Dichloroacetate Cancer Research Results

DCA, Dichloroacetate: Click to Expand ⟱
Features:
Dichloroacetate (DCA) is a metabolic modulator that targets the altered metabolic state of cancer cells by inhibiting PDKs. This action impacts several key pathways:

• Reversal of the Warburg effect
• Restoration of mitochondrial function and promotion of apoptosis
• suppresses glycolysis and promotes oxidative phosphorylation, thereby increasing mitochondrial ROS-mediated apoptosis in tumor cells • Increase in ROS production leading to oxidative stress
• Inhibition of cell cycle progression
• Modulation of HIF-1α signaling: DCA might decrease HIF-1α stabilization, thereby reducing the expression of genes that support glycolysis, angiogenesis, and survival under low-oxygen conditions.

-DCA has been primarily used in treating congenital lactic acidosis—a rare genetic disorder characterized by the buildup of lactic acid in the body.
-DCA is an experimental anti-diabetic and lipid-lowering drug, as well as treating myocardial and cerebrovascular ischemia.

-Do not add DCA to hot or warm beverages(theorical). DCA is unstable at higher temperatures
-Caffeinated may increase effectiveness
-Vitamin B1 reduces neuropathy (500mg-2500mg/day)
-Possibly 20 grams of citric acid 20 minutes before taking DCA
-Procaine, Diclofenac or Sulindac may increase SMCT1
-Omeprazole 80mg/day to increase DCA effectiveness
-Scorpion venom to increase DCA effectiveness
-Metformin 1000mg to 1500mg/day
-Propranolol (Ref.)
-Fenbendazole shows strong synergy when combined to DCA, So it may make very much sense to combine the two.
"Note: DCA is not tumor cell specific,> and therefore the same shift in glucose metabolism that occurs in cancer cells will also take place in immune cells, leading to induction of Tregs (Ref.). In order to avoid this possibility, while using DCA I would also use Treg inhibitors such as Cimetidine (Ref.) or low dose Cyclophosphamide (Ref.)."
"DCA should not be used in association with allopurinol, NSAIDs, or flavonoids because they reduce cellular DCA uptake."
"triple association of DCA, metformin and celecoxib, which has never been experimentally tested in patients, deserves well planned phase II clinical trials"

Research Dose: 10mg/kg/day and increase slowly to about 25mg/kg/day:(1/2morn,1/2evening) take 5 days on, 2 off? OR 2wks on/ 1wk off: https://www.thedcasite.com/dca_dosage.html
Done by mixing it in water and drinking, suggested that DCA not be taken on an empty stomach.

****
DCA-induced apoptosis in cancer cells requires sodium-coupled monocarboxylates transporter SLC5A8 (SMCT1)
-Inhibitors of DNA methylation induce reactivation of SLC5A8
-Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells.
-SMCT1 was found to be stimulated by some other NSAIDs (diclofenac, meclofenamate and sulindac), by activin A143 and by the probiotic Lactobacillus plantarum.

SMCT1 has been found to be inhibited by some NSAIDs (ibuprofen, ketoprofen, fenoprofen, naproxen135 and indomethacin94), phytochemicals (resveratrol and quercetin) **** Hence these should be avoided with DCA(theorical). (also theorically AVOID Bromide, iodide and sulfite )

****
GSTZ1 an/or chloride anion transport inhibitors also reduce resistance to DCA (if the tumor expresses GSTZ1 and contains a high chloride anions level, the GSTZ1 will be stable, maintaining the resistance to DCA).

-Dichloroacetate-dca-treatment-strategy GSTZ1 an/or chloride anion transport inhibitors. .
-Etacrynic acid is a Cl(-)-ATPase inhibitor
-Lansoprazole and Omeprazole inhibit chloride channels.
-Chlorotoxin found in scorpion venom (see my post on scorpion venom) can also inhibit chlorine channels

Sources:
https://northernhealthproducts.com/shop/
https://www.dcalab.com/
Excellent DCA review

Dichloroacetate — Dichloroacetate, usually administered as sodium dichloroacetate, is a small-molecule metabolic modulator that inhibits pyruvate dehydrogenase kinases and thereby activates the mitochondrial pyruvate dehydrogenase complex. It is formally classified as an investigational metabolic drug and pyruvate dehydrogenase kinase inhibitor. DCA is a synthetic chlorinated acetate historically investigated for congenital mitochondrial and lactic-acidosis disorders; it is not an approved anticancer therapy. Its principal translational limitation is the narrow separation between concentrations that alter tumor metabolism and chronic exposures associated with peripheral neuropathy.

Primary mechanisms (ranked):

  1. Inhibition of PDK isoenzymes, especially PDK2, causing ↓ inhibitory PDH phosphorylation and ↑ pyruvate entry into mitochondrial oxidation.
  2. Partial reversal of the Warburg phenotype through ↓ lactate-producing glycolytic flux and ↑ mitochondrial oxidative phosphorylation.
  3. Remodeling of cancer-cell mitochondrial membrane potential and restoration of intrinsic apoptotic susceptibility.
  4. ↑ mitochondrial ROS and oxidative stress in susceptible cancer cells, particularly under hypoxic or treatment-stressed conditions.
  5. Attenuation of the HIF-1α–PDK metabolic adaptation to hypoxia, with context-dependent effects on tumor oxygenation and treatment resistance.
  6. Radiosensitization and chemosensitization through metabolic reprogramming, increased oxidative stress, altered autophagy and reduced hypoxia-associated resistance.
  7. Context-dependent modulation of Kv1.5, intracellular K⁺, NFAT and Ca²⁺-linked apoptotic signaling.

Bioavailability / PK relevance: Oral DCA is systemically bioavailable, but its pharmacokinetics are nonlinear and time-dependent. DCA is metabolized primarily by GSTZ1, while DCA also irreversibly inhibits GSTZ1, producing reduced clearance and progressive drug accumulation during repeated exposure. GSTZ1 genotype, age and treatment duration can substantially alter plasma exposure. Chronic exposure is limited principally by reversible or incompletely reversible peripheral sensory and motor neuropathy; gastrointestinal, hepatic and hematologic adverse effects have also been reported.

In-vitro vs systemic exposure relevance: Many anticancer studies use approximately 1–20 mM DCA, frequently 5–20 mM. Sustained human plasma concentrations at the upper end of this range are generally not achievable without substantial toxicity. Clinical PK data indicate that tolerated concentrations may inhibit constitutive PDK2 but may be inadequate for less-sensitive or highly induced PDK isoforms. Consequently, strong cytotoxicity observed at high millimolar concentrations should not be assumed to translate directly to patients.

Clinical evidence status: Extensive preclinical evidence; several small phase I and phase II human studies; one randomized placebo-controlled phase II adjunct study with cisplatin chemoradiotherapy; no phase III validation and no regulatory approval for cancer. Early trials demonstrate measurable metabolic effects and generally manageable short-term administration, but objective anticancer efficacy remains inconsistent and unproven. A randomized head-and-neck cancer study did not establish a clear survival advantage, while reporting increased low-grade fever and thrombocytopenia. DCA remains an investigational adjunct rather than a standard anticancer treatment.


Dichloroacetate Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 PDK inhibition and PDH activation ↓ PDK activity
↓ p-PDH
↑ active PDH		 ↓ PDK activity
↑ glucose oxidation		 P–G Redirects pyruvate toward acetyl-CoA and mitochondrial oxidation Canonical mechanism. PDK2 is relatively sensitive; inhibition of other PDK isoforms may require higher exposure.
2 Warburg metabolism and glycolysis ↓ glycolytic dependence
↓ ECAR
↓ lactate production		 Variable metabolic shift R–G Reduces fermentative glucose metabolism and extracellular acidification Effect magnitude depends on PDK expression, mitochondrial competence, substrate availability and tumor lineage.
3 Mitochondrial respiration ↑ pyruvate oxidation
↑ OCR
↑ OXPHOS		 ↑ glucose oxidation
↑ mitochondrial workload		 R–G Restores mitochondrial use of glucose-derived carbon Increased respiration is not intrinsically cytotoxic and can support survival in metabolically flexible tumors.
4 Mitochondrial membrane potential and apoptosis ↓ pathological hyperpolarization
↑ cytochrome c release
↑ caspase activation		 Usually less pronounced R–G Lowers the threshold for intrinsic apoptosis Strongest in models with cancer-associated mitochondrial hyperpolarization; not universal across tumor types.
5 Mitochondrial ROS increase ↑ mt-ROS
↑ oxidative damage (context-dependent)		 ↔ or ↑ ROS with prolonged exposure R–G Produces redox stress and apoptotic sensitization ROS direction is model-dependent. Increased respiration can raise ROS, but improved electron flow may reduce ROS in some systems.
6 HIF-1α and hypoxic adaptation ↓ HIF-1α signaling
↓ PDK1-mediated adaptation (context-dependent)		 Limited evidence G Weakens hypoxia-driven glycolysis, survival and treatment resistance DCA can also increase cellular oxygen consumption; the net effect on tumor hypoxia depends on perfusion and oxygen delivery.
7 Radiosensitization ↑ radiation sensitivity
↑ ROS-mediated injury
↓ hypoxic resistance		 Potential normal-tissue sensitization (context-dependent) R–G Enhances radiation response in selected models Supported preclinically and evaluated clinically as an adjunct, but a definitive therapeutic benefit has not been established.
8 Chemosensitization ↑ sensitivity to cisplatin, 5-FU, paclitaxel and selected metabolic agents (model-dependent) Potential additive toxicity G Reduces metabolic and hypoxic drug resistance Combination effects vary markedly. Preclinical synergy does not establish clinical efficacy or safe dosing.
9 Autophagy ↑ or ↓ autophagic flux (context-dependent) Insufficient evidence G May promote adaptation or enhance treatment-induced death Autophagy is bidirectional: DCA-induced autophagy can be protective in some tumors and therapeutically exploitable in others.
10 Kv1.5 NFAT and Ca²⁺ signaling ↑ Kv1.5
↓ intracellular K⁺
↓ NFAT activation
Ca²⁺ modulation		 Variable R–G Facilitates apoptotic signaling and suppresses proliferation Mechanistically important in selected early models but less consistently demonstrated than the PDK–PDH axis.
11 Transport and metabolic sensitivity SLC5A8 may ↑ intracellular DCA response
GSTZ1 and chloride modify sensitivity		 GSTZ1 controls systemic clearance G Determines cellular exposure, metabolism and resistance SLC5A8 dependence is model-specific. GSTZ1 genotype and self-inactivation are clinically important determinants of exposure and neuropathy.
12 Clinical Translation Constraint High millimolar concentrations often required
heterogeneous PDK expression
metabolic plasticity		 Peripheral neuropathy
variable clearance
possible hepatic and hematologic toxicity		 G Restricts sustained target coverage and therapeutic index Human exposure may inhibit PDK2 yet remain below concentrations used for broad in-vitro cytotoxicity. DCA is investigational and not an approved cancer treatment.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr



Older Table:
Rank Pathway / Target Axis Direction Primary Effect Notes / Cancer Relevance Ref
1 Pyruvate dehydrogenase kinase (PDK) → PDH gatekeeper ↓ PDK activity → ↑ active PDH (dephosphorylated) Warburg reversal (pyruvate into TCA) DCA’s canonical mechanism: inhibits PDK, restoring PDH activity and oxidative metabolism in cancer (ref)
2 Glycolysis output (lactate / ECAR) ↓ lactate production / ↓ ECAR Reduced acidification; metabolic reprogramming DCA decreases PDH phosphorylation and lowers glycolytic output (lactate/ECAR) in cancer models (ref)
3 Mitochondrial membrane potential remodeling (ΔΨm) ↓ cancer-associated mitochondrial hyperpolarization (depolarization) Restores apoptosis susceptibility Glioblastoma work: DCA reverses cancer-specific mitochondrial remodeling (hyperpolarization → depolarization), enabling apoptosis (ref)
4 ROS generation (especially under hypoxia) ↑ ROS Oxidative stress trigger DCA increases ROS in hypoxic cancer cells (reported strongly under hypoxia), linking metabolic shift to cytotoxic stress (ref)
5 Voltage-gated K+ channel axis (Kv1.5) / NFAT signaling ↑ Kv1.5 expression/activity Pro-apoptotic electrophysiology shift Endometrial cancer study: DCA engages mitochondrial + NFAT–Kv1.5 mechanisms associated with apoptosis sensitization (ref)
6 Intrinsic apoptosis (mitochondrial pathway) ↑ apoptosis Programmed cell death DCA induces apoptosis in glioblastoma and endometrial cancer models as mitochondrial remodeling is reversed (ref)
7 PUMA-mediated apoptotic priming ↑ PUMA-dependent sensitization Lower apoptotic threshold Endometrial cancer paper explicitly reports a PUMA-mediated component in DCA apoptosis sensitization (ref)
8 Hypoxia resistance axis (HIF-1α / PDK1) ↓ hypoxia-associated resistance (HIF-1α/PDK1 axis engaged) Improved treatment responsiveness DCA attenuates hypoxia-associated resistance in gastric cancer context with reported linkage to HIF-1α and PDK1 (ref)
9 Radiosensitization (hypoxic tumor cells) ↑ radiosensitivity (esp. under hypoxia) Therapy potentiation DCA increases ROS under hypoxia and enhances radiotherapy response in TNBC models (ref)
10 In vivo / translational anti-tumor activity (glioblastoma) ↓ tumor growth / ↓ proliferation (model-dependent) Demonstrated anti-tumor effect Glioblastoma study includes translational evidence that DCA can reverse tumor metabolic remodeling with anti-tumor effects (ref)


Scientific Papers found: Click to Expand⟱
5196- DCA,    Dichloroacetate induces apoptosis in endometrial cancer cells
- in-vitro, Var, NA
selectivity↑, Initiation of apoptosis was observed in five low to moderately invasive cancer cell lines including Ishikawa, RL95-2, KLE, AN3CA, and SKUT1B while treatment had no effect on non-cancerous 293T cells.
MMP↓, a decrease in mitochondrial membrane potential, and decreased Survivin transcript abundance, which are consistent with a mitochondrial-regulated mechanism.
survivin↓,
Ca+2↓, DCA treatment decreased intracellular calcium levels in most apoptotic responding cell lines which suggests a contribution from the NFAT-Kv1.5-mediated pathway.
P53↑, DCA treatment increased p53 upregulated modulator of apoptosis (PUMA) transcripts in cell lines with an apoptotic response, suggesting involvement of a p53-PUMA-mediated mechanism.
PDK1↓, DCA binds to PDK and attenuates inhibition of PDH activity.
PDH↑,
Glycolysis↓, The increased PDH activity shifts metabolism from glycolysis to glucose oxidation and decreases mitochondrial membrane potential (MMP) hyperpolarization
OXPHOS↑,
ROS↑, translocation of reactive oxygen species (ROS) and cytochrome c from the mitochondria to the cytoplasm, subsequently inducing apoptosis through the activation of caspases
Cyt‑c↑,
Apoptosis↑,
Casp↑,
tumCV↓, DCA Reduces Endometrial Cancer Cell Viability in a Dose-Dependent Manner
PUMA↑, DCA Increases PUMA Expression

1883- DCA,    In vivo metabolic response of glucose to dichloroacetate in humans
- Analysis, Var, NA
BG↓, Dichloroacetate (DCA), which is known to increase the rate of pyruvate oxidation, has been shown to lower plasma glucose concentrations in normal fasting subjects
glucoNG↓, These results suggest that DCA may decrease gluconeogenesis by limiting the availability of the precursor substrates lactate and alanine.

1884- DCA,  Sal,    Dichloroacetate and Salinomycin Exert a Synergistic Cytotoxic Effect in Colorectal Cancer Cell Lines
- in-vitro, CRC, DLD1 - in-vitro, CRC, HCT116
eff↑, The effect of combination of dichloracetate and salinomycin on multicellular spheroid size was stronger than the sum of both monotherapies, particularly in HCT116 cells
pH↓, and in contrast, it is not related to dichloroacetate-induced reduction of intracellular pH
PDKs↓, Dichloroacetate (DCA) is a small synthetic molecule that is known as a pyruvate dehydrogenase kinase inhibitor. Its anticancer properties involve reversing the Warburg effect by switching ATP production back to oxidative phosphorylation
Warburg↓,

1885- DCA,    Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate
- in-vitro, CRC, HCT116 - in-vitro, CRC, SW-620 - in-vitro, CRC, HT-29
SMCT1∅, SLC5A8 transports dichloroacetate very effectively with high affinity. This transporter is expressed in normal cells, but the expression is silenced in tumor cells via epigenetic mechanisms.
eff↓, lack of the SLC5A8 transporter makes tumor cells resistant to the antitumor activity of dichloroacetate.
eff↑, However, if the transporter is expressed in tumor cells ectopically, the cells become sensitive to the drug at low concentrations. This is evident in breast cancer cells, colon cancer cells, and prostate cancer cells.
eff↑, our findings suggest that combining dichloroacetate with a DNA methylation inhibitor would offer a means to reduce the doses of dichloroacetate to avoid detrimental effects associated with high doses but without compromising antitumor activity.
PDKs↓, Dichloroacetate is an inhibitor of pyruvate dehydrogenase kinase (PDK), which phosphorylates the E1α subunit of PDC and inactivates the complex
MMP↓, depolarization of the mitochondrial membrane,
Glycolysis↓, suppression of glycolysis
mitResp↑, enhancement of mitochondrial oxidation
ROS↑, production of reactive oxygen species,
eff↑, In control cells, which did not express the transporter, dichloroacetate did not have any significant effect. However, under identical conditions, SLC5A8-expressing cells underwent apoptosis to a marked extent. This phenomenon was seen in all three c

1887- DCA,    GSTZ1 expression and chloride concentrations modulate sensitivity of cancer cells to dichloroacetate
- in-vitro, Var, NA
GSTZ1∅, high levels of GSTZ1 expression confers resistance to the effect of high concentrations of DCA on cell viability
eff↓, These results may have important clinical implications in determining intratumoral metabolism of DCA and, consequently, appropriate oral dosing.
PDKs↓, inhibitor of mitochondrial pyruvate dehydrogenase kinase (PDK), DCA maintains the pyruvate dehydrogenase complex (PDC) in its active, unphosphorylated state
Chl∅, [Cl-] in tumors is often abnormally high compared to the surrounding tissue
eff↓, changes in [Cl-] could have an impact on DCA treatment, because a tumor with high GSTZ1 expression and high [Cl-] could exhibit atypical resistance to the anti-tumor effects of the drug.

1889- DCA,    A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth
- Review, Var, NA
PDKs↓, Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK)
Glycolysis↓, shifts metabolism from glycolysis to glucose oxidation
mt-H2O2↑, increases mitochondrial H2O2
Apoptosis↑, DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity
TumCP↓,
TumCG↓,
toxicity∅,

4901- DCA,  Sal,    Dichloroacetate and Salinomycin as Therapeutic Agents in Cancer
- Review, NSCLC, NA
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.

5194- DCA,    Metabolic modulation of glioblastoma with dichloroacetate
- vitro+vivo, GBM, NA
MMP↓, Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA.
mt-ROS↑, DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo.
Apoptosis↑,
CSCs↓,
Hif1a↓, DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro.
P53↑,
angioG↓,
toxicity↓, and there was no hematologic, hepatic, renal, or cardiac toxicity.
PDKs↓, sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas.

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.

1865- DCA,    Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo
- in-vivo, BC, NA - in-vitro, BC, MCF7 - in-vitro, BC, T47D
TumCG↓, growth of several breast cancer cell lines (MCF-7, T47D, 13762 MAT and V14 cells) was found to be inhibited by DCA in vitro.
TumCP↓, inhibition of proliferation
AntiCan↑, demonstrate the anti-cancer potential of DCA and the reversing the glycolytic phenotype.

5197- DCA,  5-FU,    Dichloroacetate attenuates hypoxia-induced resistance to 5-fluorouracil in gastric cancer through the regulation of glucose metabolism
- in-vitro, GC, NA
Glycolysis↓, dichloroacetate (DCA), an inhibitor of the glycolytic pathway.
ChemoSen↑, DCA treatment was able to re-sensitize gastric cancer cells with hypoxia-induced resistance to 5-FU through the alteration of glucose metabolism.
PDK1↓, Dichloroacetate (DCA) is a well-known inhibitor of PDK

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, NA
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.

6679- DCA,    GSTZ1 genotypes correlate with dichloroacetate pharmacokinetics and chronic side effects in multiple myeloma patients in a pilot phase 2 clinical trial
- Trial, Melanoma, NA
PDK1↓, Dichloroacetate (DCA) is an investigational drug targeting the glycolytic hallmark of cancer by inhibiting pyruvate dehydrogenase kinases (PDK).
Half-Life↝, The initial half‐life of DCA was shorter in two patients, correlating with heterozygosity for GSTZ1*A genotype, a high enzyme activity variant.
eff↑, Over 3 months, one patient maintained DCA trough concentrations approximately threefold higher than other patients, which correlated with a low activity promoter genotype (−1002A, rs7160195) for GSTZ1.
NP/CIPN↑, This patient displayed the strongest response, but also the strongest neuropathy.
Dose↝, single oral dose of 25 mg/kg taken at approximately 9 am.
Half-Life↝, DCA was then cleared with a mean half‐life of 93 min (Table 2), with 90% of the drug being cleared by 6 hours, and DCA being undetectable at 24 hours

6680- DCA,    The PI3K/Akt Pathway Regulates Oxygen Metabolism via Pyruvate Dehydrogenase (PDH)-E1α Phosphorylation
- NA, Laryn, FaDu
PDH↓, Pre-treatment of SQ20B cells with dichloroacetate (DCA), which inhibits PDH-E1α phosphorylation by inhibiting dehydrogenase kinases (PDKs), reversed the decrease in OCR in response to PI3K/Akt/mTOR inhibition.
PDKs↓,
OCR↑, Treatment of cells with DCA along with BEZ235 reversed the effect of BEZ235 on decreasing OCR

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.

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
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.

6683- DCA,    Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts
- Review, Var, NA
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.

1881- DCA,  Chemo,    Co-treatment of dichloroacetate, omeprazole and tamoxifen exhibited synergistically antiproliferative effect on malignant tumors: in vivo experiments and a case report
- in-vitro, NA, HT1080 - in-vitro, NA, WI38 - Case Report, Var, NA
eff↑, DCA combined with OPZ and TAM exhibited more potent antitumor activity than DCA alone in HT1080 fibrosarcoma cells, but did not influence proliferation of WI-38 human fibroblasts.
selectivity↑,
OS↑, Disease progression was successfully blocked (the rise of serum CA19-9 value) for three months, also confirmed by CT.

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 - 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.

1866- DCA,  MET,  BTZ,    Targeting metabolic pathways alleviates bortezomib-induced neuropathic pain without compromising anticancer efficacy in a sex-specific manner
- in-vivo, NA, NA
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

1867- DCA,  Chemo,    Sensitization of breast cancer cells to paclitaxel by dichloroacetate through inhibiting autophagy
- in-vivo, BC, NA - in-vitro, BC, NA
TumCG↓, Synergistic inhibition of tumor growth in mice treated with Dox and DCA.
eff↑, DCA markedly enhances Doxorubicin-induced breast cancer cell death and anti-proliferation in vitro.
OS↑, Moreover, the combined therapy of Dox and DCA could significantly inhibit tumor growth in vivo and prolong mouse survival time.
PDKs↓, Dichloroacetate (DCA) is a small inhibitor of pyruvate dehydrogenase kinase (PDK), which activates pyruvate dehydrogenase (PDH), and increases glucose oxidation by promoting influx of pyruvate into the Krebs cycle.
PDH↑,

1868- DCA,  MET,    Long-term stabilization of stage 4 colon cancer using sodium dichloroacetate therapy
- Case Report, NA, NA
eff↑, DCA therapy resulted in tumour stabilization of stage 4 colon cancer in a 57 years old female for a period of nearly 4 years, with no serious toxicity
toxicity∅,
MMP↓, In the initial 2007 paper by Bonnet et al[1], it was reported that DCA reduced mitochondrial membrane potential resulting in selective apoptosis in cancer cells.
Apoptosis↑,
selectivity↑,
pH↝, alteration of pH regulators V-ATPase and MCT1
Dose↝, The neuropathy risk with inclusion of natural neuroprotective agents was roughly 20% with 20-25 mg/kg per day dosing on a 2 wk on/1 wk off cycle.
Dose↝, 3 natural supplements were prescribed: Alpha lipoic acid (racemic) 500 mg i.v. with each DCA dose, oral R-alpha lipoic acid 150 mg 3 times a day, oral acetyl L-carnitine 500 mg 3 times a day, and oral benfotiamine 80 mg twice a day.
eff↑, Oral metformin was added to help sensitize the cancer to the chemotherapy, starting at 500 mg orally once a day with titration up to 500 mg 3 times a day

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

1870- DCA,  Rad,    Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation
- in-vitro, Pca, PC3
TumCCA↑, DCA alone produced significant cytotoxic effects and was associated with G1 cell cycle arrest.
Apoptosis↑, DCA was associated with an increased rate of apoptosis
MMP↓, DCA therapy resulted in a significant change in mitochondria membrane potential
eff↑, demonstrate DCA can effectively sensitize wild-type and over expressing Bcl-2 human prostate cancer cells to radiation by modulating the expression of key members of the Bcl-2 family.
RadioS↑,

1872- DCA,    Dichloroacetate, a selective mitochondria-targeting drug for oral squamous cell carcinoma: a metabolic perspective of treatment
- in-vitro, Oral, HSC2 - in-vitro, Oral, HSC3
PDKs↓, Dichloroacetate (DCA) is a specific inhibitor of the PDH-regulator PDK proved to foster mitochondrial oxidation of pyruvate.
ROS↑, enhanced production of reactive oxygen species
OCR↑, DCA - a mildly cytotoxic concentration - caused, indeed, an increase of the resting endogenous OCR in all the three OSCC cell lines
other↑, Consequently, the OxPhos/Glycolysis flux ratio increased largely in HSC-2 and scantly in PE15 with an intermediate value for HSC-3

1873- DCA,    Dual-targeting of aberrant glucose metabolism in glioblastoma
- in-vitro, GBM, U87MG - in-vitro, GBM, U251
PDKs↓, dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor.
eff↑, By combining DCA with PENAO, the two drugs worked synergistically to inhibit cell proliferation (but had no significant effect on non-cancerous cells)
selectivity↑,
MMP↓, induced oxidative stress and depolarized mitochondrial membrane potential, which in turn activated mitochondria-mediated apoptosis
ROS↑,
Apoptosis↑,
Warburg↓, Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor that reverses the Warburg effect
eff↑, DCA has been demonstrated to sensitize cancer cells towards apoptosis and enhance the effects of several anti-cancer agents, including arsenic trioxide [20], cisplatin [22,23] and metformin [24].
Dose∅, IC50 values of DCA were at suprapharmacological millimolar level
toxicity∅, whilst the IC50 values of DCA for non-cancerous cells were not reached (DCA concentration in this study was tested up to 50 mM)

1874- DCA,    Dichloroacetate induces apoptosis of epithelial ovarian cancer cells through a mechanism involving modulation of oxidative stress
- in-vitro, Ovarian, SKOV3 - in-vitro, Ovarian, MDAH-2774
Apoptosis↑, Dichloroacetate induced apoptosis, reduced MPO, iNOS, and HIF-1a,
MPO↓,
iNOS↓, 40 and 80 mg/mL DCA doses,
Hif1a↓,
SOD↑, increased SOD
Casp3↑, Treatment with DCA significantly ncreased caspase 3 activity in SKOV-3 cells, in a dose-dependent manner, from 6.53 to 12.2, 16.9, and 22.1 mmol/L in the 20, 40, and 80 mg/mL doses, respectively

1875- DCA,    Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells
- in-vitro, neuroblastoma, NA - in-vivo, NA, NA
selectivity↑, acting specifically on the mitochondria of cancer cells without perturbing the physiology of nonmalignant cells.
AntiCan↑, DCA exhibits an unexpected anticancer effect on NB tumor cells
TumVol↓, growth inhibition became statistically significant when mice were treated with 25 mg/kg/dose of DCA (55% of reduction compared with control group)
PDKs↓, effects of DCA are related to PDK inhibition, mitochondrial oxidative phosphorylation activation and specific mitochondrial hyperpolarization reduction,
mt-OXPHOS↑,
MMP↓,
Glycolysis↓, shifting cellular metabolism from glycolysis to glucose oxidation, without any deleterious effect on normal cells.
toxicity↓, Indeed, more than 40 clinical trials of DCA report that the most significant adverse effect of long-term DCA administration is a reversible peripherical neuropathy.
Warburg↓, indeed, DCA is able to reverse the Warburg effect by inhibiting PDK, restoring mitochondrial membrane potential and increasing ROS production.
ROS↑,
eff↑, DCA was celebrated as the magic bullet against cancer, even if it is currently not yet approved for cancer treatment.

1876- DCA,  Chemo,    In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines
- in-vivo, Lung, H727
eff↑, DCA (10 mM) inhibited the growth of UMC- 11 cells by 22% and sensitised these highly resistant cells to carboplatin, satraplatin and JM118 1.4-2.4-fold.
TumCG↓,
Glycolysis↓, DCA that promotes mitochondrial respiration over aerobic glycolysis
mitResp↑,

1877- DCA,    Non-Hodgkin′s Lymphoma Reversal with Dichloroacetate
- Case Report, lymphoma, NA
Remission↑, Refusing all suggested chemotherapies, the patient began self-administering dichloroacetate (DCA) 900 mg daily with a PET scan showing complete remission four months later.
p‑PDKs↓, DCA has been shown to block this phosphorylation by PDK at the mitochondrial membrane level and decrease glycolysis in favor of glucose oxidation
Glycolysis↓,
i-Ca+2↓, This return to a normal metabolism of glucose allows for major changes including a decrease in Ca++ intracellularly, and stabilization of the mitochondria allowing a reactivation of caspases in cancer cells leading to apoptosis
toxicity↓, A reversible, minimal nerve damage can be considerably reduced by a daily thiamine intake of several hundred milligrams for humans. thiamine amount varies from 50 mg/day to 100 mg/day depending on whether it is administered orally or injected
Dose∅, A Non-Hodgkin′s lymphoma patient taking 10 mg/kg [750 mg] of dichloroacetate daily of his own accord, had a complete remission of his Non-Hodgkin′s lymphoma cancer after four months

1878- DCA,  5-FU,    Synergistic Antitumor Effect of Dichloroacetate in Combination with 5-Fluorouracil in Colorectal Cancer
- in-vitro, CRC, LS174T - in-vitro, CRC, LoVo - in-vitro, CRC, SW-620 - in-vitro, CRC, HT-29
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↑,

1879- DCA,    Long-term stabilization of metastatic melanoma with sodium dichloroacetate
- Case Report, Melanoma, NA
OS↑, DCA therapy, with no concurrent conventional therapy, resulted in regression and stabilization of recurrent metastatic melanoma for over 4 years’ duration, with trivial side effects.
toxicity↓, DCA was noted to have an absence of renal, pulmonary, bone marrow and cardiac toxicity
Dose∅, Active hexose correlated compound or AHCC , dandelion root, curcumin, and astragalus root. Parenteral therapy was also started, which consisted of intravenous vitamin C twice weekly and subcutaneous European mistletoe extract. +vegan diet
Dose∅, DCA 500 mg 3 times per day, which was equivalent to 17 mg/kg per day (manufacturer: Tokyo Chemical Industry, United States) in addition to maintaining the other natural therapies. 2 wk on and 1 wk off
Dose∅, To minimize the occurrence of DCA side effects, 3 additional natural medications were prescribed: Oral acetyl L-carnitine 500 mg 3 times a day, oral benfotiamine 80 mg twice a day and oral R-alpha lipoic acid 150 mg 3 times a day
QoL∅, DCA therapy can be used without reducing quality of life

1880- DCA,    A Novel Form of Dichloroacetate Therapy for Patients With Advanced Cancer: A Report of 3 Cases
- Case Report, Var, NA
OS↑, 3 cases with patients who had recurrent cancers and for whom all conventional therapies had failed
angioG↓, (1) inhibition of angiogenesis
Hif1a↝, (2) alteration of expression of hypoxia-inducible factor 1-α (HIF1-α)
pH↝, (3) alteration of pH regulators vacuolar-type H + -ATPase (V-ATPase) and monocarboxylate transporter 1 (MCT1)
QoL↑, DCA has the potential to extend life without reducing patients’ quality of life with debilitating side effects or compromising physiological function, even for disease in a very advanced stage

1882- DCA,    Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer
- Analysis, NA, 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.

6859- FBZ,  DCA,    Synergistic anti-tumor effect of fenbendazole and diisopropylamine dichloroacetate in immunodeficient BALB/c nude mice transplanted with A549 lung cancer cells
- in-vivo, Lung, A549
Remission↑, 100 mg/kg DADA and 40 mg/kg FZ resulted in a 50% reduction in complete tumor regression,
eff↑, The combination therapy showed superior efficacy in reducing tumor size and inducing tumor loss compared to either treatment alone.

5616- NaHCO3,  DCA,    Bicarbonate and dichloroacetate: Evaluating pH altering therapies in a mouse model for metastatic breast cancer
- vitro+vivo, BC, MDA-MB-231
OS↑, Survival was longest in mice administered bicarbonate-based therapies.
e-pH↑, This study reported that systemic bicarbonate buffered the extracellular pH in tumors to neutral levels (a pH of 7.2) and inhibited the spread of metastases which led to improved survival.
TumMeta↓,
eff↝, Urine pH in DCA treated mice was the same as measured in untreated mice.
TumCG↝, In our study, treating MDA-MB-231 tumor bearing mice with DCA and DB did not impact primary tumor growth.

2044- PB,  DCA,    Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate
- in-vivo, NA, NA
PDK1↓, We investigated the inhibitory activity of phenylbutyrate toward PDKs and found that PDK isoforms 1-to-3 are inhibited whereas PDK4 is unaffected.
PDKs↓,
eff↑, phenylbutyrate combined to DCA results in greater increase of PDHC activity compared to each drug alone.
PDH↑,

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


Showing Research Papers: 1 to 38 of 38

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 38

Pathway results for Effect on Cancer / Diseased Cells:


NA, unassigned(tgid=0) ⓘ

miR-375↑, 1,  

Redox & Oxidative Stress(tgid=1) ⓘ

antiOx↑, 1,   GSTZ1↓, 1,   GSTZ1↝, 1,   GSTZ1∅, 1,   mt-H2O2↑, 1,   MPO↓, 1,   OXPHOS↑, 4,   mt-OXPHOS↑, 1,   ROS↑, 12,   ROS∅, 1,   mt-ROS↑, 1,   SOD↑, 1,  

Metal & Cofactor Biology(tgid=2) ⓘ

Ferritin↓, 1,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

AIF↑, 1,   ATP↓, 1,   mitResp↑, 3,   MMP↓, 9,   MPT↑, 1,   OCR↑, 4,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

ECAR↓, 1,   FAO↑, 1,   glucoNG↓, 1,   GlucoseCon↓, 3,   Glycolysis↓, 11,   Glycolysis↑, 1,   HMG-CoA↓, 1,   lactateProd↓, 12,   LDH↑, 1,   lipoGen↓, 1,   NAD↑, 1,   NADH:NAD↓, 1,   PDH↓, 1,   PDH↑, 5,   p‑PDH↓, 2,   p‑PDH↑, 1,   PDK1↓, 9,   PDKs↓, 16,   PDKs↑, 1,   p‑PDKs↓, 1,   Warburg↓, 4,  

Cell Death(tgid=5) ⓘ

Apoptosis↑, 11,   BAX↑, 1,   Bcl-2↓, 1,   Casp↑, 3,   Casp3↑, 5,   Cyt‑c↑, 3,   iNOS↓, 1,   MCT1↓, 1,   PUMA↑, 1,   survivin↓, 2,  

Transcription & Epigenetics(tgid=7) ⓘ

other↑, 1,   other↝, 2,   tumCV↓, 3,  

Protein Folding & ER Stress(tgid=8) ⓘ

ER Stress↑, 1,  

Autophagy & Lysosomes(tgid=9) ⓘ

LC3II↑, 1,   LC3s↓, 1,   p62↑, 1,   TumAuto↑, 3,  

DNA Damage & Repair(tgid=10) ⓘ

DNA-PK↑, 1,   DNAdam↑, 1,   P53↑, 2,   cl‑PARP↑, 2,   γH2AX↑, 1,   p‑γH2AX↑, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

TumCCA↑, 2,  

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

CSCs↓, 4,   EMT↓, 1,   mTOR↓, 4,   TumCG↓, 9,   TumCG↝, 1,  

Migration(tgid=13) ⓘ

Ca+2↓, 1,   i-Ca+2↓, 1,   Chl∅, 1,   TumCI↓, 1,   TumCP↓, 3,   TumMeta↓, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 3,   Hif1a↓, 4,   Hif1a↝, 1,  

Barriers & Transport(tgid=15) ⓘ

SMCT1∅, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

COX2↑, 1,  

Cellular Microenvironment(tgid=17) ⓘ

pH↓, 1,   pH↑, 1,   pH↝, 2,   e-pH↑, 2,   i-pH↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↑, 1,   ChemoSen↑, 3,   Dose↝, 7,   Dose∅, 7,   eff↓, 6,   eff↑, 29,   eff↝, 2,   Half-Life↓, 1,   Half-Life↝, 2,   Half-Life∅, 1,   RadioS↑, 5,   selectivity↓, 1,   selectivity↑, 9,  

Clinical Biomarkers(tgid=22) ⓘ

BG↓, 1,   Ferritin↓, 1,   LDH↑, 1,  

Functional Outcomes(tgid=23) ⓘ

AntiCan↑, 2,   fatigue↓, 1,   neuroP↑, 1,   NP/CIPN↑, 2,   OS↑, 7,   OS∅, 1,   QoL↑, 1,   QoL∅, 1,   Remission↑, 3,   toxicity↓, 6,   toxicity↑, 2,   toxicity↝, 3,   toxicity∅, 3,   TumVol↓, 3,   TumW↓, 2,  
Total Targets: 118

Pathway results for Effect on Normal Cells:


Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↑, 1,   Half-Life↓, 1,  

Functional Outcomes(tgid=23) ⓘ

toxicity∅, 1,  
Total Targets: 3

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

 

Home Page