Dichloroacetate Research Articles

Case report: Dichloroacetate-induced methaemoglobinaemia in a G6PD-deficient neonate.

A 3-week-old neonate with glucose-6-phosphate dehydrogenase (G6PD) deficiency and primary lactic acidosis developed haemolytic jaundice and methaemoglobinaemia following treatment with dichloroacetate (DCA), a standard treatment for primary lactic acidosis. While this mechanism has been reported in the sheep model, it has not been described in humans. Our case reinforces the uncommon observation that a G6PD-deficient individual experiencing oxidative stress may develop concurrent methaemoglobinaemia. In this case, methylene blue, the standard treatment for methaemoglobinaemia, may result in further oxidative stress. The judicious use of blood transfusion to correct the oxygen-carrying capacity of our patient led to reversal of the methaemoglobinaemia.

Dichloroacetate reduces cisplatin-induced apoptosis by inhibiting the JNK/14-3-3/Bax/caspase-9 pathway and suppressing caspase-8 activation via cFLIP in murine tubular cells

Cisplatin-induced injury to renal proximal tubular cells stems from mitochondrial damage-induced apoptosis and inflammation. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, a potential generator of ROS and ATP, protects against cisplatin-induced nephrotoxicity by promoting the TCA cycle. However, its effects on apoptotic pathways and ROS production in renal tubular cells remain unclear. Here, we investigated the detailed molecular mechanisms of the DCA’s effects by immunoblot, RT-PCR, RNA-sequencing, and RNA-silencing in a murine renal proximal tubular (mProx) cell line and mouse kidneys. In mProx cells, DCA suppressed cisplatin-induced apoptosis by attenuating the JNK/14-3-3/Bax/caspase-9 and death receptor/ligand/caspase-8 pathways without impeding inflammatory signaling. RNA-sequencing demonstrated that DCA increased the cisplatin-reduced expression of cFLIP, a caspase-8 inactivator, and decreased the expression of almost all oxidative phosphorylation (OXPHOS) genes. DCA also increased NF-kB activation and ROS production, probably enhancing the cFLIP induction and OXPHOS gene reduction, respectively. Furthermore, cFLIP silencing weakened the DCA’s anti-apoptotic effects. Finally, in mouse kidneys, DCA attenuated cisplatin-caused injuries such as functional and histological damages, caspase activation, JNK/14-3-3 activation, and cFLIP reduction. Conclusively, DCA mitigates cisplatin-induced nephrotoxicity by attenuating the JNK/14-3-3/Bax/caspase-9 pathway and inhibiting the caspase-8 pathways via cFLIP induction, probably outweighing the cisplatin plus DCA-derived cytotoxic effects including ROS.

Selective Inhibition of Deamidated Triosephosphate Isomerase by Disulfiram, Curcumin, and Sodium Dichloroacetate: Synergistic Therapeutic Strategies for T-Cell Acute Lymphoblastic Leukemia in Jurkat Cells

T-cell acute lymphoblastic leukemia (T-ALL) is a challenging childhood cancer to treat, with limited therapeutic options and high relapse rates. This study explores deamidated triosephosphate isomerase (dTPI) as a novel therapeutic target. We hypothesized that selectively inhibiting dTPI could reduce T-ALL cell viability without affecting normal T lymphocytes. Computational modeling and recombinant enzyme assays revealed that disulfiram (DS) and curcumin (CU) selectively bind and inhibit dTPI activity without affecting the non-deamidated enzyme. At the cellular level, treatment with DS and CU significantly reduced Jurkat T-ALL cell viability and endogenous TPI enzymatic activity, with no effect on normal T lymphocytes, whereas the combination of sodium dichloroacetate (DCA) with DS or CU showed synergistic effects. Furthermore, we demonstrated that dTPI was present and accumulated only in Jurkat cells, confirming our hypothesis. Finally, flow cytometry confirmed apoptosis in Jurkat cells after treatment with DS and CU or their combination with DCA. These findings strongly suggest that targeting dTPI represents a promising and selective target for T-ALL therapy.

Advanced reduction processes initiated by oxidative radicals for trichloroacetic acid degradation: Performance, radical generation, and mechanism

The degradation of haloacetic acids (HAAs) in aqueous environments poses a challenge due to their oxidative resistance. Given that HAAs are highly carcinogenic disinfection byproducts, it is imperative to develop effective degradation methods to reduce their potential health risk. In this study, we found that only 27.2% of 200 μM trichloroacetic acid (TCA) was removed in the UV-activated persulfate (PS) system after 2 h, while complete removal was achieved with the addition of 15 mM formic acid (FA). The main products of TCA degradation were dichloroacetic acid and monochloroacetic acid. Results from free radical quenching experiments and electron paramagnetic resonance spectroscopy analyses indicated that reductive carbon dioxide radical (CO2•−) was the main active species responsible for TCA reduction. Oxidative radicals (i.e., SO4•− and •OH) generated from PS activation reacted with FA to form CO2•−, efficiently degrading TCA. The effects of PS and FA concentrations, solution pH, anions (e.g., Cl−, SO42−, and HCO3−), and small organic molecules (e.g., methanol, ethanol, and acetic acid) on degradation efficiency were examined. Overall, this study proposes a simple and efficient method to improve the degradation efficiency of HAAs in the UV/PS system and provides new insights into the advanced reduction processes used for water treatments.

8071 Prevention Of Acute Kidney Injury By Reducing Mitochondrial Dysfunction In Diabetic Mice

Abstract Disclosure: M. Kim: None. C. Oh: None. A. Khang: None. J. Jeon: None. I. Lee: None. Background: Acute Kidney Injury (AKI) significantly contributes to the pathogenesis of diabetic kidney disease, often exacerbating chronic kidney disease (CKD) and accelerating the need for dialysis. Mitochondrial dysfunction, induced by an increase in reactive Oxygen Species (ROS) and inflammation, plays a crucial role in AKI. This study investigates the prevention of AKI by reducing mitochondrial dysfunction through pyruvate dehydrogenase kinase (PDK) inhibition in an ischemia-reperfusion (IR)-induced AKI model using streptozotocin (STZ)-induced diabetic mice. Methods: We utilized an IR-induced AKI model in STZ-induced diabetic C57BL6/J mice, subjecting them to IR by clamping both renal pedicles. Mitochondrial function tests, cellular apoptosis, and inflammatory markers were evaluated in NRK-52E cells and mouse primary tubular cells after hypoxia and reoxygenation using a hypoxia workstation. Results: In diabetic mice experiencing AKI following IR injury, there was a significant increase in pyruvate dehydrogenase E1α (PDHE1α) phosphorylation. This correlated with a notable increase in mitochondrial damage - TEM images of mice with IR-induced kidney injury revealed distension, loss of cristae, and fragmentation of the mitochondria. We also observed a decrease in oxygen consumption rate (OCR) accompanied by increased ROS, as well as increased production of inflammatory markers. Remarkably, the pan-PDK inhibitor, sodium dichloroacetate (DCA), mitigated apoptosis, attributable to the reduction of PDHE1α phosphorylation levels as well as normalized mitochondrial morphology and function. DCA treatment lessened oxidative stress and decreased the production of inflammatory markers following IR-induced AKI or hypoxia-reoxygenation injury. Conclusion: Restoration of mitochondrial function by DCA effectively alleviated renal injury by decreasing ROS production and inflammation, highlighting its critical role in IR-mediated damage. These results suggest another potential target for renal protection during AKI; therefore, the prevention of acute kidney injury through the inhibition of PDK could be a promising therapeutic approach for treating Diabetic Kidney Disease (DKD). Presentation: 6/1/2024

Curcumin-Dichloroacetate Hybrid Molecule as an Antitumor Oral Drug against Multidrug-Resistant Advanced Bladder Cancers.

Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10-15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers.

In Vitro Cytotoxic Potential and In Vivo Antitumor Effects of NOS/PDK-Inhibitor T1084.

Previously, we showed the antitumor activity of the new NOS/PDK inhibitor T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). The present study included an assessment of in vitro cytotoxicity against human malignant and normal cells according to the MTT-test and in vivo antitumor effects in solid tumor models in comparison with precursor compounds T1023 (NOS inhibitor; 1-isobutanoyl-2-isopropylisothiourea hydrobromide) and Na-DCA (PDK inhibitor; sodium dichloroacetate), using morphological, histological, and immunohistochemical methods. The effects of T1084 and T1023 on the in vitro survival of normal (MRC-5) and most malignant cells (A375, MFC-7, K562, OAW42, and PC-3) were similar and quantitatively equal. At the same time, melanoma A375 cells showed 2-2.5 times higher sensitivity (IC50: 0.39-0.41 mM) to the cytotoxicity of T1023 and T1084 than other cells. And only HeLa cells showed significantly higher sensitivity to the cytotoxicity of T1084 compared to T1023 (IC50: 0.54 ± 0.03 and 0.81 ± 0.02 mM). Comparative studies of the in vivo antitumor effects of Na-DCA, T1023, and T1084 on CC-5 cervical cancer and B-16 melanoma in mice were conducted with subchronic daily i.p. administration of these agents at an equimolar dose of 0.22 mmol/kg (33.6, 60.0, and 70.7 mg/kg, respectively). Cervical cancer CC-5 fairly quickly evaded the effects of both Na-DCA and T1023. So, from the end of the first week of Na-DCA or T1023 treatment, the tumor growth inhibition (TGI) began to decrease from 40% to an insignificant level by the end of the observation. In contrast, in two independent experiments, CC-5 showed consistently high sensitivity to the action of T1084: a significant antitumor effect with high TGI (43-58%) was registered throughout the observation, without any signs of neoplasia adaptation. The effect of precursor compounds on melanoma B-16 was either minimal (for Na-DCA) or moderate (for T1023) with TGI only 33%, which subsequently decreased by the end of the experiment. In contrast, the effect of T1084 on B-16 was qualitatively more pronounced and steadily increasing; it was accompanied by a 3-fold expansion of necrosis and dystrophy areas, a decrease in proliferation, and increased apoptosis of tumor cells. Morphologically, the T1084 effect was 2-fold superior to the effects of T1023-the TGI index reached 59-62%. This study suggests that the antitumor effects of T1084 develop through the interaction of NOS-dependent and PDK-dependent pathophysiological effects of this NOS/PDK inhibitor. The NOS inhibitory activity of T1084 exerts an anti-angiogenic effect on neoplasia. At the same time, the PDK inhibitory activity of T1084 enhances the cytotoxicity of induced intratumoral hypoxia and suppresses the development of neoplasia adaptation to anti-angiogenic stress. Such properties allow T1084 to overcome tumor resistance and realize a stable synergistic antitumor effect.

Efficient degradation of haloacetic acids by vacuum ultraviolet-activated peroxymonosulfate: Kinetics, mechanisms and theoretical calculations

Efficient degradation of haloacetic acids (HAAs) is crucial due to their potential risks. This study firstly proposed vacuum ultraviolet - activated peroxymonosulfate (VUV/PMS) to remove HAAs (i.e., monochloroacetic acid (MCAA), monobromoacetic acid (MBAA), dichloroacetic acid (DCAA), etc). VUV/PMS achieved 99.51 % MCAA and 63.29 % TOC removal within 10 min. Electron paramagnetic resonance (EPR), quenching and probe experiments demonstrated that •OH was responsible for MCAA degradation. MCAA degradation followed pathways of dehalogenation (major) and decarboxylation (minor). VUV/PMS showed application potential under various reaction parameters. Broad spectrum of VUV/PMS on various HAAs was further explored. Chlorinated HAAs (Cl-HAAs) were primarily degraded by oxidation reactions, while brominated HAAs (Br-HAAs) by direct VUV photolysis. The density functional theory-based calculations (DFT) revealed that reaction rates of HAAs correlated with the highest occupied molecular orbital (HOMO) and energy gap (ΔE), indicating that HAAs degradation depends on their chemical structures. The Fukui function (f0 values) and bond length showed vulnerability of the halogen atom in Cl-HAAs and C–Br bond in Br-HAAs. Overall, this study provides an in-depth perspective on the oxidation performance and mechanism of HAAs using VUV/PMS. It not only demonstrates a green and efficient method but also inspires new strategies for HAAs remediation.

Dichloroacetate Prevents Sepsis Associated Encephalopathy by Inhibiting Microglia Pyroptosis through PDK4/NLRP3.

Dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, is often used to treat lactic acidosis and malignant tumors. Increasing studies have shown that DCA has neuroprotective effects. Here, we explored the role and mechanism of DCA in Sepsis associated encephalopathy (SAE). Single-cell analysis was used to determine the important role of PDK4 in SAE and identify the cell type. GO and GSEA analysis were used to determine the correlation between DCA and pyroptosis. Through LPS + ATP stimulation, a microglia pyroptosis model was established to observe the expression level of intracellular pyroptosis-related proteins under DCA intervention, and further detect the changes in intracellular ROS and JC-1. Additionally, a co-culture environment of microglia and neuron was simply constructed to evaluate the effect of DCA on activated microglia-mediated neuronal apoptosis. Finally, Novel object recognition test and the Morris water maze were used to explore the effect of DCA on cognitive function in mice from different groups after intervention. Based on the above experiments,this study concludes thatDCA can improve the ratio of peripheral and central M1 macrophages, inhibit NLRP3-mediated pyroptosis through ROS and mitochondrial membrane potential (MMP). 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.

Health Risk Assessment of Employees Exposed to Chlorination By-products of Recreational Water in Large Amusement Parks in Shanghai

Objective Chlorination is often used to disinfect recreational water in large amusement parks; however, the health hazards of chlorination disinfection by-products (DBPs) to occupational populations are unknown. This study aimed to assess the exposure status of chlorinated DBPs in recreational water and the health risks to employees of large amusement parks.Methods Exposure parameters of employees of three large amusement parks in Shanghai were investigated using a questionnaire. Seven typical chlorinated DBPs in recreational water and spray samples were quantified by gas chromatography, and the health risks to amusement park employees exposed to chlorinated DBPs were evaluated according to the WHO's risk assessment framework.Results Trichloroacetic acid, dibromochloromethane, bromodichloromethane, and dichloroacetic acid were detected predominantly in recreational water. The carcinogenic and non-carcinogenic risks of the five DBPs did not exceed the risk thresholds. In addition, the carcinogenic and non-carcinogenic risks of mixed exposure to DBPs were within the acceptable risk limits.Conclusion Typical DBPs were widely detected in recreational water collected from three large amusement parks in Shanghai; however, the health risks of DBPs and their mixtures were within acceptable limits.

Metabolic regulating enhanced immunological activating nanocomposites for tumor microenvironment normalization and immunotherapy

The mitochondrial energy metabolic reprogramming of tumors leads to the hypoxic, acidic, and immunosuppressive microenvironment. To regulate the reprogrammed mitochondrial energy metabolism and the abnormal tumor microenvironment (TME) intracellularly and extracellularly, herein, we purposely constructed the metabolic regulating and immunological activating nanocomposites (NCs) formed by the manganese dioxide (MnO2) nanoparticles loaded with lactate oxidase (LOX), dichloroacetic acid (DCA) and SR-717, camouflaged by the cell membrane of tumors. After the NCs targeting to the tumors, the loaded DCA inhibited the glycolysis and triggered the produced pyruvate into mitochondria for further degradation. DCA also reduced the amount of CD39 and CD73, thereby promoting the accumulation of ATP intracellularly. The cascade of MnO2 and LOX catalyzed the lactate to pyruvate together with oxygen for the relief of the hypoxic and immunosuppressive TME. The regulation of the mitochondrial metabolism together with the degradation of lactate contributed to activating the immune cells. Meanwhile, the loaded SR-717 together with the release of Mn2+ activated the cyclic guanosine monophosphate adenosine monophosphate synthase/interferon gene stimulator signaling pathway for efficient antitumor effects and immunotherapy. Taken together, the designed multifunctional nanocomposites realized an effective tumor immunotherapy by regulating the reprogrammed mitochondrial energy metabolism intracellularly, relieving the abnormal TME and activating the innate antitumor immunological effects extracellularly. Our work established an approach to the enhanced immunotherapy by regulating the reprogrammed metabolism for efficient cancer treatment.

Pharmacological activation of pyruvate dehydrogenase by dichloroacetate protects against obesity-induced muscle atrophy in vitro and in vivo

Obesity-induced muscle atrophy leads to physical impairment and metabolic dysfunction, which are risky for older adults. The activity of pyruvate dehydrogenase (PDH), a critical regulator of glucose metabolism, is reduced in obesity. Additionally, PDH activator dichloroacetate (DCA) improves metabolic dysfunction. However, the effects of PDH activation on skeletal muscles in obesity remain unclear. Thus, this study aimed to evaluate the effects of PDH activation by DCA treatment on obesity-induced muscle atrophy in vitro and in vivo and elucidate the possible underlying mechanisms. Results showed that PDH activation by DCA treatment ameliorated muscle loss, decreased the cross-sectional area, and reduced grip strength in C57BL/6 mice fed a high-fat diet (HFD). Elevation of muscle atrophic factors atrogin-1 and muscle RING-finger protein-1 (MuRF-1) and autophagy factors LC3BII and p62 were abrogated by DCA treatment in palmitate-treated C2C12 myotubes and in the skeletal muscles of HFD-fed mice. Moreover, p-Akt, p-FoxO1, and p-FoxO3 protein levels were reduced and p-NF-κB p65 and p-p38 MAPK protein levels were elevated in palmitate-treated C2C12 myotubes, which were restored by DCA treatment. However, the protective effects of DCA treatment against myotube atrophy were reversed by treatment with Akt inhibitor MK2206. Taken together, our study demonstrated that PDH activation by DCA treatment can alleviate obesity-induced muscle atrophy. It may serve as a basis for developing novel strategies to prevent obesity-associated muscle loss.

Characteristics of disinfection byproducts from dissolved organic matter during chlor(am)ination of source water in Tibetan Plateau, China

The Tibetan Plateau, a typical high-altitude area, is less affected by human activities such as industrial development, and the external pollution to water sources is extremely low. Then it is also an important source of water samples for exploring the molecular characteristics of precursors in the dissolved organic matter (DOM) of disinfection byproducts (DBPs) in drinking water. Research data on DBPs in drinking water on the Tibet Plateau remains insufficient, leading to uncertainty about DBP contamination in the area. This study explores the formation potential of 35 typical DBPs, including 6 trihalomethanes (THMs), 9 haloacetic acids (HAAs), 2 halogenated ketones (HKs), 9 nitrosamines (NAs), and 9 aromatic DBPs, during chlorination and chloramination of typical source water samples in the Tibet Plateau of China. Moreover, in order to further investigate the characteristics of the generation of DBPs, the molecular composition of DOM in the collected water samples was characterized by Fourier transform ion cyclotron resonance mass spectrometry. The findings reveal that, for chlorination and chloramination, the average concentration of the five classes of DBPs was ranked as follows (chlorination, chloramination): HAAs (268.1 μg/L, 54.2 μg/L) > THMs (44.0 μg/L, 2.0 μg/L) > HKs (0.7 μg/L, 1.8 μg/L) > NAs (26.5 ng/L, 74.6 ng/L) > Aromatics (20.4 ng/L, 19.5 ng/L). The dominant compounds in THMs, HAAs, and NAs are trichloromethane, dichloroacetic acid, trichloroacetic acid, and nitrosopyrrolidine, respectively. This study highlights a significant positive correlation between DBP generation and UV254, SUV254, and the double bond equivalents of DOM in the source water. It systematically elucidates DOM molecular composition characteristics and DBP formation potential in high-altitude water sources, shedding light on key factors influencing DBP generation at the molecular level in high-altitude areas.

Enhanced removal of selected ionizable micro-pollutants from drinking water by adsorption on activated carbon fiber filters under electrochemical assistance

Micro-pollutants have raised serious concerns for drinking water safety because of their great harm to the ecological environment and public health. Traditional water purification technologies, including coagulation and sand filtration, are commonly insufficient to treat micro-pollutants. Adsorption process through carbon-based material has the potential to remove micro-pollutants from aqueous solution. However, the adsorption efficiency is restrained by insufficient adsorption capacity of the adsorbent. Ionization is a common character of most micro-pollutants in aquatic environment, which enables the possibility to improve adsorption capacity by enhance the electrostatic interaction through electrochemical ways. In this work, the activated carbon fiber (ACF) filter possessing high inherent adsorption capacity was prepared and the electrochemical assistance was adopted to improve the adsorption capacity by enhancing the electrostatic attraction between ionizable micro-pollutant and the adsorbent. The adsorption behavior under electrochemical assistance was well fitted by the pseudo-second-order kinetic model. The initial adsorption rates v0 for dichloroacetic acid (DCAA), levofloxacin (LVFX) and ciprofloxacin (CIP) reached 10.8 mg·g−1·h−1 (2.0 V), 48.3 mg·g−1·h−1 (−2.0 V) and 39.4 mg·g−1·h−1 (−2.0 V), respectively, which were 1.1–2.0 times higher than those without electrochemical assistance. The Langmuir model well fitted the adsorption isotherms of the three pollutants under electrochemical assistance. The calculated adsorption capacities (qm) of DCAA, LVFX and CIP under electrochemical assistance were 1.9, 1.3 and 1.1 times higher than those without electrochemical assistance. Furthermore, the adsorption of DCAA of 100 μg·L−1 by ACF filters under continuous flow-through mode was further investigated. The DCAA concentration in effluent maintained lower than the World Health Organization (WHO) limitation of 50 μg·L−1 for 3150 bed volumes under electrochemical assistance, which was 2.4 times higher than that without electrochemical assistance. This work provided a new approach for the efficient removal of ionizable micro-pollutants during drinking water treatment.

A NIR iridium(III) complex-based luminescence probe for imaging mitochondria pyruvate dehydrogenase kinase 1 in triple-negative breast cancer cells

The aberrant expression of mitochondrial pyruvate dehydrogenase kinase 1 (PDK1) is highly associated with tumorigenesis and metastasis of triple-negative breast cancer (TNBC). However, because of the dearth of highly sensitive and targetable probes for PDK1, the precise imaging of mitochondrial PDK1 in TNBC cells remains challenging. We herein describe the first near-infrared (NIR) luminescence probe for visualizing PDK1 in TNBC living cells through conjugating a PDK1 inhibitor, dichloroacetic acid (DCA), to an iridium(III) complexes. This probe retains not only the favorable optical characteristics of iridium(III) complexes, but also the specific binding ability of DCA for PDK1. The probe can sensitively and specifically detect mitochondria PDK1 in TNBC cells, as verified by cellular thermal shift assay (CETSA), knockdown and selectivity experiments. Moreover, complex 1 has the capability for imaging TNBC spheroids and zebrafish models with good imaging contrast and penetration, presumably benefiting from its PDK1 target ability and NIR property. Importantly, the probe shows negligible luminescence in normal cell lines with low expression of PDK1, demonstrating its ability to discriminate TNBC cells from normal cells. This probe, which acts through the interplay of both low oxygen diffusion and a rigid microenvironment upon binding to PDK1, could provide mechanistic insights into the biological roles of PDK1 in TNBC and support the development of PDK1-based TNBC diagnostic probes in vivo.

Reversing Reprogramming of Cancer Cell Metabolism by Singlet Oxygen Triggered Release of Dichloroacetate Enhances Photodynamic Cytotoxicity

AbstractCancer cells change their glucose metabolism towards lactic acid production for various defensive and proliferative advantages. Dichloroacetate (DCA) is an inhibitor of a key enzyme and thus, changes back the OX‐PHOS to glycolysis ratio. We designed and synthesized a singlet oxygen triggered source of dichloroacetate which releases this inhibitor during photodynamic singlet oxygen generation. Synergistic action of DCA and singlet oxygen results in significant enhancement of photocytotoxicity. The results suggest that this approach could offer significant improvement in the therapeutic outcome of PDT.

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

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of cancer treatment that significantly impacts patients' quality of life. This study investigated the effects of targeting metabolic pathways on bortezomib-induced neuropathic pain and tumor growth using a Lewis lung carcinoma (LLC) mouse model, while exploring potential sex differences. Male and female C57BL/6J mice were implanted with LLC cells and treated with bortezomib alone or in combination with metformin, dichloroacetate (DCA), or oxamate. Tactile allodynia was assessed using von Frey filaments. Tumor volume and weight were measured to evaluate tumor growth. Metformin, DCA, and oxamate effectively attenuated bortezomib-induced neuropathic pain without compromising the anticancer efficacy of bortezomib in both male and female mice. The LLC model exhibited a paraneoplastic neuropathy-like phenotype. Significant sex differences were observed, with male mice exhibiting larger tumors compared to females. Oxamate was more effective in alleviating allodynia in males, while metformin and DCA showed greater efficacy in reducing tumor growth in females. Targeting metabolic pathways can alleviate CIPN without interfering with bortezomib's anticancer effects. The LLC model may serve as a tool for studying paraneoplastic neuropathy. Sex differences in tumor growth and response to metabolic interventions highlight the importance of considering sex as a biological variable in preclinical and clinical studies investigating cancer biology, CIPN, and potential therapeutic interventions.

Porphyrin photosensitizers compatible with both aqueous and non-aqueous conditions: Acid dependent spectral, solubility and photocatalytic properties of meso-tetra(pyridyl)porphyrins

The aerobic photooxidation of 1,3-diphenylisobenzofuran (DPBF) as a specific singlet oxygen quencher was studied in the presence of meso-tetra(aryl)porphyrins (aryl = 2-pyridyl, 3-pyridyl and 4-pyridyl) and their diprotonated and hexaprotonated derivatives to investigate the influence of the position of pyridine nitrogen atom, solvent, core protonation (with HCl or dichloroacetic acid) and full protonation of the porphyrins on their photocatalytic activity and photooxidative stability. The pseudo-first order rate constants (kobs) for the oxidation of DPBF with singlet oxygen were determined to compare the relative activity of the photosensitizers. 1,4-benzoquinone as a scavenger of superoxide anion radical provided evidence for the absence of this species in these photocatalytic systems. The singlet oxygen quantum yields (φΔ) of the porphyrin photosensitizers were estimated by determining the initial rate constants for the oxidation of DPBF. H4T(2-Py)P(Cl)2 and H4T(2-Py)P(CHCl2COO)2 were the most efficient photosensitizers of the series of the meso-tetra(2-, 3- or 4-pyridyl)porphyrins and the protonated derivatives.

Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts.

Rarely has a chemical elicited as much controversy as dichloroacetate (DCA). DCA was initially considered a dangerous toxic industrial waste product, then a potential treatment for lactic acidosis. However, the main controversies started in 2008 when DCA was found to have anti-cancer effects on experimental animals. These publications showed contradictory results in vivo and in vitro such that a thorough consideration of this compound's in cancer is merited. Despite 50 years of experimentation, DCA's future in therapeutics is uncertain. Without adequate clinical trials and health authorities' approval, DCA has been introduced in off-label cancer treatments in alternative medicine clinics in Canada, Germany, and other European countries. The lack of well-planned clinical trials and its use by people without medical training has discouraged consideration by the scientific community. There are few thorough clinical studies of DCA, and many publications are individual case reports. Case reports of DCA's benefits against cancer have been increasing recently. Furthermore, it has been shown that DCA synergizes with conventional treatments and other repurposable drugs. Beyond the classic DCA target, pyruvate dehydrogenase kinase, new target molecules have also been recently discovered. These findings have renewed interest in DCA. This paper explores whether existing evidence justifies further research on DCA for cancer treatment and it explores the role DCA may play in it.

Targeting glucose metabolism with dichloroacetate (DCA) reduces zika virus replication in brain cortical progenitors at different stages of maturation

The underlying threat of new Zika virus (ZIKV) outbreaks remains, as no vaccines or therapies have yet been developed. In vitro research has shown that glycolysis is a key factor to enable sustained ZIKV replication in neuroprogenitors. However, neither in vivo nor clinical investigation of glycolytic modulators as potential therapeutics for ZIKV-related fetal abnormalities has been conducted. Accordingly, we tested the therapeutic potential of metabolic modulators in relevant in vitro systems comprising two pools of neuroprogenitors (NPCs), which resemble early and late stages of pregnancy. Effective doses of metabolic modulators [3.0 μM] dimethyl fumarate (DMF), [3.2 mM] dichloroacetate (DCA), and [6.3 μM] VER-246608 were determined for these cells by their effect on lactate release, pyruvate dehydrogenase (PDH) activity and cell survival. The drugs were used in a 24h pre-treatment and kept throughout ZIKV infection of NPCs. Drug effects and ZIKV replication were assessed at 24- and 56-h post-infection. In early NPCs treated with DMF, DCA and VER-246608, there was a significant reduction in the extracellular release of ZIKV potentially by PDH-mediated increased mitochondrial oxidation of glucose. Out of the three drugs, only DCA was observed to reduce viral replication in late NPCs treated with DCA. Altogether, our findings suggest that reduction of anaerobic glycolysis could be of therapeutic potential against ZIKV-related fetal abnormalities and that clinical translation should consider the use of specific glycolytic modulators over different trimesters.