Long-term stabilization of stage 4 colon cancer using sodium dichloroacetate therapy

Oral dichloroacetate sodium(DCA) has been investigated as a novel metabolic therapy for various cancers since 2007, based on data from Bonnet et al that DCA can trigger apoptosis of human lung, breast and brain cancer cells. Response to therapy in human studies is measured by standard response evaluation criteria for solid tumours definitions, which define "response" by the degree of tumour reduction, or tumour disappearance on imaging. However, Blackburn et al have demonstrated that DCA can also act as a cytostatic agent in vitro and in vivo, without causing apoptosis(programmed cell death). A case is presented in which oral 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. Since the natural history of stage 4 colon cancer consists of steady progression leading to disability and death, this case highlights a novel use of DCA as a cytostatic agent with a potential to maintain long-term stability of advanced-stage cancer.

Effects of adding sodium dichloroacetate to low-protein diets on nitrogen balance and amino acid metabolism in the portaldrained viscera and liver of pigs

Background:Identifying regulatory measures to promote glucose oxidative metabolism while simultaneously reducing amino acid oxidative metabolism is one of the foremost challenges in formulating low-protein(LP)diets designed to reduce the excretion of nitrogen-containing substances known to be potential pollutants.In this study,we investigated the effects of adding sodium dichloroacetate(DCA)to a LP diet on nitrogen balance and amino acid metabolism in the portal-drained viscera(PDV)and liver of pigs.To measure nitrogen balance,18 barrows(40±1.0 kg)were fed one of three diets(n=6 per group):18%crude protein(CP,control),13.5%CP(LP),and 13.5%CP+100 mg DCA/kg dry matter(LP-DCA).To measure amino acid metabolism in the PDV and liver,15 barrows(40±1.0 kg)were randomly assigned to one of the three diets(n=5 per group).Four essential amino acids(Lys,Met,Thr,and Trp)were added to the LP diets such that these had amino acid levels comparable to those of the control diet.Results:The LP-DCA diet reduced nitrogen excretion in pigs relative to that of pigs fed the control diet(P<0.05),without any negative effects on nitrogen retention(P>0.05).There were no differences between the control and LP-DCA groups with respect to amino acid supply to the liver and extra-hepatic tissues in pigs(P>0.05).The net release of ammonia into the portal vein and production rate of urea in the liver of pigs fed the LP-DCA diet was reduced relative to that of pigs fed the control and LP diets(P<0.05).Conclusion:The results indicated that addition of DCA to a LP diet can efficiently reduce nitrogen excretion in pigs and maximize the supply of amino acids to the liver and extra-hepatic tissues.

Sodium dichloroacetate could inhibit the endothelial-to-mesenchymal transition:a novel treatment target for pulmonary arterial hypertension

Background and Purpose Recent studies found endothelialto-mesenchymal transition(EndoMT)played an important role in the pathogenesis of pulmonary arterial hypertension.Our pilot research demonstrated the existence of Warburg effect in the lung tissue of idiopathic pulmonary arterial hypertension patients.However the relationships and the underlying mechanisms between EndoMT and Warburg effect have not been elucidated.Therefore,the purpose of this study is to determine whether metabolic reprogramming happens in EndoMT cells.We also want to investigate whether sodium dichloroacetate(DCA),a metabolic modulator,could prevent EndoMT by inhibiting Warburg effect.

Long-term stabilization of metastatic melanoma with sodium dichloroacetate

Sodium dichloroacetate(DCA) has been studied as a metabolic cancer therapy since 2007, based on a publication from Bonnet et al demonstrating that DCA can induce apoptosis(programmed cell death) in human breast, lung and brain cancer cells. Classically, the response of cancer to a medical therapy in human research is measured by Response Evaluation Criterial for Solid Tumours definitions, which define "response" by the degree of tumour reduction, or tumour disappearance on imaging, however disease stabilization is also a beneficial clinical outcome. It has been shown that DCA can function as a cytostatic agent in vitro and in vivo, without causing apoptosis. A case of a 32-year-old male is presented in which 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. This case demonstrates that DCA can be used to reduce disease volume and maintain longterm stability in patients with advanced melanoma.

Pharmacokinetics of intravenously administered sodium dichloroacetate in rabbits

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Effects of dichloroacetate on the activation of the mitochondrial pathway in C6 cells in vitro

Mitochondria are increasingly recognized as important targets for tumor treatment because of their central roles in apoptotic pathways and cellular metabolism. Dichloroacetate （DCA）, a low molecular weight mitochondria-targeting agent, exhibits potential therapeutic effects for tumors. Based on the effects of DCA on tumor cellular metabolism, we carried out this study to investigate the anti-tumor activity of DCA in C6 glioma cells in vitro. The results showed that DCA was able to increase the activity of pyruvate dehydrogenase （PDH）, induce the production of reactive oxygen species （ROS） and reduce the mitochondrial membrane potential （MMP） in C6 ceils in vitro （P〈0.05 or 0.01）, indicating that the anti-tumor effects of DCA in C6 cells could be through the activation of the mitochondrial pathway. In conclusion, mitochondria could be a viable therapeutic target for the treatment of glioma.

Dichloroacetate enhances the antitumor effect of pirarubicin via regulating the ROS-JNK signaling pathway in liver cancer cells

Aim:Liver cancer is one of the most common malignancies and has a high recurrence rate.However,current treatment strategies do not achieve satisfactory outcomes in the clinic.To explore a new strategy to enhance the effectiveness of chemotherapy in liver cancer,we investigated whether dichloroacetate(DCA)could enhance the sensitivity of liver cancer cells to pirarubicin(THP).Methods:Liver cancer cells were treated with DCA alone,THP alone,or DCA and THP combined.Cell viability was determined by the CCK-8 assay.Cell apoptosis was analyzed by flow cytometer.Reactive oxygen species(ROS)were detected using a CM-H2DCFDA fluorescence probe.Protein levels were identified by immunoblotting.Results:The results revealed that DCA significantly enhanced the antitumor effect of THP in liver cancer cells.Changes in morphology and adherence ability were observed,as well as decreased cell viability.The results of flow cytometry showed that the combination of THP and DCA significantly increased apoptosis of liver cancer cells.Moreover,compared with THP alone,combination treatment with DCA significantly increased THP-triggered ROS generation in liver cancer cells.The antioxidant N-acetyl-L-cysteine reversed the synergistic effect of DCA and THP on ROS generation,cell viability and apoptosis.Furthermore,phosphorylation of c-Jun N-terminal kinase(JNK)was significantly increased in the DCA and THP combination group.The effects of DCA and THP on cell viability and apoptosis were inhibited by the JNK inhibitor SP600125.Conclusion:The results obtained in the present study indicated that DCA enhanced the antitumor effect of THP in liver cancer cells via regulating the ROS-JNK signaling pathway.

DCA降低家兔血乳酸值的实验研究

目的 :为研究Dichloroacetate(DCA)降低血乳酸的疗效。方法 :采用作者改良的BarKer氏法观测正常及高乳酸血症 (HLA)家兔血乳酸值在接受DCA后的动态变化。结果 :静脉注射DCA( 50mg/kg)后 1 5及 3 0min时 ,正常 (P<0 .0 5)与HLA家兔血乳酸值 (P <0 .0 1 )均显著下降。结论 :DCA具有降低血乳酸的作用。

Behaviour of Haloacetic Acids in Drinking Water Distribution Systems

To guarantee the safety of drinking water quality after chlorination, the formation, distribution and factors influencing the concentrations of haloacetic acids (HAAs) in a water distribution system (WDS) were investigated both on a full-scale WDS (FWDS) and pilot-scale WDS (PWDS) within a city in northern China. The results of both investigations showed that trichloroacetic acid (TCAA) and dichloroacetic acid (DCAA) were the dominating types of HAAs. In the FWDS, variations in the HAA content showed negative correlations with total residual chlorine, pH and non-purgeable organic carbon (NPOC) and positive correlations with temperature and UV254. In the PWDS, the concentration of HAAs after rechlorination followed the rule of ‘first rise and then fall’; therefore, locating an appropriate rechlorination point and lowering the single chlorine dosage could be used as effective measures to control the HAA content in WDSs. © 2016, Tianjin University and Springer-Verlag Berlin Heidelberg.

REFRACTOMETRY AND TEXTURES OF METHYL-CYANOETHYL CELLULOSE/DICHLOROACETIC ACID LIQUID CRYSTA LLI NE SOLUTIONS^+

An Abbe refractometer with a rotatable polarizer mounted on the eyepiece is used for determining the two principal refractive indices of methyl-cyanoethyl cellulose/dichloroacetic acid liquid crystalline solutions. The critical concentration where the mesophase appears can be determined according to the variation of the increment of the refractive index with the concentration. Mesophase textures of the liquid crystalline solutions are observed and the influence of the concentration on mesophase textures is also discussed.

Dichloroacetic Acid (DCA)-Induced Cytotoxicity in Human Breast Cancer Cells Accompanies Changes in Mitochondrial Membrane Permeability and Production of Reactive Oxygen Species

Cancer cells utilize cytosolic glycolysis for their energy production even in the presence of adequate levels of oxygen (Warbug effect) due to mitochondrial defects. Dichloroacetic acid (DCA) shifts cytosolic glucose metabolism to aerobic oxidation by inhibiting mitochondrial pyruvate dehydrogenase kinase (PDK) and increasing pyruvate uptake. Therefore, DCA has potential in reversing the glycolytic metabolism defect in cancerous cells. DCA is also known to induce apoptosis in a number of cancer cell lines, the mechanism of which is not well understood. In this study, an attempt has been made to investigate the effects of DCA on aggressive human breast cancer (MCF-7) cells as compared with less aggressive mouse osteoblastic (MC3T3) cells. Cell cytotoxicity was determined by MTT, crystal violet and Trypan blue exclusion assays. Western blot was used to detect any changes in the expression of apoptotic markers. Flow cytometry was used to measure apoptotic and necrotic effects of DCA. Mitochondrial integrity was determined by change in mitochondrial membrane potential (Δψm), whereas oxidative damage was determined by production of reactive oxygen species (ROS). DCA caused a concentration-dependent cytotoxicity both in MCF-7 and MC3T3 cell lines. MCF-7 cells were most affected. Flow cytometry results showed a significantly higher apoptosis in MCF-7 even at lower concentrations of DCA. However, higher concentrations of DCA were necrotic. Western blotting showed an increased expression of Mn-SOD-1 upon DCA treatment. Further, DCA decreased Δψm and increased ROS production. The effects of DCA were more pronounced on MCF-7 cells as compared to MC3T3 cells. Our results suggest that DCA-induced cytotoxicity in cancerous cells is mediated via changes in Δψm and production of ROS.

Treatment Process for the Low Residual of Dichloroacetic Acid in Lauramidopropyl Betaine

Without using sodium sulfite or oxides,The content of residual dichloroacetic acid in lauramidopropyl betaine was reduced by technology improvement.The effects of reaction temperature,pressure,reaction time,pH and color on the residual dichloroacetic acid were studied.The optimum conditions were screened out,i.e.processing time of 3 h,processing temperature of 120℃,pressure of 0.11 MPa and pH of 12.0.Hereby the dichloroacetic acid residues could be reduced from 450 mg/kg to less than 50 mg/kg,and the color of the product was below 70 hazen.

Dichloroacetic acid and rapamycin synergistically inhibit tumor progression

Mammalian target of rapamycin(mTOR)controls cellular anabolism,and mTOR signaling is hyperactive in most cancer cells.As a result,inhibition of mTOR signaling benefits cancer patients.Rapamycin is a US Food and Drug Administration(FDA)-approved drug,a specific mTOR complex 1(mTORC1)inhibitor,for the treatment of several different types of cancer.However,rapamycin is reported to inhibit cancer growth rather than induce apoptosis.Pyruvate dehydrogenase complex(PDHc)is the gatekeeper for mitochondrial pyruvate oxidation.PDHc inactivation has been observed in a number of cancer cells,and this alteration protects cancer cells from senescence and nicotinamide adenine dinucleotide(NAD^(+))exhaustion.In this paper,we describe our finding that rapamycin treatment promotes pyruvate dehydrogenase E1 subunit alpha 1(PDHA1)phosphorylation and leads to PDHc inactivation dependent on mTOR signaling inhibition in cells.This inactivation reduces the sensitivity of cancer cells'response to rapamycin.As a result,rebooting PDHc activity with dichloroacetic acid(DCA),a pyruvate dehydrogenase kinase(PDK)inhibitor,promotes cancer cells'susceptibility to rapamycin treatment in vitro and in vivo.

The associated killing of hepatoma cells using multilayer drug-loaded mats combined with fast neutron therapy

Chemotherapeutic and radiation therapy have emerged as two most important treatment strategies to treat cancer in clinical practice;however,to improve anticancer efficacy,combination chemotherapy still remains challenge.Dichloroacetate(DCA)could produce significant cytotoxic effects in certain tumor cells through its distinct mechanism.Radiation therapy with fast neutrons(FNT)has high relative biolgical effectiveness compared to other radiotherapeutics.Herein,we reported the combination chemotherapy with FNT for effective tumor growth inhibition with the assistance of a multilayered nanofiber loading DCA and DCA derivatives.We first synthesized a biodegradable polylysine to condense DCA with negative charge,or to conjugate DCA by condensing synthesis,to obtain Ion-DCA and Co-DCA,respectively.DCA,Ion-DCA or Co-DCA was then loaded into fibers to form multilayer drug-loaded mats.Upon adhesion on the surface of subcutaneous and orthotopic liver tumors,the multilayer drug-loaded mats realized a controllable release of DCA,which reversed the Warburg effect and inhibited cancer cell proliferation.Meantime,irradiation of fast neutrons could seriously damage DNA structure.Combination of the controllable release of DCA and FNT resulted in synergistic cell apoptosis in vitro,and the tumor inhibition in vivo.This study thus provides a new approach to integrate chemotherapy and FNT with the assistance of biocompatible nanofiber for synergistic tumor therapy.

Inhibition of pyruvate dehydrogenase kinase improves carbohydrate utilization in Nile tilapia by regulating PDK2/4-PDHE1αaxis and insulin sensitivity

Pyruvate dehydrogenase kinases(PDKs)-pyruvate dehydrogenase E1αsubunit(PDHE1α)axis plays an important role in regulating glucose metabolism in mammals.However,the regulatory function of PDKsPDHE1α axis in the glucose metabolism of fish is not well known.This study determined whether PDKs inhibition could enhance PDHE1αactivity,and improve glucose catabolism in fish.Nile tilapia fingerlings(1.90±0.11 g)were randomly divided into 4 treatments in triplicate(30 fish each)and fed control diet without dichloroacetate(DCA)(38% protein,7% lipid and 45% corn starch)and the control diet supplemented with DCA,which inhibits PDKs through binding the allosteric sites,at 3.75(DCA3.75),7.50(DCA7.50)and 11.25 g/kg(DCA11.25),for 6 wk.The results showed that DCA3.75,DCA7.50 and DCA11.25significantly increased weight gain,carcass ratio and protein efficiency ratio(P<0.05)and reduced feed efficiency(P<0.05)of Nile tilapia.To investigate the effects of DCA on growth performance of Nile tilapia,we selected the lowest dose DCA3.75 for subsequent analysis.Nile tilapia fed on DCA3.75significantly reduced the mesenteric fat index,serum and liver triglyceride concentration and total lipid content in whole fish,and down-regulated the expressions of genes related to lipogenesis(P<0.05)compared to the control.The DCA3.75 treatment significantly improved glucose oxidative catabolism and glycogen synthesis in the liver,but significantly reduced the conversion of glucose to lipid(P<0.05).Furthermore,the DCA3.75 treatment significantly decreased the PDK2/4 gene and protein expressions(P<0.05),accordingly stimulated PDHE1αactivity by decreasing the phosphorylated PDHE1αprotein level.In addition,DCA3.75 treatment significantly increased the phosphorylated levels of key proteins involved in insulin signaling pathway and glycogen synthase kinase 3β(P<0.05).Taken together,the present study demonstrates that PDK2/4 inhibition by using DCA promotes glucose utilization in Nile tilapia by activating PDHE1αand improving insulin sensitivity.Our study helps to understand the regulatory mechanism of glucose metabolism for improving dietary carbohydrate utilization in farmed fish.

Enhanced ozonation of dichloroacetic acid in aqueous solution using nanometer ZnO powders

Nanometer zinc oxide （ZnO） powders were used as a catalyst to enhance the ozonation for the degradation of dichloroacetic acid （DCAA） in aqueous solution. The batch experiments were carded out to investigate the effects of key factors such as catalyst dosage, ozone dosage, solution pH and tert-butyl alcohol （t-BuOH） on the degradation efficiency of DCAA. Density functional theory （DFT） was adopted to explore the mechanism of generating hydroxyl radical （＇OH） on the ZnO surface. The results showed that adsorption and ozonation processes were not effective for DCAA removal, and the addition of ZnO catalyst improved the degradation efficiency of DCAA during ozonation, which caused an increase of 22.8% for DCAA decomposition compared to the case of ozonation alone after 25 min. Under the same experimental conditions, the DCAA decomposition was enhanced by increasing catalyst dosage from 100 to 500 mg/L and ozone dosage from 0.83 to 3.2 mg/L. The catalytic ozonation process is more pronounced than the ozonation process alone at pH 3.93, 6.88, and 10. With increasing the concentration of t-BuOH from 10 to 200 rag/L, the degradation of DCAA was significantly inhibited in the process of catalytic ozonation, indicating that ZnO catalytic ozonation followed ＂OH reaction mechanism. Based on the experimental results and DFT analysis, it is deduced that the generation of ＂OH on the ZnO surface is ascribed to the adsorption of molecule ozone followed by the interaction of adsorbed ozone with active sites of the catalyst surface. It is also concluded that ZnO may be an effective catalyst for DCAA removal, which could promote the formation of .OH derived from the catalytic decomposition of ozone.

Determination of Glycolate Acid, Mono- and Dichloroacetic Acids in Synthetical Betaine by Anion-exchange Chromatography

An anion-exchange chromatography method combined solid phase extraction （SPE） was developed for the simultaneous analysis of glycolate acid （GL）, monochloroacetic acid （MCA） and dichloroacetic acid （DCA） in synthetical betaine products. The analytes and unknown anionic impurities were well separated on a Metrosep A supp5 anion-exchange column （150 mm×4 mm） with 2.0 mmol/L Na2CO3＋2.0 mmol/L NaHCO3 solution as eluent. Suppressed conductivity detection was used. A strong cation exchange （SCX） solid phase extraction （SPE） cartridge was used to reduce the concentration of matrix betaine and a Cleanert IC-Ag pretreatment cartridge was used to remove high Cl- concentration. The detection limits of GL, MCA and DCA were 0.09, 0.017 and 0.05 μg/L, respectively. The relative standard deviations （RSDs） of the retention times and peak areas were less than 0.09% and 0.49%, respectively. The recoveries of the three analytes were between 90.6% and 100.8%. The analytical results showed that GL and DCA were present in high concentration and no MCA was found when the proposed ion chromatography method was applied to three synthetical betaine samples. The proposed method is simple, sensitive and timesaving, and is also suitable for routine analysis in quality control of synthetical betaine products.

Cocrystallization-like strategy for the codelivery of hydrophobic and hydrophilic drugs in a single carrier material formulation

Codelivery of drugs by drug carriers is a promising strategy against several diseases such as infections and cancer.However,traditional drug carriers are typically characterized by low drug payload,limiting their treatment efficacy.Using nanocrystals of insoluble drug as carriers,a carrier free platform was developed previously to deliver a second insoluble drug for codelivery.To extend the concept,we hypothesized,herein,that the platform allows for codelivery of hydrophobic and hydrophilic drugs using a cocrystalization-like strategy.To obtain proof-of-concept,paclitaxel(PTX),an insoluble chemotherapeutic agent,and dichloroacetic acid(DCA),a water-soluble inhibitor of pyruvate dehydrogenase kinase,were utilized as model drugs.PTX-DCA hybrid nanocrystals(PTX-DCA NCs)were prepared by antisolvent precipitation and characterized.Their in vitro antitumor activity against cancer cells was evaluated.PTX-DCA NCs prepared from the optimized formulation had a diameter of 160 nm and a rodshape morphology and possessed encapsulated efficacy of approximately 30%for DCA.The use of the hybrid crystals enabled synergy to kill cancer cells,in particular in PTX-resistant cells in a dosedependent pattern.In conclusion,by using a cocrystalization-like strategy,a hydrophilic drug can be formulated into a drug’s nanocrystal for codelivery.

Preparation and characterization of Pd/Fe bimetallic nanoparticles immobilized on Al_2O_3/PVDF membrane:Parameter optimization and dechlorination of dichloroacetic acid

Using a liquid-solid phase inversion method, a hybrid matrix poly（vinylidene fluoride）（PVDF） membrane was prepared with alumina（Al2O3） nanoparticle addition. Pd/Fe nanoparticles（NPs） were successfully immobilized on the Al2O3/PVDF membrane, which was characterized by Scanning Electron Microscopy（SEM） and Transmission Electron Microscopy（TEM）. The micrographs showed that the Pd/Fe NPs were dispersed homogeneously. Several important experimental parameters were optimized, including the mechanical properties, contact angle and surface area of Al2O3/PVDF composite membranes with different Al2O3 contents. At the same time, the ferrous ion concentration and the effect of hydrophilization were studied. The results showed that the modified Al2O3/PVDF membrane functioned well as a support. The Al2O3/PVDF membrane with immobilized Pd/Fe NPs exhibited high efficiency in terms of dichloroacetic acid（DCAA） dechlorination. Additionally, a reaction pathway for DCAA dechlorination by Pd/Fe NPs immobilized on the Al2O3/PVDF membrane system was proposed.