In this review, the current progress in the research and development of butyrylcholinesterase (BChE) reactivators is summarised and the advantages or disadvantages of these reactivators are critically discussed. Organophosphorus compounds such as nerve agents (sarin, tabun, VX) or pesticides (chlorpyrifos, diazinon) cause irreversible inhibition of acetylcholinesterase (AChE) and BChE in the human body. While AChE inhibition can be life threatening due to cholinergic overstimulation and crisis, selective BChE inhibition has presumably no adverse effects. Because BChE is mostly found in plasma, its activity is important for the scavenging of organophosphates before they can reach AChE in the central nervous system. Therefore, this enzyme in combination with its reactivator can be used as a pseudo-catalytic scavenger of organophosphates. Three structural types of BChE reactivators were found, i.e. bisquaternary salts, monoquaternary salts and uncharged compounds. Although the reviewed reactivators have certain limitations, the promising candidates for BChE reactivation were found in each structural group.

• MeSH
• Acetylcholinesterase metabolism   chemistry   MeSH
• Butyrylcholinesterase * metabolism   chemistry   MeSH
• Cholinesterase Inhibitors * chemistry   pharmacology   chemical synthesis   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Organophosphorus Compounds * chemistry   pharmacology   MeSH
• Cholinesterase Reactivators pharmacology   chemistry   chemical synthesis   MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Triphenylphosphonium (TPP) derivatives are commonly used to target chemical into mitochondria. We show that alkyl-TPP cause reversible, dose- and hydrophobicity-dependent alterations of mitochondrial morphology and function and a selective decrease of mitochondrial inner membrane proteins including subunits of the respiratory chain complexes, as well as components of the mitochondrial calcium uniporter complex. The treatment with alkyl-TPP resulted in the cleavage of the pro-fusion and cristae organisation regulator Optic atrophy-1. The structural and functional effects of alkyl-TPP were found to be reversible and not merely due to loss of membrane potential. A similar effect was observed with the mitochondria-targeted antioxidant MitoQ.

• MeSH
• Antioxidants * pharmacology   MeSH
• Cations metabolism   pharmacology   MeSH
• Membrane Proteins metabolism   MeSH
• Membrane Potential, Mitochondrial MeSH
• Mitochondrial Membranes metabolism   MeSH
• Mitochondria * metabolism   MeSH
• Organophosphorus Compounds pharmacology   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.

• MeSH
• Anaplastic Lymphoma Kinase MeSH
• Lymphoma, Large-Cell, Anaplastic * drug therapy   pathology   MeSH
• Child MeSH
• Heterografts MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Crizotinib pharmacology   therapeutic use   MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   MeSH
• Lung Neoplasms * drug therapy   MeSH
• Carcinoma, Non-Small-Cell Lung * MeSH
• Organophosphorus Compounds pharmacology   therapeutic use   MeSH
• Receptor Protein-Tyrosine Kinases therapeutic use   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The enantiomers of racemic 2-hydroxyimino-N-(azidophenylpropyl)acetamide-derived triple-binding oxime reactivators were separated, and tested for inhibition and reactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibited with tabun (GA), cyclosarin (GF), sarin (GB), and VX. Both enzymes showed the greatest affinity toward the methylimidazole derivative (III) of 2-hydroxyimino-N-(azidophenylpropyl)acetamide (I). The crystal structure was determined for the complex of oxime III within human BChE, confirming that all three binding groups interacted with active site residues. In the case of BChE inhibited by GF, oximes I (kr = 207 M-1 min-1) and III (kr = 213 M-1 min-1) showed better reactivation efficiency than the reference oxime 2-PAM. Finally, the key mechanistic steps in the reactivation of GF-inhibited BChE with oxime III were modeled using the PM7R6 method, stressing the importance of proton transfer from Nε of His438 to Oγ of Ser203 for achieving successful reactivation.

• MeSH
• Acetylcholinesterase chemistry   metabolism   MeSH
• Enzyme Activation drug effects   MeSH
• Butyrylcholinesterase chemistry   metabolism   MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Catalytic Domain MeSH
• Kinetics MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Organophosphates pharmacology   MeSH
• Organophosphorus Compounds pharmacology   MeSH
• Oximes chemistry   isolation & purification   metabolism   pharmacology   MeSH
• Sarin pharmacology   MeSH
• Stereoisomerism MeSH
• In Vitro Techniques MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The mitochondrion has emerged as a promising therapeutic target for novel cancer treatments because of its essential role in tumorigenesis and resistance to chemotherapy. Previously, we described a natural compound, 10-((2,5-dihydroxybenzoyl)oxy)decyl) triphenylphosphonium bromide (GA-TPP+C10), with a hydroquinone scaffold that selectively targets the mitochondria of breast cancer (BC) cells by binding to the triphenylphosphonium group as a chemical chaperone; however, the mechanism of action remains unclear. In this work, we showed that GA-TPP+C10 causes time-dependent complex inhibition of the mitochondrial bioenergetics of BC cells, characterized by (1) an initial phase of mitochondrial uptake with an uncoupling effect of oxidative phosphorylation, as previously reported, (2) inhibition of Complex I-dependent respiration, and (3) a late phase of mitochondrial accumulation with inhibition of α-ketoglutarate dehydrogenase complex (αKGDHC) activity. These events led to cell cycle arrest in the G1 phase and cell death at 24 and 48 h of exposure, and the cells were rescued by the addition of the cell-penetrating metabolic intermediates l-aspartic acid β-methyl ester (mAsp) and dimethyl α-ketoglutarate (dm-KG). In addition, this unexpected blocking of mitochondrial function triggered metabolic remodeling toward glycolysis, AMPK activation, increased expression of proliferator-activated receptor gamma coactivator 1-alpha (pgc1α) and electron transport chain (ETC) component-related genes encoded by mitochondrial DNA and downregulation of the uncoupling proteins ucp3 and ucp4, suggesting an AMPK-dependent prosurvival adaptive response in cancer cells. Consistent with this finding, we showed that inhibition of mitochondrial translation with doxycycline, a broad-spectrum antibiotic that inhibits the 28 S subunit of the mitochondrial ribosome, in the presence of GA-TPP+C10 significantly reduces the mt-CO1 and VDAC protein levels and the FCCP-stimulated maximal electron flux and promotes selective and synergistic cytotoxic effects on BC cells at 24 h of treatment. Based on our results, we propose that this combined strategy based on blockage of the adaptive response induced by mitochondrial bioenergetic inhibition may have therapeutic relevance in BC.

• MeSH
• Antineoplastic Agents pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Doxycycline pharmacology   MeSH
• Gentisates chemistry   pharmacology   MeSH
• Heterocyclic Compounds chemistry   pharmacology   MeSH
• Ketoglutarate Dehydrogenase Complex antagonists & inhibitors   genetics   MeSH
• Humans MeSH
• Mitochondria drug effects   pathology   MeSH
• Breast Neoplasms drug therapy   genetics   pathology   MeSH
• Organophosphorus Compounds chemistry   pharmacology   MeSH
• Oxidative Phosphorylation drug effects   MeSH
• Cell Proliferation drug effects   MeSH
• Protein Kinases genetics   MeSH
• Protein Biosynthesis drug effects   MeSH
• Ribosomes drug effects   MeSH
• Drug Synergism MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Phytohormones, similar to soil enzymes, are synthesized and secreted into the soil environment by fungi and microorganisms. Phytohormones are involved in regulating microbial community activity in the rhizosphere. This paper examines how auxins, cytokinins, ethephon and chlorocholine chloride affect the activity of native soil proteases in the organo-mineral horizon of an alpine meadow. In the meadow habitat, native soil proteases were inhibited by auxins whereas the effect of cytokinins on these enzymes was not statistically significant. A similar inhibitory effect on the activity of proteases was shown for ethephon and chlorocholine chloride, both of which also inhibited the activity of native soil proteases in the alpine meadow soil. Overall, the inhibitory effect of phytohormones on the activity of native protease activity may affect plant nutrition by retarding the nitrogen cycle in the soil. This work contributes to our understanding of the influence of substances produced by the rhizosphere that can actively participate in the activity of soil microorganisms and consequently influence the soil nitrogen cycle.

• MeSH
• Chlormequat pharmacology   MeSH
• Cytokinins pharmacology   MeSH
• Nitrogen chemistry   MeSH
• Indoleacetic Acids pharmacology   MeSH
• Organophosphorus Compounds pharmacology   MeSH
• Grassland MeSH
• Peptide Hydrolases metabolism   MeSH
• Soil Microbiology MeSH
• Plant Growth Regulators pharmacology   MeSH
• Rhizobiaceae enzymology   MeSH
• Plant Proteins metabolism   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

V posledních letech zaznamenala léčba nemalobuněčného karcinomu plic (NSCLC) zlepšení výsledků, a to především díky lepšímu porozumění molekulární biologii nádorů. Byla identifikována řada genetických změn, které vedly k vývoji malých molekul tyrosinkinázových inhibitorů (TKI), jejichž cílem je narušit modifikované signální dráhy u nádorů s těmito genetickými změnami. Mezi ně patří i přestavba genu ALK (kináza anaplastického lymfomu). Léčba inhibitory ALK prokázala větší účinnost než léčba cytotoxická, a stala se tak standardem léčby pacientů s ALK-pozitivním NSCLC. Nicméně i při této léčbě musíme počítat se vznikem rezistence, a ve snaze o její překonání jsou proto vyvíjeny inhibitory ALK vyšších generací. V poslední dekádě byly vyvinuty již 3 generace těchto inhibitorů: první generace – krizotinib; druhá generace – ceritinib, alektinib, brigatinib a ensartinib; třetí generace – lorlatinib.

In recent years, non-small cell lung carcinoma (NSCLC) treatment has been improving, mainly due to a better understanding of the molecular biology of tumors. A number of genetic changes have been identified that have led to the development of small tyrosine kinase inhibitor (TKI) molecules to disrupt altered signaling pathways in tumors with these genetic changes. These include the reconstruction of the ALK gene (anaplastic lymphoma kinase). Treatment with ALK inhibitors has shown greater efficacy than cytotoxic therapy and has become a standard of treatment for patients with ALK- -positive NSCLC. However, even with this treatment, we must count on the emergence of resistance, and in order to overcome it, therefore, ALK inhibitors of higher generations are developed. In the last decade, three generations of ALK inhibitors have been developed: the first generation – crizotinib, the second generation – ceritinib, alectinib, brigatinib and ensartinib, the third generation – lorlatinib.

• Keywords
• ALECENSA (alectinib),
• MeSH
• Survival Analysis MeSH
• Anaplastic Lymphoma Kinase antagonists & inhibitors   genetics   MeSH
• Drug Resistance, Neoplasm drug effects   MeSH
• Progression-Free Survival MeSH
• Crizotinib administration & dosage   pharmacology   MeSH
• Humans MeSH
• Lactams, Macrocyclic administration & dosage   pharmacology   MeSH
• Carcinoma, Non-Small-Cell Lung * drug therapy   pathology   MeSH
• Organophosphorus Compounds administration & dosage   pharmacology   MeSH
• Piperidines administration & dosage   pharmacology   MeSH
• Antineoplastic Combined Chemotherapy Protocols MeSH
• Pyrimidines administration & dosage   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Controlled Clinical Trial MeSH

2-(Phosphonomethyl)pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase-II (GCPII) with efficacy in multiple neurological and psychiatric disease models, but its clinical utility is hampered by low brain penetration due to the inclusion of multiple acidic functionalities. We recently reported an improvement in the brain-to-plasma ratio of 2-PMPA after intranasal (IN) dosing in both rodents and primates. Herein, we describe the synthesis of several 2-PMPA prodrugs with further improved brain delivery of 2-PMPA after IN administration by masking of the γ-carboxylate. When compared to IN 2-PMPA in rats at 1 h post dose, γ-(4-acetoxybenzyl)-2-PMPA (compound 1) resulted in significantly higher 2-PMPA delivery to both plasma (4.1-fold) and brain (11-fold). Subsequent time-dependent evaluation of 1 also showed high brain as well as plasma 2-PMPA exposures with brain-to-plasma ratios of 2.2, 0.48, and 0.26 for olfactory bulb, cortex, and cerebellum, respectively, as well as an improved sciatic nerve to plasma ratio of 0.84. In contrast, IV administration of compound 1 resulted in similar plasma exposure of 2-PMPA versus the IN route (AUCIV: 76 ± 9 h·nmol/mL versus AUCIN: 99 ± 24 h·nmol/mL); but significantly lower nerve and brain tissue exposures with tissue-to-plasma ratios of 0.21, 0.03, 0.04, and 0.04 in nerve, olfactory bulb, cortex, and cerebellum, respectively. In primates, IN administration of 1 more than doubled 2-PMPA concentrations in the cerebrospinal fluid relative to previously reported levels following IN 2-PMPA. The results of these experiments provide a promising strategy for testing GCPII inhibition in neurological and psychiatric disorders.

• MeSH
• Administration, Intranasal MeSH
• Esters analysis   chemistry   pharmacology   MeSH
• Glutamate Carboxypeptidase II antagonists & inhibitors   MeSH
• Blood-Brain Barrier drug effects   MeSH
• Administration, Intravenous MeSH
• Rats MeSH
• Macaca mulatta MeSH
• Brain drug effects   MeSH
• Cerebrospinal Fluid drug effects   MeSH
• Neuroprotective Agents analysis   chemistry   pharmacology   MeSH
• Organophosphorus Compounds analysis   chemistry   pharmacology   MeSH
• Rats, Wistar MeSH
• Prodrugs analysis   chemistry   pharmacology   MeSH
• Tissue Distribution MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

We previously demonstrated that alkyl gallates coupled to triphenylphosphine have a selective and efficient antiproliferative effect by inducing mitochondrial uncoupling in vitro due to the increased mitochondrial transmembrane potential of tumor cells. Therefore, in this work, the in vivo antitumor activities of alkyl gallate triphenylphosphonium derivatives (TPP(+)C8, TPP(+)C10 and TPP(+)C12) were evaluated in a syngeneic murine model of breast cancer. We found that TPP(+)C10 increased the cytosolic ADP/ATP ratio and significantly increased the AMP levels in a concentration-dependent manner in TA3/Ha murine mammary adenocarcinoma cells. Interestingly, TPP(+)C10 induced a decrease in the levels of cellular proliferation markers and promoted caspase-3 activation in tumor-bearing mice. Additionally, TPP(+)C10 inhibited tumor growth in the syngeneic mouse model. Importantly, 30days of intraperitoneal (i.p.) administration of the combination of TPP(+)C10 (10mg/kg/48h) and the antibiotic doxycycline (10mg/kg/24h) completely eliminated the subcutaneous tumor burden in mice (n=6), without any relapses at 60days post-treatment. This enhancement of the individual activities of TPP(+)C10 and doxycycline is due to the uncoupling of oxidative phosphorylation by TPP(+)C10 and the inhibition of mitochondrial biogenesis by doxycycline, as demonstrated by loss of mitochondrial mass and overexpression of PGC1-α as an adaptive response. Moreover, i.p. administration of TPP(+)C10 (10mg/kg/24h) to healthy mice did not produce toxicity or damage in organs important for drug metabolism and excretion, as indicated by hematological, biochemical and histological assessments. These findings suggest that the combination of TPP(+)C10 with doxycycline is a valuable candidate therapy for breast cancer management.

• MeSH
• Adenocarcinoma drug therapy   genetics   metabolism   pathology   MeSH
• Adenosine Triphosphate metabolism   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Organelle Biogenesis MeSH
• Time Factors MeSH
• Doxycycline pharmacology   MeSH
• Mammary Neoplasms, Experimental drug therapy   genetics   metabolism   pathology   MeSH
• Caspase 3 metabolism   MeSH
• Gallic Acid analogs & derivatives   pharmacology   MeSH
• Mitochondria drug effects   metabolism   pathology   MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Breast Neoplasms, Male drug therapy   genetics   metabolism   pathology   MeSH
• Organophosphorus Compounds pharmacology   MeSH
• Oxidative Phosphorylation drug effects   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Combined Chemotherapy Protocols pharmacology   MeSH
• Signal Transduction drug effects   MeSH
• Oxygen Consumption drug effects   MeSH
• Tumor Burden drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Butyryl cholinesterase (BChE) has been seen as a key enzyme in the search for new strategies in the treatment of poisoning by organophosphates (OPs), since human BChE (HssBChE), complexed with the appropriate oxime, can be a suitable scavenger and deactivator for OPs in the blood stream. However, the efficacy of HssBChE is limited by its strict stoichiometric scavenging, slow reactivation, and propensity for aging. The improvement of the reactivation rate by new and more efficient oximes could contribute to mitigate this problem and increase the HssBChE efficiency as scavenger. Several oximes have been synthesized and tested with this goal, some with promising results, but the mechanistic aspects of the reactivation reaction are not fully understood yet. In order to better investigate this mechanism, docking and mixed quantum and molecular mechanics combined with principal components analysis were performed here to evaluate the capacity of reactivation and determine the preferred route for the reactivation reaction of two new oximes on HssBChE inhibited by the neurotoxic agents cyclosarin and sarin. Plots of potential energies were calculated and all the transition states of the reactional mechanism were determined. Our results showed a good correlation with experimental data and pointed to the most efficient oxime with both OPs. The protocol used could be a suitable tool for a preliminary evaluation of the HssBChE reactivation rates by new oximes.

• MeSH
• Butyrylcholinesterase chemistry   MeSH
• Models, Chemical MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Humans MeSH
• Models, Molecular MeSH
• Organophosphorus Compounds chemistry   pharmacology   MeSH
• Oximes chemistry   pharmacology   MeSH
• Cholinesterase Reactivators chemistry   pharmacology   MeSH
• Sarin chemistry   pharmacology   MeSH
• Protein Binding MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH