dichloroacetate topical

The synergistic anticancer effects of the FZ-DADA combination were confirmed at both cellular and protein levels in A549 lung cancer cells. The combination modulates key apoptotic proteins, induces cell cycle arrest, and increases mitochondrial ROS production, suggesting a promising approach for lung cancer treatment that warrants further investigation and development.

In etomoxir-treated TEM, inhibition of fatty acid oxidation was compensated through upregulation of glycolysis, catabolism of intracellular amino acids, and consumption of extracellular branched chain alpha-ketoacids (BCKA) and citrate. Overall, our results offer a comprehensive view of the metabolic signature of each MD in breast TEM and highlight putative correlations with phenotypic effects.

The effect of kinase inhibitors on Warburg effect was variable in different cell types, whereas dichloroacetate caused a shift toward oxidative metabolism. Our findings suggest that these originally anti-cancer inhibitors may also be candidates for anti-inflammatory therapy.

DCA can reduce neuron death caused by SAE and improve cognitive function in LPS mice. In SAE, DCA may be a potential candidate drug for the treatment of microglia-mediated neuroinflammation.

P1, N=16, Not yet recruiting, Yale University | Trial completion date: May 2024 --> Dec 2025 | Trial primary completion date: May 2024 --> Oct 2025

We have established a model of natural killer (NK) cell exhaustion to investigate the impact of dichloroacetate (DCA) on NK cell function...Furthermore, in a subcutaneous HCC mouse model, DCA combined with NK cell treatment resulted in retarding cancer progression. This study indicates the potential of DCA in rescuing NK cell exhaustion and eliciting anti-tumor immunity.

Compound [PtCl(OH)2{(CH3)2N(CH2)2NCH(4-FC6H3)}] (3) was prepared by the oxidative addition of hydrogen peroxide to [C,N,N'] Pt(II) cyclometallated compound [PtCl{(CH3)2N(CH2)2NCH(4-FC6H3)}] (1) and further the reaction of compound 3 with dichloroacetate or trifluoroacetate anhydrides led to the formation of the corresponding compounds [PtCl(CHCl2COO)2{(CH3)2N(CH2)2NCH(4-FC6H3)}] (4) and [PtCl(CF3COO)2{(CH3)2N(CH2)2NCH(4-FC6H3)}] (5)...Interestingly, the antiproliferative activity of these compounds against the HCT116 CRC cell line, which is in all cases higher than that of cisplatin, follows the same trend as the reduction potentials so that the most easily reduced compound 2 is the most potent...The most active compound 2 does not modify the DNA electrophoretic mobility while the less potent compound 3 is the most efficient in binding to DNA. Although compounds 2 and 3 have only a slight effect on cell cycle distribution and apoptosis induction, generation of ROS to a higher extent for the most easily reduced compound 2 was observed.

Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors...SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.

Small-molecule inhibitors of CCNE2/CDK2 (dinaciclib) and PDK1 (dichloroacetate) exhibited synergistic anti-tumor effects with PI3KCA inhibitor (alpelisib) in vitro. Inhibition of FOXK2 by dinaciclib synergistically enhanced the anti-tumor effects of alpelisib in a xenograft mouse model. Collectively, these findings highlight the oncogenic function of FOXK2 and suggest that FOXK2 and its downstream genes represent potential therapeutic targets in breast cancer.

P=N/A, N=30, Completed, University of Edinburgh | Unknown status --> Completed

G-Rh2 could target and down-regulate the expression of HIF-1α, resulting in decreased expression of glycolytic enzymes and inhibition of aerobic glycolysis in tumors. Additionally, by directly targeting mitochondrial PDK, it elevated mitochondrial oxidative phosphorylation and enhanced ROS accumulation, thereby promoting tumor cells to undergo normal apoptotic processes.

Such treatment, markedly reduced reactive oxygen species levels, as measured by flow‑cytometry, in K‑562 cells and affected the oxidative phosphorylation and glycolytic biomarkers in all lines examined. These findings indicated, that targeting of cancer mitochondrial bioenergetics with such a combination treatment was very effective, although chemoresistance to IM in leukemia and the absence of a full length p53 in colorectal cells affected its impact.

Notably, sodium dichloroacetate (DCA) attenuated renal IR injury-induced apoptosis which can be attributed to reducing PDK4 expression and PDHE1α phosphorylation levels...PDK4 inhibition alleviated renal injury with decreased ROS production and inflammation, supporting a critical role for PDK4 in IR mediated damage. This result indicates another potential target for reno-protection during IR injury; accordingly, the role of PDK4 inhibition needs to be comprehensively elucidated in terms of mitochondrial function during renal IR injury.

Dichloroacetate (DCA) which has been associated with immune regulation of T cells, was found to be significantly associated with a large number of immune factors (Figure 1)... The median age of the entire cohort (N=20) was 69 years (range: 38-92), with 11 female patients (55%). Two patient samples did not provide any signals on the cytokine panel so those samples were removed from the entire analysis (n=18 remaining samples). Analysis was adjusted for age and sex.

PDHK inhibition by the classic enzyme inhibitor, dichloroacetate, led to neuroprotection from Aβ-induced cell injury similarly to KU-32. Inhibition of PDHK in neurons would lead to activation of the PDH complex, increased acetyl-CoA generation, stimulation of the tricarboxylic acid cycle and Complex I in the electron transfer chain, and enhanced oxidative phosphorylation. A focus of future studies may be on the potential value of PDHK as a target in AD therapy.

In vivo liquid chromatography-mass spectrometry/mass spectrometry studies suggest that DCA treatment may preserve membrane potential, postpone proteolysis, and relieve oxidative stress in muscle of tumor-bearing mice. In all, this study provides evidence for DCA as a novel pharmaceutical treatment to maintain physical function and motivation in murine models of CRF.

The antiproliferative activity of the new 5-FU derivatives was assessed in vitro on SK-MEL-28 and WM793 human melanoma cell lines in 2D culture as well as on A549 human lung carcinoma, MDA-MB-231 breast adenocarcinoma, LL24 normal lung tissue, and HMF normal breast tissue as a multicellular 3D spheroid model cultured in standard (static) conditions and with the use of microfluidic systems, which to a great extent resembles the in vivo environment. In all cases, new mutual prodrugs showed a higher cytotoxic activity toward cancer models and lower to normal cell models than the parent 5-FU itself.

We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth.

DCA and OMP, alone or in combination, did not alter OCR at the concentrations tested in either cell line. Since the combination of DCA and OMP potentialized the inhibition of viability and increased cell death in a synergistic manner in melanoma cells, this approach may represent a new repurposing strategy to treat cancer.

This study underscores the importance of integrated omics approaches in deciphering the complex molecular mechanisms of DCA treatment in lung cancer. The identification of key metabolic pathways and the novel finding of citric acid elevation, together with its interaction with the MIF gene, provide promising directions for the development of targeted therapeutic strategies and improving clinical outcomes for lung cancer patients.

In this study, we found that PDK1 silence and dichloroacetic acid (DCA) significantly inhibited the growth of ESCC cells and induced cell apoptosis...Moreover, DCA and cisplatin (cis-diammine-dichloroplatinum, DDP) synergistically inhibited the progression and glycolysis ability of ESCC cells both in vitro and in vivo by increasing oxidative stress via the inhibition of the Keap1/Nrf2 signaling pathway. And, Tert-butylhydroquinone (TBHQ), a specific activator of the Keap1/Nrf2 signaling, could diminish the synergic antitumor effects of DCA and DDP on ESCC cells. Collectively, our findings indicate that PDK1 may regulate the progression of ESCC by metabolic reprogramming, which provides new strategy for the treatment of ESCC.

Inhibition of PDK by dichloroacetate in human renal cancer cell lines resulted in lower cell viability, which was accompanied by an increase in pAKT. Together, our findings suggest a differential role for PDK enzymes in ccRCC progression, and highlight PDK as actionable metabolic proteins in relation with PI3K signalling and exhausted CD8 T cells in ccRCC.

Previous data from our lab indicate the pan-PDK inhibitor dichloroacetate (DCA) or acute genetic knockdown of PDK4 blocks proliferation of bladder cancer (BCa) cells...When animals were treated with cisplatin, PDK4 animals still had larger tumors than WT mice...Similar results were observed in human samples, wherein tumors had less expression of PDK4 than benign tissue. In summary, PDK4 has a complex, multifunctional role in BCa and may represent an underrecognized tumor suppressor.

Dichloroacetic acid (DCA) is the first PDK inhibitor that has entered phase II clinical; however, several side effects associated with weak anticancer activity and excessive drug dose (100 mg/kg) have led to its limitation in clinical application. Remarkably, preliminary in vivo studies performed on a highly aggressive and metastatic Kras-mutant solid tumor model confirm the ability of the most representative compound 5i to target the PDH/PDK axis in vivo and highlighted its equal efficacy and better tolerability profile with respect to those elicited by the reference FDA approved drugs, cisplatin and gemcitabine. Collectively, the data highlights the promising anticancer potential of these novel PDK-targeting derivatives toward obtaining clinical candidates for combatting highly aggressive KRAS-mutant pancreatic ductal adenocarcinomas.

Despite DCA inducing intracellular changes in a cell-type specific way, the increase in cell death by apoptosis was clearly correlated with an increase in death receptor 5 (DR5) surface expression in all cell lines. Therefore, DCA-induced metabolic shift emerges as a suitable option to overcome TRAIL resistance in cancer cells.

The glycolysis pathway was inhibited by knocking down alpha-enolase (ENO1) or the use of a glycolysis inhibitor (dichloroacetic acid, DCA); and we found that EV71 infection were inhibited by depleting ENO1 or using DCA...Our study indicates that EV71 may reprogram glucose metabolism by activating glycolysis, and EV71 infection can be inhibited by interrupting the glycolysis pathway. ENO1 may be a potential target against EV71; and DCA could act as an inhibitor of EV71.

The DCA treatment did not affect the SLC12A2, SLC12A5, and SLC5A8 expression in cells but increased CDH1 expression in SF8628. The tumor response to DCA at different doses indicated that a contrast between NaDCA and MgDCA effectiveness reflects the differences in the tested cells' biologies.

Similar to other related compounds, both piperidones were found to act as proteasome inhibitors by increasing the levels of poly-ubiquitinated proteins in both lymphoma and colon cell lines. Hence, the two piperidones exhibited attractive cytotoxic properties and suitable mechanisms of action, which makes them good candidates as anticancer drugs.

Striking effects of PDHKs inhibition using dichloroacetate were observed in vitro on cell morphology and metabolism, resulting in increased intracellular ROS levels and decreased proliferation and invasion. In vivo findings confirmed a reduction in tumor size and better survival of mice implanted with PDHK1 and PDHK2 knockout cells. Adding a radiotherapeutic protocol further resulted in a reduction in tumor size and improved mouse survival in our model.

In addition, we studied the subcellular localization of PDK2 and PDK3, and the effects of the PDK inhibitor dichloroacetate (DCA) in the growth, proliferation, and mitochondrial respiration of PCa cells...Furthermore, PDK2 expression associated with poor PCa prognosis. This highlights a potential for PDH complex components as targets for intervention in PCa.

Similarly, Dichloroacetate (DCA), an pyruvate dehydrogenase kinase 1 (PKD1) inhibitor, has gained huge attention as a potential anticancer drug...Treatment by oral gavage of a transgenic mouse BC and metastatic BC tumor-bearing mice with CMC2 significantly reduced tumor growth and metastasis. Overall, our study provides strong evidence that CUR and DCA conjugates have a significant anticancer properties at a sub-micromolar concentration and overcome the clinical limitation of using CUR and DCA as potential anticancer drugs.

In this study, we investigated the metabolic profile of FA synthesis using combination therapy of melatonin and diisopropylamine dichloroacetate (DADA), a PDK4 inhibitor, in EAE mice...Finally, while melatonin increased lactate and PDK4 expression levels and greatly reduced PDC activity, co-therapy significantly restored PDC function while reducing the lactate levels. In summary, administration of melatonin with DADA increased the efficiency of melatonin treatment by eliminating the inhibitory effects of PDK4 on PDC's function, a critical step for proper FA synthesis during remyelination.

Inhibition of aerobic glycolysis by DCA can reduce the viability of G401 cells, promote cells apoptosis and inhibit cells invasion and migration. Therefore, aerobic glycolysis may be a potential therapeutic target for Wilms' tumor.

These were then treated with PDK inhibitor dichloroacetate (DCA) to determine effects on viability and metabolic phenotype. Furthermore, we investigated whether DCA synergized with treatment with the glutaminase inhibitor CB-839...We conclude that DCA can indeed reprogram cellular metabolism in melanoma and synergizes with other metabolically targeted drugs in antitumor activity, while keeping the antitumor reactivity of CD8+ T cells intact. Supported by the Dutch Cancer Foundation (10913 / 2017-1).

In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. Given the small size and blood-brain-barrier permeability of the drug, further research into its mechanism of action with respect to APP proteolysis may lead to the development of therapies for slowing the progression of Alzheimer's disease.

Based on these results, metformin might be a promising therapeutic agent for canine urogenital tumors. Further studies on kinetics, toxicology, bioavailability, and application of metformin in dogs are necessary.

This composed of hyaluronic acid (HA) and folic acid (FA) conjugated to a 2-deoxy glucose (2DG) shell linked to a layer of dichloroacetate (DCA) and a magnesium oxide (MgO) core (2DG@DCA@MgO; DDM) to enhance the localized chemo-radiotherapy for effective BC treatment...By highlighting DDM mechanisms as an antitumor and radio-sensitizing reagent, our data suggest that glycolytic and OXPHOS pathway modulation occurs via the PI3K/AKT/mTOR/NF-κB/VEGF and P53 signaling pathway. In conclusion, the multi-functionalized DDM opposed tumor-associated metabolic reprogramming via multiple signaling pathways in BC cells as a promising targeted metabolic approach.

The results showed that compound 1b is the most active as PDK1 and LDHA inhibitor with IC values (μg/mL) of 57.10 and 64.10 compared to 25.75 and 15.60, which were produced by the standard inhibitors sodium dichloroacetate and sodium oxamate, respectively. Thus, NPs12a and compound 3b would be considered as promising candidates suitable for further optimization to develop new chemopreventive and chemotherapeutic agents against these types of CRC cell lines. Besides, molecular docking in the colchicine binding site of the tubulin (TUB) domain revealed a good binding affinity of 3b to the protein; in addition, the absorption, distribution, metabolism, and excretion (ADME) analyses showed its desirable drug-likeness and oral bioavailability characteristics.

Moreover, DCA and sorafenib's effects on Mcl-1 degradation and apoptosis could also be inhibited by JNK inhibitor 'SP'600125. These findings indicate that DCA enhances the anti-tumor effect of sorafenib via the ROS-JNK-Mcl-1 pathway in liver cancer cells. This study may provide new insights to improve the chemotherapeutic effect of sorafenib, which may be beneficial for further clinical application of sorafenib in liver cancer treatment.