ACLY Cancer Research Results

ACLY, ATP citrate lyase: Click to Expand ⟱
Source:
Type:
ACLY links energy metabolism provided by catabolic pathways to biosynthesis. ACLY, which has been found to be overexpressed in many cancers, converts citrate into acetyl-CoA and OAA.ATP citrate lyase exhibited upregulation in various tumours.
General Tumour Biomarker
•ACLY is a key enzyme in cancer metabolism.
•ACLY is involved in glucose and lipid metabolism.
•Many ACLY inhibitors were developed as anti-cancer agents.

ACLY is a key enzyme in cellular metabolism that converts citrate into acetyl‐CoA and oxaloacetate. Acetyl‐CoA is a substrate for lipid synthesis and protein acetylation, processes that are often upregulated in cancer cells to support rapid growth and proliferation.

ACLY is found overexpressed in many aggressive cancers. ACLY abundantly consumes citrate from nutrient catabolism (especially glucose and glutamine) to support protein acetylation and intense nucleotide and lipid synthesis. The significant decrease in cytosolic citrate appears to play a central role in cancer metabolism by enhancing the Warburg effect and activating the PI3K / AKT axis promoting ACLY activity in a feedback loop. Thus, the inhibition of factors regulating its expression (such as SREBP1) and its activation (such as AKT) could have an anti-proliferative effect.

Elevated ACLY expression has been observed in a number of cancers. In many studies, high levels of ACLY have been associated with more aggressive disease and poorer prognoses.

Natural ACLY Inhibitors
-Hydroxycitrate (HCA):(widely studied)
-EGCG
-Quercetin
-Resveratrol
-Luteolin
-Citrate
-Cucurbitacin B
-Emodin?
Scientific Papers found: Click to Expand⟱
289- ALA,  HCA,  EA,    Cancer Metabolism: Fasting Reset, the Keto-Paradox and Drugs for Undoing
- Analysis, NA, NA
ACLY↓,

3166- Ash,    Exploring the Multifaceted Therapeutic Potential of Withaferin A and Its Derivatives
- Review, Var, NA
*p‑PPARγ↓, preventing the phosphorylation of peroxisome proliferator-activated receptors (PPARγ)
*cardioP↑, cardioprotective activity by AMP-activated protein kinase (AMPK) activation and suppressing mitochondrial apoptosis.
*AMPK↑,
*BioAv↝, The oral bioavailability was found to be 32.4 ± 4.8% after 5 mg/kg intravenous and 10 mg/kg oral WA administration.
*Half-Life↝, The stability studies of WA in gastric fluid, liver microsomes, and intestinal microflora solution showed similar results in male rats and humans with a half-life of 5.6 min.
*Half-Life↝, WA reduced quickly, and 27.1% left within 1 h
*Dose↑, WA showed that formulation at dose 4800 mg having equivalent to 216 mg of WA, was tolerated well without showing any dose-limiting toxicity.
*chemoPv↑, Here, we discuss the chemo-preventive effects of WA on multiple organs.
IL6↓, attenuates IL-6 in inducible (MCF-7 and MDA-MB-231)
STAT3↓, WA displayed downregulation of STAT3 transcriptional activity
ROS↓, associated with reactive oxygen species (ROS) generation, resulted in apoptosis of cells. The WA treatment decreases the oxidative phosphorylation
OXPHOS↓,
PCNA↓, uppresses human breast cells’ proliferation by decreasing the proliferating cell nuclear antigen (PCNA) expression
LDH↓, WA treatment decreases the lactate dehydrogenase (LDH) expression, increases AMP protein kinase activation, and reduces adenosine triphosphate
AMPK↑,
TumCCA↑, (SKOV3 andCaOV3), WA arrest the G2/M phase cell cycle
NOTCH3↓, It downregulated the Notch-3/Akt/Bcl-2 signaling mediated cell survival, thereby causing caspase-3 stimulation, which induces apoptosis.
Akt↓,
Bcl-2↓,
Casp3↑,
Apoptosis↑,
eff↑, Withaferin-A, combined with doxorubicin, and cisplatin at suboptimal dose generates ROS and causes cell death
NF-kB↓, reduces the cytosolic and nuclear levels of NF-κB-related phospho-p65 cytokines in xenografted tumors
CSCs↓, WA can be used as a pharmaceutical agent that effectively kills cancer stem cells (CSCs).
HSP90↓, WA inhibit Hsp90 chaperone activity, disrupting Hsp90 client proteins, thus showing antiproliferative effects
PI3K↓, WA inhibited PI3K/AKT pathway.
FOXO3↑, Par-4 and FOXO3A proapoptotic proteins were increased in Pten-KO mice supplemented with WA.
β-catenin/ZEB1↓, decreased pAKT expression and the β-catenin and N-cadherin epithelial-to-mesenchymal transition markers in WA-treated tumors control
N-cadherin↓,
EMT↓,
FASN↓, WA intraperitoneal administration (0.1 mg) resulted in significant suppression of circulatory free fatty acid and fatty acid synthase expression, ATP citrate lyase,
ACLY↓,
ROS↑, WA generates ROS followed by the activation of Nrf2, HO-1, NQO1 pathways, and upregulating the expression of the c-Jun-N-terminal kinase (JNK)
NRF2↑,
HO-1↑,
NQO1↑,
JNK↑,
mTOR↓, suppressing the mTOR/STAT3 pathway
neuroP↑, neuroprotective ability of WA (50 mg/kg b.w)
*TNF-α↓, WA attenuate the levels of neuroinflammatory mediators (TNF-α, IL-1β, and IL-6)
*IL1β↓,
*IL6↓,
*IL8↓, WA decreases the pro-inflammatory cytokines (IL-6, TNFα, IL-8, IL-18)
*IL18↓,
RadioS↑, radiosensitizing combination effect of WA and hyperthermia (HT) or radiotherapy (RT)
eff↑, WA and cisplatin at suboptimal dose generates ROS and causes cell death [41]. The actions of this combination is attributed by eradicating cells, revealing markers of cancer stem cells like CD34, CD44, Oct4, CD24, and CD117

1172- Ash,    Withaferin A Inhibits Fatty Acid Synthesis in Rat Mammary Tumors
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231 - in-vivo, NA, NA
FASN↓,
ACLY↓,
ACC1↓,
CPT1A↓, FASN and CPT1A proteins were also decreased significantly upon WA treatment
SREBP1↓,

5510- bemA,    Combined inhibition of ACLY and CDK4/6 reduces cancer cell growth and invasion
- in-vitro, BC, MDA-MB-231 - in-vitro, PC, NA
eff↑, Inhibition of ACLY using bempedoic acid used in combination with palbociclib reduced cell viability in a panel of breast and pancreatic cancer cell lines.
Apoptosis↑, Mechanistically, palbociclib inhibited cell proliferation, whereas bempedoic acid stimulated apoptosis.
TumCI↓, ACLY inhibition blocked cell invasion, when used alone or in combination with palbociclib.
ACLY↓, In 2019, an inhibitor of ACLY, bempedoic acid (BA), was FDA-approved to reduce levels of low-density lipoprotein cholesterol in patients (21).
LDL↓,
eff↑, The present study aimed to determine the combined effect of ACLY inhibition using BA and CDK4/6 inhibition using Palb on the proliferation and EMT/invasion of cancer cells.
TumCP↓, Palb inhibits proliferation, while BA induces apoptosis

5509- bemA,    Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis
- Review, Nor, NA
LDL↓, Bempedoic acid (ETC-1002) is a small molecule intended to lower LDL-C in hypercholesterolemic patients,
AMPK↑, demonstrated that ETC-1002 treatment increased AMP-activated protein kinase (AMPK)26,
ACLY↓, ETC-1002 inhibits ACL and increases AMPK activity,

5511- bemA,    Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation
- in-vitro, Var, NA
ACLY↓, Here, we show that ACLY inhibition up-regulates PD-L1 immune checkpoint expression in cancer cells
PD-L1↑,
mtDam↑, Mechanistically, ACLY inhibition causes polyunsaturated fatty acid (PUFA) peroxidation and mitochondrial damage, which triggers mitochondrial DNA leakage to activate the cGAS-STING innate immune pathway.
cGAS–STING↑, ACLY inhibition leads to cGAS-STING activation
LDL↓, bempedoic acid (BemA; also named ETC-1002) has been recently approved by U.S. Food and Drug Administration (FDA) for lowering low-density lipoprotein cholesterol
eff↑, dietary PUFA supplementation is sufficient to mimic the enhanced efficacy of PD-L1 blockade by ACLY inhibition, providing promising combinational strategies for immunotherapy-resistant tumors therapy.

5512- bemA,    Recent advance of ATP citrate lyase inhibitors for the treatment of cancer and related diseases
- Review, Var, NA
ACLY↓, the well-known Bempedoic acid (BA, Fig. 2), a prodrug of ACLY inhibitor developed by Esperion company
other↝, Overexpression of ACLY is related to poor survival in various types of breast cancer cells, such as MDA-MB-231, T47D and MCF-7 cells [32], [33].
CSCs↓, the knockdown of ACLY significantly suppressed the cell stemness [53].

5513- bemA,    ACLY inhibition promotes tumour immunity and suppresses liver cancer
- in-vitro, Liver, NA
ACLY↓, Bempedoic acid competitively inhibits ACLY activity and allosterically activates AMP-activated protein kinase-β1 (AMPKβ1)-
AMPK↑,
eff↑, unlike bempedoic acid30, EVT0185-CoA inhibited rather than activated AMPKβ1-containing complexes (Extended Data Fig. 5d), and also inhibited ACC1, ACC2 and ACSS2
other↝, Given the role of AMPK in pro-survival signalling38 and the compensatory upregulation of ACSS2 upon ACLY inhibition8,9,12, these findings highlight key mechanistic differences between EVT0185 and bempedoic acid
eff↝, EVT0185 reduced tumour burden, whereas bempedoic acid had limited efficacy

5514- bemA,    Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients
- Trial, Nor, NA
*ACLY↓, Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events
*LDL↓, mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter
*MusCon↓,
Dose↝, receive oral bempedoic acid, 180 mg daily, or placebo
cardioP↑, Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization)

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

1588- Citrate,    ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism
- Review, NA, NA
ACLY↓, HCA proved to be a weak competitive inhibitor with respect to citrate (Ki = 0.3 mM) [63].

1587- Citrate,    ATP citrate lyase: A central metabolic enzyme in cancer
- Review, NA, NA
ACLY↓, administration of citrate at high level mimics a strong inhibition of ACLY and could be tested to strengthen the effects of current therapies. -a strong ACLY inhibition could be mimicked by by flooding the cytosol with citrate.
other↓, ACLY inhibition by simple drugs such as HCA or bempedoic acid should be tested, optimally associated with glycolytic inhibitors (or glucose starvation diet) and current therapies.
PFK1↓, citrate promotes: - the inactivation of PFK1 and decreases ATP production [
ATP↓,
PFK2↓, inhibition of PFK2 in ascite cancer cells
Mcl-1↓, deactivation of the anti-apoptotic factor Mcl-1 and the activation of caspases such as caspase 2, 3 and 9
Casp3↑,
Casp2↑,
Casp9↑,
IGF-1R↓, downregulation of the IGF-1R/PI3K/AKT
PI3K↓,
Akt↓,
p‑Akt↓, decreased phosphorylation of AKT and ERK in non-small cell lung cancer
p‑ERK↓,
PTEN↑, activation of PTEN suppressor,
Snail↓, reversion of dedifferentiation (in particular through Snail inhibition with E-cadherin expression) and stimulation of T lymphocytes response
E-cadherin↑,
ChemoSen↑, increasing the sensitivity of tumors to cisplatin

1586- Citrate,    Extracellular Citrate Is a Trojan Horse for Cancer Cells
- in-vitro, Liver, HepG2
Dose?, At low concentration, citrate increased both histone H4 acetylation and lipid deposition; at high concentration, citrate inhibited both
ac‑H4↓,
lipidDe↓,
ACLY↓, Considering the strong demand for acetyl-CoA but not for OAA in tumor cells, the exogenous citrate would behave like a trojan horse that carries OAA inside the cells and reduces ACLY expression and cellular metabolism.
selectivity↑, in non-tumor cells, changes of acetylated histone level do not correspond to a change of ACLY expression, as instead shown by HepG2 cells.
*ACLY∅, In contrast, ACLY expression in IHH (normal)cells was not modified after citrate exposure, suggesting that, in this case, ACLY expression was not regulated by histone H4 acetylation
Glycolysis↓, strong inhibition of glycolysis, which leads to a decrease in NADH necessary for OAA reduction
NADH↓,
OAA↑, exogenous citrate would behave like a trojan horse that releases OAA in the cells, where it could exert its therapeutic effect also on hepatoma cells.
other↑, most important discovery is undoubtedly the demonstration that high concentrations of citrate decrease the availability of acetyl-CoA, a key molecule both in the metabolism of sugars and lipids

1578- Citrate,    Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update
- Review, Var, NA
TCA↑,
FASN↑, Cytosolic acetyl-CoA sustains fatty acid (FA) synthesis (FAS)
Glycolysis↓,
glucoNG↑, while it enhances gluconeogenesis by promoting fructose-1,6-biphosphatase (FBPase)
PFK1↓, citrate directly inhibits the main regulators of glycolysis, phosphofructokinase-1 (PFK1) and phosphofructokinase-2 (PFK2)
PFK2↓, well-known inhibitor of PFK
FBPase↑, enhances gluconeogenesis by promoting fructose-1,6-biphosphatase (FBPase)
TumCP↓, inhibits the proliferation of various cancer cells of solid tumors (human mesothelioma, gastric and ovarian cancer cells) at high concentrations (10–20 mM),
eff↑, promoting apoptosis and the sensitization of cells to cisplatin
ACLY↓, higher concentrations (10 mM or more) decreased both acetylation and ACLY expression
Dose↑, In various cell lines, a high concentration of citrate—generally above 10 mM—inhibits the proliferation of cancer cells in a dose dependent manner
Casp3↑,
Casp2↑,
Casp8↑,
Casp9↑,
Bcl-xL↓,
Mcl-1↓,
IGF-1R↓, citrate at high concentration (10 mM) also inhibits the insulin-like growth factor-1 receptor (IGF-1R)
PI3K↓, pathways
Akt↓, activates PTEN, the key phosphatase inhibiting the PI3K/Akt pathway
mTOR↓,
PTEN↑, high dose of citrate activates PTEN
ChemoSen↑, citrate increases the sensibility of cells to chemotherapy (in particular, cisplatin)
Dose?, oral gavage of citrate sodium (4 g/kg twice a day) for several weeks (4 to 7 weeks) significantly regressed tumors

1590- Cuc,    ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism
- Review, NA, NA
ACLY↓, ACLY was identified as the main molecular target, since it resulted to be downregulated after Cucurbitacin B treatment both in vitro and in vivo assays

292- HCA,    Hydroxycitric Acid Inhibits Chronic Myelogenous Leukemia Growth through Activation of AMPK and mTOR Pathway
- in-vitro, AML, K562
ACLY↓,
AMPK↑,
mTOR↑,
eIF2α↑,
ATFs↑, ATF4
TumCG↓,

293- HCA,  Tam,    Hydroxycitric acid potentiates the cytotoxic effect of tamoxifen in MCF-7 breast cancer cells through inhibition of ATP citrate lyase
- in-vitro, BC, MCF-7
TumCG↓,
Apoptosis↑,
ACLY↓,
ACC-α↓,
Fas↓,

1412- HCA,    Identification of ATP Citrate Lyase as a Positive Regulator of Glycolytic Function in Glioblastomas
- in-vitro, GBM, U87MG - in-vitro, GBM, LN229
ACLY↓, Inhibition of ACLY with hydroxycitrate suppressed (p < 0.05) in vitro glioblastoma cell migration, clonogenicity and brain invasion under glycolytic conditions and enhanced the suppressive effects of a Met inhibitor on cell migration.
TumCMig↓,

1589- HCA,    ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism
- Review, NA, NA
ACLY↓, most well-known ACLY inhibitor is (‒)-hydroxycitric acid or (2S,3S)- 2-hydroxycitrate [59] (compound 1, HCA,
eff↑, HCA calcium salt with ALA ( METABLOC). ALA is a cofactor of the pyruvate dehydrogenase complex, a multi-enzymatic system linking glycolysis to Krebs cycle, since it promoted the transformation of pyruvate to acetyl-CoA

1625- HCA,    In S. cerevisiae hydroxycitric acid antagonizes chronological aging and apoptosis regardless of citrate lyase
- Review, Nor, NA
CRM↑, Hydroxycitric acid (HCA) is considered a bona fide CRM since it depletes acetyl-CoA pools by acting as a competitive inhibitor of ATP citrate lyase (ACLY), ultimately repressing protein acetylation and promoting autophagy.
ACLY↓, competitive inhibitor of ATP citrate lyase (ACLY)
TumAuto↑, promoting autophagy.
Inflam↓, reduce inflammation and tumour development
TumCG↓,
toxicity∅, HCA appear to have a low or negligible impact in terms of acute or chronic toxicity, genotoxicity, reproductive failure and teratogenicity
lipoGen↓, decreases lipogenesis, insulin resistance, inflammation and oxidative stress
*ROS↓, H2O2 treatment: Strikingly, the molecule was able to largely prevent the massive cell death (PI+ cells) caused by the intense oxidative stress. In parallel there was a sharp increase of live cells with high ROS levels
*OCR↓, chronic exposure to 5 mM HCA (from cell seeding) down-regulated yeast OCR

1627- HCA,  CRMs,  Sper,    Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance
- Review, Var, NA
ChemoSen↑, short-term fasting or autophagy-inducing caloric restriction mimetics, such as hydroxycitrate and spermidine, improves the antitumor efficacy of chemotherapy in vivo
eff↑, combination of MTX and HC (but neither of these two agents alone) markedly reduced the frequency of tumor-infiltrating CD4+CD25+Foxp3+ Tregs
ACLY↓, HC acts as a competitive inhibitor of the ATP citrate lyase (ACLY)
LC3‑Ⅱ/LC3‑Ⅰ↑, ACLY inhibitors (SB-204990, BMS-303141) stimulated autophagic flux in cultured cancer cells, as indicated by the autophagy-associated conversion of LC3 I to LC3 II
TumAuto↑, starvation can enhance chemotherapy-induced immunosurveillance in an autophagy-dependent fashion.
other↓, causes Treg depletion, which in turn improves immunosurveillance against KRas-induced neoplasia.

1628- HCA,  ALA,    Addition of Hydroxy Citrate improves effect of ALA
- Review, Var, NA
ACLY↓, Hydroxycitrate is a known inhibitor of ATP citrate lyase ( also called ATP-citric synthase
other↓, Lipoic Acid Increases PDC (pyruvate dehydrogenase complex)
ROS↑, oxidative onslaught, making the cancer cell susceptible to oxidative therapies such as alpha lipoic acid.
eff↑, the addition of hydroxycitrate increases the effect of ALA.
PDKs↓, An inhibitory effect of lipoic acid on PDKs would result in… increased PDC pyruvate dehydrogenase complex (PDC) activity.

1629- HCA,  Tam,    Hydroxycitric acid reverses tamoxifen resistance through inhibition of ATP citrate lyase
- in-vitro, BC, MCF-7
ACLY↓, Hydroxycitric acid (HCA) is a powerful competitive inhibitor of the enzyme ACLY
eff↓, co-treatment synergistically diminished LCC2 and MCF7 cell viability
tumCV↓,
eff↑, co-treatment decreases the expression level of ACLY in LCC2 by 74 %, while in MCF7 by only 59 %
Casp3↑,
BAX↑,
Bcl-2↓,

1630- HCA,    Chemistry and biochemistry of (-)-hydroxycitric acid from Garcinia
- Review, NA, NA
ACLY↓, HCA was shown to be a potent inhibitor of ATP citrate lyase
FASN↓, Extensive animal studies indicated that (-)-HCA suppresses the fatty acid synthesis, lipogenesis, food intake, and induced weight loss.
lipoGen↓,
Weight↓,

1631- HCA,    An overview of the safety and efficacy of a novel, natural(-)-hydroxycitric acid extract (HCA-SX) for weight management
- Review, Obesity, NA
*ACLY↓, HCA is a competitive inhibitor of ATP citrate lyase
*toxicity∅, No remarkable toxicity results were detected, demonstrating the safety of HCA-SX.
*Dose∅, 4666.7 mg HCA-SX (providing 2,800 mg HCA) in three equally divided doses 30-60 min before meals,

1575- statins,  Citrate,    Inhibition of Lung Cancer Growth: ATP Citrate Lyase Knockdown and Statin Treatment Leads to Dual Blockade of Mitogen-Activated Protein Kinase (MAPK) and Phosphatidylinositol-3-Kinase (PI3K)/AKT Pathways
- in-vitro, NSCLC, A549
eff↑, we find that statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which act downstream of ACL in the cholesterol synthesis pathway, dramatically enhance the anti-tumor effects of ACL inhibition, even regressing tumors
HMG-CoA↓, statins, inhibitors of (HMG-CoA) reductase
eff↑, statins dramatically enhance the anti-tumor effects of ACL inhibition
AntiTum↑,
EGFR↓, reduce the growth of EGF receptor
eff↑, ACL knockdown cells, H2O2 induced more apoptosis, which was further amplified with statin treatment (Fig. 1I). These data suggest that oxidant stress can tip ACL knockdown cells into apoptosis and that statin treatment magnifies this effect.
ROS↑, suggesting involvement of reactive oxygen species (ROS) in the induction of apoptosis by PI3K inhibitors.
EMT↓, Reversal of EMT
E-cadherin↑, increase in E-cadherin
MUC1↑, Mucin staining in ACL knockdown tumors is markedly increased, further suggesting that differentiation is induced in this condition
p‑ACLY↓, Statin treatment downregulates the phosphorylation of ACL and AKT
p‑Akt↓,
eff↑, . In A549 cells, Na-citrate supplementation caused a slight downregulation of AKT phosphorylation

3140- VitC,    Vitamin-C-dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest
- in-vitro, PC, MIA PaCa-2 - in-vitro, Nor, HEK293
citrate↓, pharmacological doses of vitamin C are capable of exerting an inhibitory action on the activity of CS, reducing glucose-derived citrate levels
FASN↓, Moreover, ascorbate targets citrate metabolism towards the de novo lipogenesis pathway, impairing fatty acid synthase (FASN) and ATP citrate lyase (ACLY) expression.
ACLY↓,
LDH↓, correlated with a remarkable decrease in extracellular pH through inhibition of lactate dehydrogenase (LDH) and overall reduced glycolytic metabolism.
Glycolysis↓,
Warburg↓, Dismissed citrate metabolism correlated with reduced Warburg effectors such as the pyruvate dehydrogenase kinase 1 (PDK1) and the glucose transporter 1 (GLUT1),
PDK1↓,
GLUT1↓,
LDHA↓, Reduced LDHA expression was also observed after vitamin C exposure, leading to a vast extracellular acidification rate (ECAR) reduction.
ECAR↓,
PDH↑, enhancing PDH activity
eff↑, Surprisingly, an impressive 85% of tumor growth inhibition is described in the combinatory treatment of vitamin C and gemcitabine in our preclinical PDAC PDX model


Showing Research Papers: 1 to 27 of 27

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 27

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

HO-1↑, 1,   lipidDe↓, 1,   NADH↓, 1,   NQO1↑, 1,   NRF2↑, 1,   OXPHOS↓, 1,   ROS↓, 1,   ROS↑, 5,  

Mitochondria & Bioenergetics ⓘ

ATP↓, 1,   mtDam↑, 1,  

Core Metabolism/Glycolysis ⓘ

ACC-α↓, 1,   ACC1↓, 1,   ACLY↓, 24,   p‑ACLY↓, 1,   AMPK↑, 5,   citrate↓, 1,   cMyc↓, 1,   CPT1A↓, 1,   CRM↑, 1,   ECAR↓, 1,   FASN↓, 5,   FASN↑, 1,   FBPase↑, 1,   GLS↓, 1,   glucoNG↑, 1,   Glycolysis↓, 4,   HK2↓, 1,   HMG-CoA↓, 1,   LDH↓, 3,   LDHA↓, 1,   LDL↓, 3,   lipoGen↓, 2,   NADPH↓, 1,   OAA↑, 1,   PDH↓, 1,   PDH↑, 1,   PDK1↓, 1,   PDKs↓, 1,   PFK↓, 1,   PFK1↓, 2,   PFK2↓, 2,   PKM2↓, 1,   SREBP1↓, 1,   TCA↑, 1,   Warburg↓, 1,  

Cell Death ⓘ

Akt↓, 3,   p‑Akt↓, 2,   Apoptosis↑, 4,   BAX↓, 1,   BAX↑, 1,   Bcl-2↓, 3,   Bcl-xL↓, 1,   Casp2↑, 2,   Casp3↑, 4,   Casp8↑, 1,   Casp9↑, 2,   Fas↓, 1,   JNK↑, 1,   Mcl-1↓, 2,   TumCD↑, 1,  

Transcription & Epigenetics ⓘ

ac‑H4↓, 1,   other↓, 3,   other↑, 1,   other↝, 2,   tumCV↓, 1,  

Protein Folding & ER Stress ⓘ

ATFs↑, 1,   eIF2α↑, 1,   HSP90↓, 1,  

Autophagy & Lysosomes ⓘ

LC3‑Ⅱ/LC3‑Ⅰ↑, 1,   TumAuto↑, 2,  

DNA Damage & Repair ⓘ

PCNA↓, 1,  

Cell Cycle & Senescence ⓘ

cycD1/CCND1↓, 1,   TumCCA↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

CSCs↓, 2,   EMT↓, 2,   p‑ERK↓, 1,   FOXO3↑, 1,   IGF-1R↓, 2,   mTOR↓, 2,   mTOR↑, 1,   NOTCH3↓, 1,   PI3K↓, 3,   PTEN↑, 2,   STAT3↓, 1,   TumCG↓, 3,  

Migration ⓘ

E-cadherin↑, 2,   MUC1↑, 1,   N-cadherin↓, 1,   Snail↓, 1,   TumCI↓, 1,   TumCMig↓, 1,   TumCP↓, 2,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature ⓘ

EGFR↓, 1,   Hif1a↓, 1,  

Barriers & Transport ⓘ

GLUT1↓, 2,   GLUT3↓, 1,  

Immune & Inflammatory Signaling ⓘ

IL6↓, 1,   Inflam↓, 1,   NF-kB↓, 1,   PD-L1↑, 1,  

Cellular Microenvironment ⓘ

cGAS–STING↑, 1,  

Drug Metabolism & Resistance ⓘ

ChemoSen↑, 3,   Dose?, 2,   Dose↑, 1,   Dose↝, 1,   eff↓, 1,   eff↑, 17,   eff↝, 1,   RadioS↑, 1,   selectivity↑, 1,  

Clinical Biomarkers ⓘ

EGFR↓, 1,   IL6↓, 1,   LDH↓, 3,   PD-L1↑, 1,  

Functional Outcomes ⓘ

AntiTum↑, 1,   cardioP↑, 1,   neuroP↑, 1,   toxicity∅, 1,   Weight↓, 1,  
Total Targets: 120

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

ROS↓, 1,  

Mitochondria & Bioenergetics ⓘ

OCR↓, 1,  

Core Metabolism/Glycolysis ⓘ

ACLY↓, 2,   ACLY∅, 1,   AMPK↑, 1,   LDL↓, 1,   p‑PPARγ↓, 1,  

Immune & Inflammatory Signaling ⓘ

IL18↓, 1,   IL1β↓, 1,   IL6↓, 1,   IL8↓, 1,   TNF-α↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↝, 1,   Dose↑, 1,   Dose∅, 1,   Half-Life↝, 2,  

Clinical Biomarkers ⓘ

IL6↓, 1,  

Functional Outcomes ⓘ

cardioP↑, 1,   chemoPv↑, 1,   MusCon↓, 1,   toxicity∅, 1,  
Total Targets: 21

Scientific Paper Hit Count for: ACLY, ATP citrate lyase
11 HydroxyCitric Acid
6 bempedoic acid
5 Citric Acid
2 Alpha-Lipoic-Acid
2 Ashwagandha(Withaferin A)
2 tamoxifen
1 Ellagic acid
1 Caffeic acid
1 Metformin
1 Cucurbitacin
1 Calorie Restriction Mimetics
1 Spermidine
1 statins
1 Vitamin C (Ascorbic Acid)
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#:2  State#:%  Dir#:1
  wNotes=on  sortOrder:rid,rpid

 

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