotective
*TNF-α↓, chrysin reduces levels of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2).
*IL2↓,
*PI3K↓, induction of the PI3K/Akt signaling pathway by chrysin contributes to a reduction in oxidative stress and inflammation during cerebral I/R injury
*Akt↓,
*ROS↓,
*cognitive↑, Chrysin (25, 50, and 100 mg/kg) improves cognitive capacity, inflammation, and apoptosis to ameliorate traumatic brain injury
eff↑, chrysin and silibinin is beneficial in suppressing breast cancer malignancy via decreasing cancer proliferation
cycD1/CCND1↓, chrysin and silibinin induced cell cycle arrest via down-regulation of cyclin D1 and hTERT
hTERT/TERT↓,
VEGF↓, Administration of chrysin is associated with the disruption of hypoxia-induced VEGF gene expression
p‑STAT3↓, chrysin is capable of reducing STAT3 phosphorylation in hypoxic conditions without affecting the HIF-1α protein level.
TumMeta↓, chrysin is a potent agent in suppressing metastasis and proliferation of breast cancer cells during hypoxic conditions
TumCP↓,
eff↑, combination therapy of breast cancer cells using chrysin and metformin exerts a synergistic effect and is more efficient compared to chrysin alone
eff↑, combination of quercetin and chrysin reduced levels of pro-inflammatory factors, such as IL-1β, Il-6, TNF-α, and IL-10, via NF-κB down-regulation.
IL1β↓,
IL6↓,
NF-kB↓,
ROS↑, after chrysin administration, an increase occurs in levels of ROS that, subsequently, impairs the integrity of the mitochondrial membrane, leading to cytochrome C release and apoptosis induction
MMP↓,
Cyt‑c↑,
Apoptosis↑,
ER Stress↑, in addition to mitochondria, ER can also participate in apoptosis
Ca+2↑, Upon chrysin administration, an increase occurs in levels of ROS and cytoplasmic Ca2+ that mediate apoptosis induction in OC cells
TET1↑, In MKN45 cells, chrysin promotes the expression of TET1
Let-7↑, Chrysin is capable of promoting the expression of miR-9 and Let-7a as onco-suppressor factors in cancer to inhibit the proliferation of GC cells
Twist↓, Down-regulation of NF-κB, and subsequent decrease in Twist/EMT are mediated by chrysin administration, negatively affecting cervical cancer metastasis
EMT↓,
TumCCA↑, nduction of cell cycle arrest and apoptosis via up-regulation of caspase-3, caspase-9, and Bax are mediated by chrysin
Casp3↑,
Casp9↑,
BAX↑,
HK2↓, Chrysin administration (15, 30, and 60 mM) reduces the expression of HK-2 in hepatocellular carcinoma (HCC) cells to impair glucose uptake and lactate production.
GlucoseCon↓,
lactateProd↓,
Glycolysis↓, In addition to glycolysis metabolism impairment, the inhibitory effect of chrysin on HK-2 leads to apoptosis
SHP1↑, upstream modulator of STAT3 known as SHP-1 is up-regulated by chrysin
N-cadherin↓, Furthermore, N-cadherin and E-cadherin are respectively down-regulated and up-regulated upon chrysin administration in inhibiting melanoma invasion
E-cadherin↑,
UPR↑, chrysin substantially diminishes survival by ER stress induction via stimulating UPR, PERK, ATF4, and elF2α
PERK↑,
ATF4↑,
eIF2α↑,
RadioS↑, Irradiation combined with chrysin exerts a synergistic effect
NOTCH1↑, Irradiation combined with chrysin exerts a synergistic effect
NRF2↓, in reducing Nrf2 expression, chrysin down-regulates the expression of ERK and PI3K/Akt pathways—leading to an increase in the efficiency of doxorubicin in chemotherapy
BioAv↑, chrysin at the tumor site by polymeric nanoparticles leads to enhanced anti-tumor activity, due to enhanced cellular uptake
eff↑, Chrysin- and curcumin-loaded nanoparticles significantly promote the expression of TIMP-1 and TIMP-2 to exert a reduction in melanoma invasion

1143-

CHr,

Chrysin inhibited tumor glycolysis and induced apoptosis in hepatocellular carcinoma by targeting hexokinase-2

in-vitro,

HCC,

HepG2

0-60uM

in-vivo,

NA,

mouse

in-vitro,

HCC,

HepG3

in-vitro,

HCC,

HUH7

HK2↓,
GlucoseCon↓,
lactateProd↓,
Glycolysis↓,
Apoptosis↑,

1585-

Citrate,

Sodium citrate targeting Ca2+/CAMKK2 pathway exhibits anti-tumor activity through inducing apoptosis and ferroptosis in ovarian cancer

in-vitro,

Ovarian,

SKOV3

15.93 mM

in-vitro,

Ovarian,

A2780S

16.8 mM

in-vitro,

Nor,

HEK293

Apoptosis↑,
Ferroptosis↑,
Ca+2↓, Sodium citrate chelates intracellular Ca2+
CaMKII ↓, inhibits the CAMKK2/AKT/mTOR/HIF1α-dependent glycolysis pathway, thereby inducing cell apoptosis.
Akt↓,
mTOR↓,
Hif1a↓,
ROS↑, Inactivation of CAMKK2/AMPK pathway reduces Ca2+ level in the mitochondria by inhibiting the activity of the MCU, resulting in excessive ROS production.
ChemoSen↑, Sodium citrate increases the sensitivity of ovarian cancer cells to chemo-drugs
Casp3↑,
Casp9↑,
BAX↑,
Bcl-2↓,
Cyt‑c↑, co-localization of cytochrome c and Apaf-1
GlucoseCon↓, glucose consumption, lactate production and pyruvate content were significantly reduced
lactateProd↓,
Pyruv↓,
GLUT1↓, sodium citrate decreased both mRNA and protein expression levels of glycolysis-related proteins such as Glut1, HK2 and PFKP
HK2↓,
PFKP↓,
Glycolysis↓, sodium citrate inhibited glycolysis of SKOV3 and A2780 cells
Hif1a↓, HIF1α expression was decreased significantly after sodium citrate treatment
p‑Akt↓, phosphorylation of AKT and mTOR was notably suppressed after sodium citrate treatment.
p‑mTOR↓,
Iron↑, ovarian cancer cells treated with sodium citrate exhibited higher Fe2+ levels, LPO levels, MDA levels, ROS and mitochondrial H2O2 levels
lipid-P↑,
MDA↑,
ROS↑,
H2O2↑,
mtDam↑, shrunken mitochondria, an increase in mitochondrial membrane density and disruption of mitochondrial cristae
GSH↓, (GSH) levels, GPX activity and expression levels of GPX4 were significantly reduced in SKOV3 and A2780 cells with sodium citrate treatment
GPx↓,
GPx4↓,
NADPH/NADP+↓, significant elevation in the NADP+/NADPH ratio was observed with sodium citrate treatment
eff↓, Fer-1, NAC and NADPH significantly restored the cell viability inhibited by sodium citrate
FTH1↓, decreased expression of FTH1
LC3‑Ⅱ/LC3‑Ⅰ↑, sodium citrate increased the conversion of cytosolic LC3 (LC3-I) to the lipidated form of LC3 (LC3-II)
NCOA4↑, higher levels of NCOA4
eff↓, test whether Ca2+ supplementation could rescue sodium citrate-induced ferroptosis. The results showed that Ca2+ dramatically reversed the enhanced levels of MDA, LPO and ROS triggered by sodium citrate
TumCG↓, sodium citrate inhibited tumor growth by chelation of Ca2+ in vivo

2304-

CUR,

Curcumin decreases Warburg effect in cancer cells by down-regulating pyruvate kinase M2 via mTOR-HIF1α inhibition

in-vitro,

Lung,

H1299

0–20 μM curcumin for 24

in-vitro,

BC,

MCF7

in-vitro,

Cerv,

HeLa

in-vitro,

Pca,

PC3

in-vitro,

Nor,

HEK293

Glycolysis↓, curcumin inhibits glucose uptake and lactate production (Warburg effect) in a variety of cancer cell lines
GlucoseCon↓,
lactateProd↓,
PKM2↓, by down-regulating PKM2 expression, via inhibition of mTOR-HIF1α axis.
mTOR↓,
Hif1a↓,
selectivity↑, however, no appreciable decrease in Warburg effect was observed in HEK 293 cells
Dose↝, Dose-dependent decrease in Warburg effect started at 2.5 μM with maximal decrease at 20 μM curcumin.
tumCV↓, Curcumin decreases viability of cancer cells

2308-

CUR,

Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells

in-vitro,

Liver,

HepG2

GlucoseCon↓, Curcumin obviated the hyperglycemia-induced modulations like elevated glucose consumption, lactate production, and extracellular acidification, and diminished nitric oxide and reactive oxygen species (ROS) production
lactateProd↓,
ECAR↓,
NO↓,
ROS↑, Curcumin favors the ROS production in HepG2 cells in normal as well as hyperglycemic conditions. ROS production was detected in cancer cells treated with curcumin, or doxorubicin, or their combinations in NG or HG medium for 24 h
HK2↓, HKII, PFK1, GAPDH, PKM2, LDH-A, IDH3A, and FASN. Metabolite transporters and receptors (GLUT-1, MCT-1, MCT-4, and HCAR-1) were also found upregulated in high glucose exposed HepG2 cells. Curcumin inhibited the elevated expression of these enzymes, tr
PFK1↓,
GAPDH↓,
PKM2↓,
LDHA↓,
FASN↓,
GLUT1↓, Curcumin treatment was able to significantly decrease the expression of GLUT1, HKII, and HIF-1α in HepG2 cells either incubated in NG or HG medium.
MCT1↓,
MCT4↓,
HCAR1↓,
SDH↑, Curcumin also uplifted the SDH expression, which was inhibited in high glucose condition
ChemoSen↑, Curcumin Prevents High Glucose-Induced Chemoresistance
ROS↑, Treatment of cells with doxorubicin in presence of curcumin was found to cooperatively augment the ROS level in cells of both NG and HG groups.
BioAv↑, Curcumin Favors Drug Accumulation in Cancer Cells
P53↑, An increased expression of p53 in curcumin-treated cells can be suggestive of susceptibility towards cytotoxic action of anticancer drugs
NF-kB↓, curcumin has therapeutic benefits in hyperglycemia-associated pathological manifestations and through NF-κB inhibition
pH↑, Curcumin treatment was found to resist the lowering of pH of culture supernatant both in NG as well in HG medium.

466-

CUR,

Curcumin circumvent lactate-induced chemoresistance in hepatic cancer cells through modulation of hydroxycarboxylic acid receptor-1

in-vitro,

Liver,

HepG2

5 and 10 μM, 24 h

in-vitro,

Liver,

HuT78

GlucoseCon↓,
lactateProd↓,
pH↑,
NO↑,
LAR↓,
Hif1a↓, gene and protein
LDHA↓,
MCT1↓,
MDR1↓,
STAT3↓,
HCAR1↓,

6685-

DAP,

Anticancer effects of some novel dichloroacetophenones through the inhibition of pyruvate dehydrogenase kinase 1

in-vitro,

Lung,

H1975

PDKs↓, 2,2-dichloroacetophenone (DAP) is a PDK1 inhibitor exhibiting weak anticancer potency and poor selectivity.
selectivity∅,
MMP↓, compounds 54, 55 and 64 depolarized mitochondrial membrane potential, induced cell apoptosis, decreased extracellular lactate formation, and increased reactive oxygen species production in NCI-H1975 cells.
Apoptosis↑,
lactateProd↓,
ROS↑,

6683-

DCA,

Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts

Review,

Var,

PDK1↓, classic DCA target, pyruvate dehydrogenase kinase
lactateProd↓, reduce lactic acid production which would push the cell towards oxidative phosphorylation: this would be the supposed function of dichloroacetate (DCA).
Apoptosis↑, They found that DCA induced apoptosis and decreased proliferation by restoring mitochondrial oxidative metabolism, without toxicity to normal cells.
TumCP↓,
selectivity↑,
other↝, many clinics, usually called “DCA Clinics” have opened, mainly in Canada and Germany.
Dose↝, DCA is sold over the counter and is produced by many laboratories. The quality of the product from these laboratories is not well established. These particulars explain many of the doubts about DCA’s real value as a therapeutic tool.
BioAv↑, DCA is an orally available molecule that is quickly and almost completely absorbed by the digestive system
Half-Life↓, With a 10 mg/kg infusion the maximum plasma concentration achieved was between 19.9 μg/ml and 24.7 μg/ml with a half life of only 20 minutes. If the infused dose was increased to 20 mg/kg the plasma concentration was between 57.3 and 74.9 μg/ml with
Glycolysis↓, facilitates the switch from a glycolytic to an oxidative metabolism.
OXPHOS↑,
Casp↑, onversion to an oxidative metabolism by DCA, is an increase in caspase-mediated apoptosis
i-pH↓, pHi decreases (at least temporarily).
COX2↑, DCA increases the expression of COX2 and the latter increases tumor resistance to DCA. Therefore, a possible integrated treatment could be COX2 inhibitor co-administered with DCA
Hif1a↓, DCA suppresses HIF-1α activity and angiogenesis through the inhibition of PDK-II
angioG↓,
HMG-CoA↓, figure 7
GSTZ1↓,
OCR↑,
lipoGen↓,
fatigue↓,
survivin↓, Survivin (an inhibitor of apoptosis) expression was decreased and miR-375 (a microRNA which acts as a tumor suppressor) levels were increased.
miR-375↑,
eff↓, African Americans are known to respond poorly to therapy compared with Caucasian American patients.
CSCs↓, DCA can inhibit the cancer stem cell like characteristics of the cells and strongly influenced the metabolic pathway of the cells causing a shift from glycolysis to oxidative phosphorylation.
TumAuto↑, DCA induced autophagy in human colon cancer cells with ROS production and mTOR inhibition,
mTOR↓,
TumCI↓, DCA induced apoptosis, inhibited invasion, and angiogenesis. In mouse experiments in vivo with the melanoma allografts, DCA reduced volume and weight of tumors.
TumVol↓,
TumW↓,
ATP↓, DCA alone reduced glycolytic activity and intracellular ATP levels and inhibited cellular growth in melanoma cells.
Warburg↓, DCA was also found to interrupt the Warburg effect and decreased proliferation.
eff↑, The co-application of metformin and DCA suppressed human liver cancer cell proliferation inducing apoptosis through inhibition of mTORC1 and increased ROS in vitro and in vivo
e-pH↑, when measuring extracellular pH in vivo found that an initial increase in extracellular pH of tumors in mice when treated with DCA.
eff↑, To avoid the development of this type of metabolic resistance DCA should be given simultaneously with other metabolic drugs such as metformin [327] or 2 deoxyglucose.
eff↑, chronic co-administration of DCA with sodium bicarbonate to tumor bearing mice prolonged survival
other↝, High doses of thiamin (vit B1) have effects similar to those of DCA: reduced PDH phosphorylation, reduced lactate prod and increased casp3 activity with reduced proliferation in colon cancer cells. can vitB1 replace DCA as a nontoxic PDK inhibitor?
RadioS↑, Dong et al. [380] found that DCA radiosensitized esophageal carcinoma cells in vitro and in vivo through increased ROS accumulation.
toxicity↓, 25 mg/Kg/day may show a mild sedative effect or drowsiness. The most serious published side effect is reversible peripheral neuropathy
Dose↝, 10 to 50 mg/kg body weight/day has been found to be a safe dose. However, single nucleotide polymorphisms (SNPs) in the gene of the enzyme GSTZ1 cause difficulties in establishing a universal dose [409] as noted above.
eff↑, There is strong evidence showing that the association of metformin and DCA has significant cytotoxic effects.
eff↑, To this approach we must add a third compound: a COX2 inhibitor like celecoxib to decrease COX2 expression induced by DCA.
eff↑, the triple association of DCA, metformin and celecoxib, which has never been experimentally tested in patients, deserves well planned phase II clinical trials.
toxicity↝, DCA will never become a stand-alone chemotherapeutic compound. The fundamental reason for this statement is that the drug can only reach micromolar blood concentrations without toxicity and requires millimolar levels to be cytotoxic.
eff↓, DCA should not be used in association with allopurinol, NSAIDs, or flavonoids because they reduce cellular DCA uptake.

6682-

DCA,

QC,

Dichloroacetate and Quercetin Prevent Cell Proliferation, Induce Cell Death and Slow Tumor Growth in a Mouse Model of HPV-Positive Head and Neck Cancer

in-vivo,

HNSCC,

MEER

mouse

PDK1↓, Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase that decreases lactate production.
lactateProd↓,
GlucoseCon↓, Quercetin is a flavonoid compound found in fruits and vegetables that inhibits glucose uptake and lactate export.
tumCV↓, Both DCA and quercetin inhibited colony formation and reduced cell viability, which were associated with mTOR inhibition and increased apoptosis through enhanced ROS production.
mTOR↓,
Apoptosis↑,
ROS↑,
TumCG↓, DCA and quercetin reduced tumor growth and enhanced survival in immune-competent mice, correlating with decreased proliferation as well as decreased acidification of the tumor microenvironment and reduction of Foxp (+) Treg lymphocytes.
pH↑,
cl‑PARP↑, increased levels of cleaved PARP (Figure 2C) in the combination treatment as well as increased caspase 3 cleavage
Casp3↑,
DNAdam↑, DCA and Quercetin Increase DNA Damage through Enhanced ROS Production
p‑γH2AX↑, increased ROS production was correlated with increased phosphorylated H2AX, which is an indicator of ROS-induced DNA damage
eff↓, NAC can partially prevent the DCA/quercetin increased ROS production and phosphorylation of H2AX, as well as the induction of cleaved PARP.
OS↑, In addition to just prolonging survival, DCA, quercetin, and more so their combination, increased the number of animals who went on to be tumor-free.

6681-

DCA,

Dichloroacetate (DCA) in Cancer Care

PDK1↓, Specifically, it inhibits pyruvate dehydrogenase kinase, which may convert metabolism from fermentative glycolysis back to oxidative phosphorylation.
Apoptosis↑, This process may induce cancer cell apoptosis through several mechanisms including increased oxidative stress and reduced lactate levels.
ROS↑,
lactateProd↓,
Dose↝, DCA can be administered orally or intravenously.
eff↝, overall, there is insufficient evidence to support the efficacy of DCA as a cancer treatment.
toxicity↓, most studies have found DCA to be reasonably safe and well tolerated, The most common side effect is reversible peripheral neuropathy.
NP/CIPN↑, One of the five patients who entered the trial with some degree of peripheral neuropathy developed a score of 3 in the Total Neuropathy Score (TNS), but this resolved within six months after DCA cessation
Dose↝, doses range from 10-50mg/kg daily, with the most common oral dosing being 6.25-12.5mg/kg taken twice daily.
*BioAv↑, DCA is a small water soluble molecule of 150 Da, allowing it to achieve 100% bioavailability when given either orally or intravenously
*Half-Life↓, Serum DCA levels rise rapidly after oral administration and exhibit a relatively short half-life. elimination half-life of 92 minutes
GSTZ1↝, DCA metabolism is affected by glutathione transferase zeta 1/maleylacetoacetate isomerase (GSTZ1/MAAI) genotype status. Individuals with at least one wild-type haplotype metabolize DCA more rapidly and thus may be able to tolerate a higher dose
Glycolysis↓, DCA acts on the mitochondrial matrix of cancer cells, diverting metabolism from fermentative glycolysis back to oxidative phosphorylation
OXPHOS↑,
MPT↑, reopening of voltage and redox sensitive mitochondrial transition pores (22). This allows for the pro-apoptotic mediators, cytochrome c and apoptosis-inducing-factor, to be released into the cytoplasm,
Cyt‑c↑,
AIF↑,
Casp↑, increasing the levels of pro-apoptotic ROS through the activation of caspases
CSCs↓, Although less well established, there is some evidence that DCA may be able to reduce stemness and induce differentiation in cancer stem cells
Remission↑, rigorous treatment cycle with DCA, alpha lipoic acid, and B vitamins and achieved complete remission of his cancer as evidenced by PET scans, CT scans, and laboratory testing. Four years later, the patient remained cancer free.
ChemoSen↑, Several preclinical studies have demonstratedsynergistic effects of DCA with chemotherapeutic agents, including carboplatin (34, 57), oxaliplatin (34, 57), 5-fluorouracil (29), paclitaxel (58, 59), doxorubicin (60), elesclomol (24), and sorafenib (6
RadioS↑, There is preliminary preclinical evidence that DCA may act as a radiosensitizer primarily by increasing levels of reactive oxygen species in tumour cells
toxicity↑, Combined with artesunate one patient experienced fatal liver and bone marrow toxicity.

6678-

DCA,

Cisplatin,

Phase II study of dichloroacetate, an inhibitor of pyruvate dehydrogenase, in combination with chemoradiotherapy for unresected, locally advanced head and neck squamous cell carcinoma

Trial,

HNSCC,

double-blind phase II study added DCA to cisplatin-based CRT in patients with LA-HNSCC.

PDK1↓, Dichloroacetate (DCA), a pyruvate dehydrogenase kinase metabolic inhibitor, reduces tumor lactate production and has been used in cancer therapy previously.
OS∅, end-of-treatment complete response rates were significantly higher in the DCA group compared to placebo (71.4% vs 37.5%, p = 0.0362), survival outcomes were not significantly different between groups.
lactateProd↓, significant drop in pyruvate (0.47, p <0.005) and lactate (0.61, p <0.005) in the DCA group.
toxicity↝, Adding DCA to cisplatin-based CRT appears safe with no detrimental effect on survival and expected metabolite changes compared to placebo.
FAO↑, DCA treated patients had enhanced fatty acid oxidation, and increased mitochondrial oxidation that may contribute to unique microbiome-related changes.

4901-

DCA,

Sal,

Dichloroacetate and Salinomycin as Therapeutic Agents in Cancer

Review,

NSCLC,

Glycolysis↓, DCA redirects mitochondrial metabolism away from glycolysis to OXPHOS by the inhibition of PDKs
OXPHOS↑,
PDKs↓,
ROS↑, DCA increases reactive oxygen species (ROS), which induce downstream changes in mitochondrial function, causing the selective apoptosis of cancer cells.
Apoptosis↑,
GlucoseCon↓, treatment with DCA decreased glucose consumption and lactate production in vitro in a manner that was statistically significant compared to the controls
lactateProd↓,
RadioS↑, it enhanced the sensitivity of A549 and H1299 cells to X-ray-induced cell killing
TumAuto↑, DCA has been shown to induce autophagy instead of inhibiting it.
mTOR↓, The DCA-induced induction of autophagy was found to be mediated by the generation of ROS, the inhibition of the mammalian targets of rapamycin (mTOR),
LC3s↓, Lu and colleagues found that LC3 decreased while p62 levels increased, both of which are hallmarks of autophagy inhibition
p62↑,
TumCG↓, In vivo studies have demonstrated that DCA inhibits the growth of A549 and H1975 tumor xenografts and enhances the survival of tumor-bearing nude mice
OS↑,
toxicity↝, the most clinically limiting side effect of DCA is peripheral neuropathy
ChemoSen↑, DCA exerts synergistic potential with the most widely used chemotherapy agent, paclitaxel, on NSCLC cells.
eff↑, DCA has also been shown to have anticancer synergies with various non-traditional agents, the most prominent of which is metformin.
eff↑, Another compound that DCA has been shown to have a strong synergism with is ivermectin.
Ferritin↓, SAL and its derivatives prevent the movement of iron from the lumen to the cytosol, triggering an iron-depletion reaction that is characterized by the rapid degradation of ferritin
CSCs↓, SAL has been shown to selectively target CSCs in vitro and in vivo, but its mode of action is not fully understood.
EMT↓, SAL has also been shown to suppress the epithelial–mesenchymal transition (EMT) as well as transforming growth factors (TGFs). EMT is a process that is pivotal to metastasis.
ROS↑, SAL triggers apoptosis by elevating intracellular ROS levels, leading to the translocation of Bax protein to the mitochondria, cytochrome c (Cytc) release, and the activation of caspase-3
Cyt‑c↑,
Casp3↑,
ER Stress↑, SAL was observed to upregulate ER stress-related proteins in a time-/dose-dependent manner
selectivity↑, SAL induced cell death in multiple apoptosis-resistant cancer cell lines, but not in normal healthy human cells
eff↑, Skeberdytė and colleagues were among the first to recognize that DCA had synergistic potential with SAL.
TumCG↓, DCA and SAL were found to significantly suppress tumor growth in vivo in the mice.

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.

1878-

DCA,

5-FU,

Synergistic Antitumor Effect of Dichloroacetate in Combination with 5-Fluorouracil in Colorectal Cancer

in-vitro,

CRC,

LS174T

57mM

in-vitro,

CRC,

LoVo

29mM

in-vitro,

CRC,

SW-620

38mM

in-vitro,

CRC,

HT-29

47mM

tumCV↓, DCA inhibited the viability of CRC cells and had synergistic antiproliferation in combination with 5-FU
eff↑, synergistic antiproliferation in combination with 5-FU
PDKs↓, Dichloroacetate (DCA) is a prototypical inhibitor of mitochondrial PDK
lactateProd↓, DCA decreases lactate production by shifting the metabolism of pyruvate from glycolysis towards oxidation in the mitochondria
Glycolysis↓,
mitResp↑, DCA restored mitochondrial function
TumCCA↑, DCA potentiated the cell cycle arrest in G1 phase.
Bcl-2↓, DCA and 5-FU decreased Bcl-2 expression significantly as compared with DCA or 5-FU alone
BAX↑, Bax and caspase-3 were significantly increased in the four CRC cell lines treated with combination of DCA and 5-FU compared to their single usage
Casp3↑,

1864-

DCA,

MET,

Dichloroacetate Enhances Apoptotic Cell Death via Oxidative Damage and Attenuates Lactate Production in Metformin-Treated Breast Cancer Cells

in-vitro,

BC,

MCF7

DCA (2.5 mM) and metformin (1 mM)

in-vitro,

BC,

T47D

in-vitro,

Nor,

MCF10

PDKs↓, Dichloroacetate (DCA) is a well-established drug used in the treatment of lactic acidosis which functions through inhibition of pyruvate dehydrogenase kinase (PDK) promoting mitochondrial metabolism
eff↑, DCA and metformin are used in combination, synergistic induction of apoptosis of breast cancer cells occurs.
ROS↑, Metformin-induced oxidative damage is enhanced by DCA through PDK1 inhibition which also diminishes metformin promoted lactate production.
PDK1↓,
lactateProd↓, also diminishes metformin promoted lactate production.
p‑PDH↑, DCA is an inhibitor of pyruvate dehydrogenase kinase (PDK) which phosphorylates pyruvate dehydrogenase (PDH), rendering it inactive
Dose∅, DCA (2.5 mM) and metformin (1 mM)
OCR↑, DCA treated cells had a significantly higher oxygen consumption rate compared to control cells.
DNA-PK↑,
γH2AX↑, phosphorylatoin of histone H2AX (p-H2AX), which is a useful surrogate marker of such DNA damage
cl‑PARP↑, large increase of cleaved PARP
selectivity↑, Importantly, we also show that this combination of drugs does not kill non-transformed breast epithelial cells MCF10A under the same conditions in which the drugs kill cancer cells.
*toxicity∅, does not kill non-transformed breast epithelial cells MCF10A under the same conditions in which the drugs kill cancer cells.

1882-

DCA,

Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer

Analysis,

NA,

PDKs↓, DCA activates PDH by inhibition of PDK at concentration of 10–250 μM
PDH↑,
lactateProd↓, decrease in lactate levels in both the blood and the cerebrospinal fluid.
Half-Life∅, Although the initial half-life with the first dose is less than one hour, this half-life increases to several hours with subsequent doses.

1869-

DCA,

Dichloroacetate induces autophagy in colorectal cancer cells and tumours

in-vitro,

CRC,

HT-29

in-vitro,

CRC,

HCT116

in-vitro,

Pca,

PC3

in-vitro,

CRC,

HT-29

LC3II↑, Increased expression of the autophagy markers LC3B II was observed following DCA treatment both in vitro and in vivo
ROS↑, increased production of reactive oxygen species (ROS)
mTOR↓, mTOR inhibition
MCT1↓, DCA is a possible competitive MCT-1 inhibitor
NADH:NAD↓, increased NAD+/NADH ratios
NAD↑,
TumAuto↑, DCA induces autophagy in cancer cells accompanied by ROS production and mTOR inhibition, reduced lactate excretion, reduced kPL and increased NAD+/NADH ratio.
lactateProd↓, DCA treatment reduces lactate excretion with no change in glucose uptake
LDH↑, Increased LDH activity

1866-

DCA,

MET,

BTZ,

Targeting metabolic pathways alleviates bortezomib-induced neuropathic pain without compromising anticancer efficacy in a sex-specific manner

in-vivo,

NA,

mice

eff↑, Metformin, DCA, and oxamate effectively attenuated bortezomib-induced neuropathic pain without compromising the anticancer efficacy of bortezomib in both male and female mice.
TumCG↓,
Hif1a↓, Metformin, a widely used antidiabetic drug, has been shown to inhibit the expression of HIF1A
PDH↑, Dichloroacetate (DCA), a small molecule inhibitor, targets PDHK, thereby activating PDH and promoting the entry of pyruvate into the mitochondrial Krebs cycle
lactateProd↓, Oxamate, an analog of pyruvate, inhibits lactate dehydrogenase, thereby reducing the production of lactate and attenuating the pain-inducing effects of extracellular acidification (25) in mice with bortezomib-induced neuropathic pain (4
TumVol↓,
TumW↓,
Glycolysis↑, These findings suggest that targeting aerobic glycolysis with DCA or oxamate can complement the anticancer efficacy of bortezomib in male tumor-bearing mice.
neuroP↑, Metformin and aerobic glycolysis inhibitors attenuate bortezomib-induced neuropathic pain without compromising anticancer efficacy in female tumor-bearing mice

6700-

DFC,

Monocarboxylate transporter 4 (MCT4) is a high affinity transporter capable of exporting lactate in high-lactate microenvironments

in-vitro,

BC,

MDA-MB-231

MCT1↓, diclofenac, a structurally-unrelated MCT1 and MCT4 blocker (32), also abrogated the influx of lactate
MCT4↓,
lactateProd↓,

6705-

DFC,

Development and Challenges of Diclofenac-Based Novel Therapeutics: Targeting Cancer and Complex Diseases

Review,

Var,

*Inflam↓, Diclofenac is a highly prescribed non-steroidal anti-inflammatory drug (NSAID) that relieves inflammation, pain, fever, and aches, used at different doses depending on clinical conditions.
*Pain↓,
*COX1↓, This drug inhibits cyclooxygenase-1 and cyclooxygenase-2 enzymes, which are responsible for the generation of prostaglandin synthesis.
*COX2↓,
*toxicity↝, critical challenge that appears with diclofenac and other drugs of the same class is their side effects, such as signs of stomach injuries, kidney problems, cardiovascular issues, hepatic issues, and diarrhea.
*BioAv↑, The potassium salt of diclofenac was developed to increase the rate of diclofenac absorption, which could be used in conditions where rapid pain relief is needed
*AntiAg↑, diclofenac’s inhibitory effect on platelet aggregation has also been reported
*neuroP↑, Neuroprotective Abilities of Diclofenac
ROS↑, inhibiting proliferation of cancer cells have also been reported, as shown in Figure 3, indicating its dual role. These mechanisms include inhibition of proteasomes [72], enhancement of ROS production [111], increase in p73 activity [112], and inhibi
p73↑,
Myc↓, inhibition of MYC expression and lactate transport
lactateProd↓,
TumCCA↑, Diclofenac is found to obstruct cell cycle in different cell lines, such as neural stem cells, human lymphatic endothelial cells (HLEC), osteoblasts, glioblastomas (GBM), ovarian cells, and VSMC.
PI3K↓, diclofenac-mediated apoptosis includes ROS-induced downregulation of the PI 3-kinase/Akt signaling pathway, inhibition of NF-kB activity, disturbance in proteasome activity
Akt↓,
NF-kB↓,
SOD2↓, Diclofenac impedes both expression levels and enzyme actions of SOD2
*neuroP↑, Recently, diclofenac as a curcumin adjuvant has been shown to aid anti-Alzheimer effects of curcumin in mice

6706-

DFC,

MET,

Frontiers | Combined Metabolic Targeting With Metformin and the NSAIDs Diflunisal and Diclofenac Induces Apoptosis in Acute Myeloid Leukemia Cells

in-vitro,

AML,

U937

lactateProd↓, Diclofenac but not diflunisal reduced lactate secretion in different AML cell lines (THP-1, U937, and KG-1) and both drugs increased respiration at low concentrations.
TumCP↓, both NSAIDs showed a limited effect on tumor cell proliferation and viability up to a concentration of 0.2 mM. In higher concentrations of 0.4–0.8 mM diflunisal alone exerted a clear effect
eff↑, However, combining all three drugs exerted a strong cytostatic and cytotoxic effect on THP-1 cells.
Glycolysis↓, Our data show that the glycolytic inhibitor 2-DG and low concentrations of the NSAID diclofenac both limit glycolysis and decrease lactate secretion of AML cell lines.

6708-

DFC,

Repurposing Drugs as Expanding Cancer Treatment Palette: Diclofenac

lactateProd↓, One of the unique properties of diclofenac is the ability to decrease lactate production dramatically.
LDHA↓, it inhibited the expression of lactate dehydrogenase-A in vitro.
TumCCA↑, dose-dependent cell growth inhibition resulted in a cell cycle arrest at the G2/M checkpoint.
TumCG↓, It resulted in a significant delay in glioma growth.
eff↑, Diclofenac appears as an ideal component for targeting lactate production and counteracting local immune suppression in malignant gliomas.

6688-

DFC,

New Aspects of an Old Drug – Diclofenac Targets MYC and Glucose Metabolism in Tumor Cells

in-vivo,

lymphoma,

U937

AntiCan↑, Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects.
COX2↓, Up to now these effects were mainly attributed to its classical role as COX-inhibitor.
Myc↓, Diclofenac significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo.
GLUT1↓, Diclofenac significantly decreased glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1 (MCT1) gene expression in line with a decrease in glucose uptake and lactate secretion.
LDHA↓,
MCT1↓,
GlucoseCon↓, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies.
lactateProd↓, Diclofenac inhibits glucose uptake and lactate secretion in tumor cells
TumCP↓, The proliferation of the human melanoma cell line MelIm was inhibited significantly (p<0.001) at 0.4 mM diclofenac
other∅, In contrast, aspirin (ASA), a typical NSAID exerted no impact on proliferation indicating a COX-independent effect of diclofenac
toxicity↝, However, NSAID use can be associated with adverse side effects, e.g. liver and kidney injury as well as gastrointestinal bleeding.

6696-

DFC,

MET,

Combined Modulation of Tumor Metabolism by Metformin and Diclofenac in Glioma

in-vitro,

GBM,

GBM

compI↓, Previous research has shown that metformin, which is an inhibitor of complex I of the respiratory chain, may inhibit some brain tumor initiating cells (BTICs), albeit at dosages that are too high for clinical use.
Glycolysis↓, explored whether a combined treatment of metformin and diclofenac, which is a non-steroidal anti-inflammatory drug (NSAID) shown to inhibit glycolysis
OCR↓, However, we observed that metformin inhibited cellular oxygen consumption and increased extracellular lactate levels, indicating glycolytic rescue mechanisms
Glycolysis↑,
lactateProd↓, Combined treatment inhibited metformin-induced lactate increase.
eff↑, Combined treatment may reduce the effective doses of the single agents and prevent metabolic rescue mechanisms.
TumCP↓, Combined Treatment of Metformin and Diclofenac Impairs Cell Proliferation and Migration
TumCMig↓,
TumCD∅, Metformin, Diclofenac, and Combined Treatment at Low Doses Do Not Increase Cell Death

6695-

DFC,

Inhibition of lactate dehydrogenase A by diclofenac sodium induces apoptosis in HeLa cells through activation of AMPK

in-vitro,

Cerv,

HeLa

other↝, Cancer cells exhibit a unique metabolic preference for the glycolytic pathway over oxidative phosphorylation for maintaining the tumor microenvironment.
Glycolysis↓, Diclofenac (DCF), a nonsteroidal anti-inflammatory drug, has been shown to exhibit anticancer effects by interfering with the glucose metabolism pathway.
LDHA↓, DCF binds to LDHA adjacent to the substrate binding site and inhibits its activity in a dose-dependent and allosteric manner in HeLa cells.
Hypoxia↓, Thus, DCF inhibits the hypoxic microenvironment and induces apoptosis-mediated cell death.
Apoptosis↑,
lactateProd↓, DCF-induced LDHA inhibition alters pyruvate, lactate, NAD+, and ATP production in cells, and this could be a possible mechanism through which DCF inhibits glucose uptake in cancer cells.
ATP↓, DCF-induced ATP deprivation leads to mitochondria-mediated oxidative stress, which results in DNA damage, lipid peroxidation, and apoptosis-mediated cell death.
mt-ROS↑,
DNAdam↑,
lipid-P↑,
AMPK↑, Reduction in intracellular ATP levels additionally activates the sensor kinase, adenosine monophosphate-activated protein kinase (AMPK), which further downregulates phosphorylated ribosomal S6 kinase (p-S6K), leading to apoptosis-mediated cell death.
p‑S6K↓,
TumCP↓, DCF inhibits proliferation in HeLa cells
Dose↝, HeLa cells with an IC50 dose of 175 ± 4.86 μm on 24 h of incubation
selectivity↑, DCF did not significantly affect the viability of normal cervical cells at 175 μm (IC50 dose in HeLa cells), where the IC50 value was found to be greater than 1 mm concentration of DCF (
i-MDA↑, The result showed that DCF treatment in HeLa cells led to a significant increase in MDA levels, suggesting an increased level of lipid peroxidation
mtDam↑, Many reports suggest that there is a strong correlation between the inhibition of LDHA and the induction of oxidative stress (ROS production) via mitochondrial damage

6694-

DFC,

Repurposing Drugs in Oncology (ReDO)—diclofenac as an anti-cancer agent

Review,

Var,

COX2↓, DCF, which is a potent inhibitor of COX-2 and prostaglandin E2 synthesis, displays a range of effects on the immune system, the angiogenic cascade, chemo- and radio-sensitivity and tumour metabolism.
PGE2↓,
angioG↓,
ChemoSen↑,
RadioS↑,
Dose↝, Typical doses for rheumatic disease and musculoskeletal disorders are in the range 75–150 mg in 2–3 divided doses, orally or rectally. Post-operative pain may be treated with diclofenac injections, either deep intramuscularly or intravenously, at a d
toxicity↝, Rare but serious adverse events include GI bleeding, anaemia, liver failure, pancreatitis and pneumonia.
toxicity↝, As with all NSAIDs, long-term use DCF is also associated with a small increase in the risk of cardiovascular events, particularly myocardial infarction and stroke.
BioAv↑, Oral DCF is rapidly absorbed and almost completely distributed to plasma and tissues with little evidence of drug accumulation after repeated dosing within the normal therapeutic range
Half-Life↝, Terminal half-life is 1.8 hours after oral dosing.
lactateProd↓, Lactate production by cells was significantly reduced at a concentration of 100 μM.
eff↑, DCF is a component of the anti-angiogenic combinational drug combination TL-118, the other components being cimetidine, low dose cyclophosphamide and sulfasalazine.
*AntiAg↑, DCF at 50 mg three times a day for six days ex vivo COX-1 level (expressed as thromboxane B2 generation in clotting whole blood) was reduced by 53% compared to base-line, and platelet aggregation was also significantly reduced

951-

DHA,

Docosahexaenoic Acid Attenuates Breast Cancer Cell Metabolism and the Warburg Phenotype by Targeting Bioenergetic Function

in-vitro,

BC,

BT474

25-100uM

in-vitro,

BC,

MDA-MB-231

in-vitro,

Nor,

MCF10

Hif1a↓, in the malignant cell lines but not in the non-transformed cell line. ****
GLUT1↓, Downstream targets of HIF-1a, including glucose transporter 1 (GLUT 1) and lactate dehydrogenase (LDH), were decreased
LDH↓,
GlucoseCon↓,
lactateProd↓,
ATP↓, 50%
p‑AMPK↑,
ECAR↓, DHA significantly decreased basal ECAR by over 60%
OCR↓, basal OCR was decreased by 80%
*toxicity↓, while not affecting non-transformed MCF-10A cells

1861-

dietFMD,

Chemo,

Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models

in-vitro,

Colon,

CT26

in-vivo,

NA,

selectivity↑, Short-term-starvation (STS) was shown to protect normal cells and organs but to sensitize different cancer cell types to chemotherapy
ChemoSen↑, STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models.
BG↓, glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect
AminoA↓,
Warburg↓,
OCR↑, characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.
ATP↓,
ROS↑, a significant increase in O2consumption rate (OCR), indicative of an increased oxidative metabolism, was observed
Apoptosis↑,
GlucoseCon↓, STS was as effective as oxaliplatin (OXP) in reducing the average tumor glucose consumption
PI3K↓, STS and in particular STS+OXP down-regulated the expression of PI3K
PTEN↑, and up-regulated PTEN expression
GLUT1↓, STS induced a profound reduction in GLUT1 , GLUT2 , HKII , PFK1, PK
GLUT2↓,
HK2↓,
PFK1↓,
PKA↓,
ATP:AMP↓, Accordingly, the ATP/AMP ratio, a good indicator of cellular energy charge, was dramatically reduced by the two STS settings
Glycolysis↓, results strongly support the effect of STS on reducing glycolysis and lactate production and increasing respiration at Complexes I-IV resulting in superoxide production/oxidative stress but in reduced ATP generation.
lactateProd↓,

1605-

EA,

Ellagic Acid and Cancer Hallmarks: Insights from Experimental Evidence

Review,

Var,

*BioAv↓, Within the gastrointestinal tract, EA has restricted bioavailability, primarily due to its hydrophobic nature and very low water solubility.
antiOx↓, strong antioxidant properties [12,13], anti-inflammatory effects
Inflam↓,
TumCP↓, numerous studies indicate that EA possesses properties that can inhibit cell proliferation
TumCCA↑, achieved this by causing cell cycle arrest at the G1 phase
cycD1/CCND1↓, reduction of cyclin D1 and E levels, as well as to the upregulation of p53 and p21 proteins
cycE/CCNE↓,
P53↑,
P21↑,
COX2↓, notable reduction in the protein expression of COX-2 and NF-κB as a result of this treatment
NF-kB↓,
Akt↑, suppressing Akt and Notch signaling pathways
NOTCH↓,
CDK2↓,
CDK6↓,
JAK↓, suppression of the JAK/STAT3 pathway
STAT3↓,
EGFR↓, decreased expression of epidermal growth factor receptor (EGFR)
p‑ERK↓, downregulated the expression of phosphorylated ERK1/2, AKT, and STAT3
p‑Akt↓,
p‑STAT3↓,
TGF-β↓, downregulation of the TGF-β/Smad3
SMAD3↓,
CDK6↓, EA demonstrated the capacity to bind to CDK6 and effectively inhibit its activity
Wnt/(β-catenin)↓, ability of EA to inhibit phosphorylation of EGFR
Myc↓, Myc, cyclin D1, and survivin, exhibited decreased levels
survivin↓,
CDK8↓, diminished CDK8 level
PKCδ↓, EA has demonstrated a notable downregulatory impact on the expression of classical isoenzymes of the PKC family (PKCα, PKCβ, and PKCγ).
tumCV↓, EA decreased cell viability
RadioS↑, further intensified when EA was combined with gamma irradiation.
eff↑, EA additionally potentiated the impact of quercetin in promoting the phosphorylation of p53 at Ser 15 and increasing p21 protein levels in the human leukemia cell line (MOLT-4)
MDM2↓, finding points to the ability of reduced MDM2 levels
XIAP↓, downregulation of X-linked inhibitor of apoptosis protein (XIAP).
p‑RB1↓, EA exerted a decrease in phosphorylation of pRB
PTEN↑, EA enhances the protein phosphatase activity of PTEN in melanoma cells (B16F10)
p‑FAK↓, reduced phosphorylation of focal adhesion kinase (FAK)
Bax:Bcl2↑, EA significantly increases the Bax/Bcl-2 rati
Bcl-xL↓, downregulates Bcl-xL and Mcl-1
Mcl-1↓,
PUMA↑, EA also increases the expression of Bcl-2 inhibitory proapoptotic proteins PUMA and Noxa in prostate cancer cells
NOXA↑,
MMP↓, addition to the reduction in MMP, the release of cytochrome c into the cytosol occurs in pancreatic cancer cells
Cyt‑c↑,
ROS↑, induction of ROS production
Ca+2↝, changes in intracellular calcium concentration, leading to increased levels of EndoG, Smac/DIABLO, AIF, cytochrome c, and APAF1 in the cytosol
Endoglin↑,
Diablo↑,
AIF↑,
iNOS↓, decreased expression of Bcl-2, NF-кB, and iNOS were observed after exposure to EA at concentrations of 15 and 30 µg/mL
Casp9↑, increase in caspase 9 activity in EA-treated pancreatic cancer cells PANC-1
Casp3↑, EA-induced caspase 3 activation and PARP cleavage in a dose-dependent manner (10–100 µmol/L)
cl‑PARP↑,
RadioS↑, EA sensitizes and reduces the resistance of breast cancer MCF-7 cells to apoptosis induced by γ-radiation
Hif1a↓, EA reduced the expression of HIF-1α
HO-1↓, EA significantly reduced the levels of two isoforms of this enzyme, HO-1, and HO-2, and increased the levels of sEH (Soluble epoxide hydrolase) in LnCap
HO-2↓,
SIRT1↓, EA-induced apoptosis was associated with reduced expression of HuR and Sirt1
selectivity↑, A significant advantage of EA as a potential chemopreventive, anti-tumor, or adjuvant therapeutic agent in cancer treatment is its relative selectivity
Dose∅, EA significantly reduced the viability of cancer cells at a concentration of 10 µmol/L, while in healthy cells, this effect was observed only at a concentration of 200 µmol/L
NHE1↓, EA had the capacity to regulate cytosolic pH by downregulating the expression of the Na+/H+ exchanger (NHE1)
Glycolysis↓, led to intracellular acidification with subsequent impairment of glycolysis
GlucoseCon↓, associated with a decrease in the cellular uptake of glucose
lactateProd↓, notable reduction in lactate levels in supernatant
PDK1?, inhibit pyruvate dehydrogenase kinase (PDK) -bind and inhibit PDK3
PDK1?,
ECAR↝, EA has been shown to influence extracellular acidosis
COX1↓, downregulation of cancer-related genes, including COX1, COX2, snail, twist1, and c-Myc.
Snail↓,
Twist↓,
cMyc↓,
Telomerase↓, EA, might dose-dependently inhibit telomerase activity
angioG↓, EA may inhibit angiogenesis
MMP2↓, EA demonstrated a notable reduction in the secretion of matrix metalloproteinase (MMP)-2 and MMP-9.
MMP9↓,
VEGF↓, At lower concentrations (10 and 20 μM), EA led to a substantial increase in VEGF levels. However, at higher doses (40 and 100 μM), a notable reduction in VEGF
Dose↝, At lower concentrations (10 and 20 μM), EA led to a substantial increase in VEGF levels. However, at higher doses (40 and 100 μM), a notable reduction in VEGF
PD-L1↓, EA downregulated the expression of the immune checkpoint PD-L1 in tumor cells
eff↑, EA might potentially enhance the efficacy of anti-PD-L1 treatment
SIRT6↑, EA exhibited statistically significant upregulation of sirtuin 6 at the protein level in Caco2 cells
DNAdam↓, increase in DNA damage

Showing Research Papers: 1 to 50 of 128
Page 1 of 3 Next

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 128

Pathway results for Effect on Cancer / Diseased Cells:

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress(tgid=1) ⓘ

antiOx↑, 2, Catalase↑, 1, GPx↑, 1, GSH↑, 2, GSR↑, 1, HO-1↑, 1, lipid-P↓, 1, MDA↓, 1, NRF2↑, 2, ROS↓, 2, SOD↑, 1,

Core Metabolism/Glycolysis(tgid=4) ⓘ

Glycolysis↑, 1, lipidLev↓, 1,

Cell Death(tgid=5) ⓘ

Akt↓, 1, Apoptosis↓, 1, Casp3↓, 1, Casp9↓, 1,

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

PI3K↓, 1,

Migration(tgid=13) ⓘ

AntiAg↑, 2,

Immune & Inflammatory Signaling(tgid=16) ⓘ

COX1↓, 1, COX2↓, 2, IL1β↓, 1, IL2↓, 1, Inflam↓, 3, NF-kB↓, 1, TNF-α↓, 2,

Synaptic & Neurotransmission(tgid=18) ⓘ

5HT↑, 1,

Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↓, 3, BioAv↑, 3, Half-Life↓, 1,

Functional Outcomes(tgid=23) ⓘ

cardioP↑, 2, cognitive↑, 1, hepatoP↑, 2, neuroP↑, 4, Pain↓, 1, RenoP↑, 1, toxicity↓, 1, toxicity↝, 1, toxicity∅, 1,
Total Targets: 39

Scientific Paper Hit Count for: lactateProd, lactate production

18 Shikonin
12 Dichloroacetate
8 Quercetin
8 Diclofenac
7 Resveratrol
5 EGCG (Epigallocatechin Gallate)
4 Artemisinin
4 Metformin
4 Rosmarinic acid
3 Betulinic acid
3 Chrysin
3 Curcumin
3 Methylene blue
3 Ursolic acid
2 Ashwagandha(Withaferin A)
2 Baicalein
2 Berberine
2 5-fluorouracil
2 Citric Acid
2 Cisplatin
2 Radiotherapy/Radiation
2 Propolis -bee glue
2 Pterostilbene
2 Silymarin (Milk Thistle) silibinin
2 Thymoquinone
2 Vitamin C (Ascorbic Acid)
2 Vitamin D3
1 3-bromopyruvate
1 Astragalus
1 Alpha-Lipoic-Acid
1 DTS(dibenzyl trisulphide) from Anamu
1 Apigenin (mainly Parsley)
1 2-DeoxyGlucose
1 tamoxifen
1 Capsaicin
1 Catechins
1 Dichloroacetophenone(2,2-)
1 salinomycin
1 Bortezomib
1 Docosahexaenoic Acid
1 diet FMD Fasting Mimicking Diet
1 Chemotherapy
1 Ellagic acid
1 Gossypol
1 Hydrogen Gas
1 Honokiol
1 Kaempferol
1 lambertianic acid
1 Melatonin
1 Magnetic Fields
1 Oroxylin-A
1 Pachymic acid
1 Proanthocyanidins
1 Phenylbutyrate
1 Sulforaphane (mainly Broccoli)
1 Selenite (Sodium)
1 triptolide
1 Vitamin B1/Thiamine
1 Arsenic trioxide
1 Wogonin
1 Worenine
1 β‐Elemene
1 γ-Tocotrienol

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#:%  Target#:739  State#:%  Dir#:1
  wNotes=on  sortOrder:rid,rpid

lactateProd Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

NA, unassigned(tgid=0) ⓘ

Redox & Oxidative Stress(tgid=1) ⓘ

Metal & Cofactor Biology(tgid=2) ⓘ

Mitochondria & Bioenergetics(tgid=3) ⓘ

Core Metabolism/Glycolysis(tgid=4) ⓘ

Cell Death(tgid=5) ⓘ

Kinase & Signal Transduction(tgid=6) ⓘ

Transcription & Epigenetics(tgid=7) ⓘ

Protein Folding & ER Stress(tgid=8) ⓘ

Autophagy & Lysosomes(tgid=9) ⓘ

DNA Damage & Repair(tgid=10) ⓘ

Cell Cycle & Senescence(tgid=11) ⓘ

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

Migration(tgid=13) ⓘ

Angiogenesis & Vasculature(tgid=14) ⓘ

Barriers & Transport(tgid=15) ⓘ

Immune & Inflammatory Signaling(tgid=16) ⓘ

Cellular Microenvironment(tgid=17) ⓘ

Hormonal & Nuclear Receptors(tgid=20) ⓘ

Drug Metabolism & Resistance(tgid=21) ⓘ

Clinical Biomarkers(tgid=22) ⓘ

Functional Outcomes(tgid=23) ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress(tgid=1) ⓘ

Core Metabolism/Glycolysis(tgid=4) ⓘ

Cell Death(tgid=5) ⓘ

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

Migration(tgid=13) ⓘ

Immune & Inflammatory Signaling(tgid=16) ⓘ

Synaptic & Neurotransmission(tgid=18) ⓘ

Drug Metabolism & Resistance(tgid=21) ⓘ

Functional Outcomes(tgid=23) ⓘ

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