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Biomolecules Oct 2022Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous...
Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous studies, we developed a novel model of drug combination using antineoplastic and different repurposed drugs. We demonstrated the combinations of doxorubicin (DOX) + artesunate, DOX + chloroquine, paclitaxel (PTX) + fluoxetine, PTX + fluphenazine, and PTX + benztropine induce significant cytotoxicity in Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. Furthermore, it was found that 5-FU + thioridazine and 5-fluorouracil (5-FU) + sertraline can synergistically induce a reduction in the viability of human colorectal adenocarcinoma cell line (HT-29). In this study, we aim to (1) evaluate the biosafety profile of these drug combinations for non-tumoral cells and (2) determine their mechanism of action in cancer cells. To do so, human fetal lung fibroblast cells (MRC-5) fibroblast cells were incubated for 48 h with all drugs, alone and in combination in concentrations of 0.25, 0.5, 1, 2, and 4 times their half-maximal inhibitory concentration (IC). Cell morphology and viability were evaluated. Next, we designed and constructed a cell microarray to perform immunohistochemistry studies for the evaluation of palmitoyl-protein thioesterase 1 (PPT1), Ki67, cleaved-poly (ADP-ribose) polymerase (cleaved-PARP), multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp), and nuclear factor-kappa-B (NF-kB) p65 expression. We demonstrate that these combinations are cytotoxic for cancer cells and safe for non-tumoral cells at lower concentrations. Furthermore, it is also demonstrated that PPT1 may have an important role in the mechanism of action of these combinations, as demonstrated by their ability to decrease PPT1 expression. These results support the use of antimalarial and central nervous system (CNS) drugs in combination regimens with chemotherapeutic agents; nevertheless, additional studies are recommended to further explore their complete mechanisms of action.
Topics: Humans; Female; MCF-7 Cells; Antimalarials; Ki-67 Antigen; Containment of Biohazards; Thioridazine; Artesunate; NF-kappa B; Fluphenazine; Benztropine; Sertraline; Fluoxetine; Michigan; Poly(ADP-ribose) Polymerase Inhibitors; Ribose; Antineoplastic Agents; Breast Neoplasms; Doxorubicin; Paclitaxel; Fluorouracil; Colonic Neoplasms; ATP Binding Cassette Transporter, Subfamily B, Member 1; Chloroquine; Adenosine Diphosphate; Drug Resistance, Neoplasm; Cell Line, Tumor
PubMed: 36291699
DOI: 10.3390/biom12101490 -
Drug and Alcohol Dependence Feb 2015Treatment of stimulant-use disorders remains a formidable challenge, and the dopamine transporter (DAT) remains a potential target for antagonist or agonist-like... (Review)
Review
BACKGROUND
Treatment of stimulant-use disorders remains a formidable challenge, and the dopamine transporter (DAT) remains a potential target for antagonist or agonist-like substitution therapies.
METHODS
This review focuses on DAT ligands, such as benztropine, GBR 12909, modafinil, and DAT substrates derived from phenethylamine or cathinone that have atypical DAT-inhibitor effects, either in vitro or in vivo. The compounds are described from a molecular mechanistic, behavioral, and medicinal-chemical perspective.
RESULTS
Possible mechanisms for atypicality at the molecular level can be deduced from the conformational cycle for substrate translocation. For each conformation, a crystal structure of a bacterial homolog is available, with a possible role of cholesterol, which is also present in the crystal of Drosophila DAT. Although there is a direct relationship between behavioral potencies of most DAT inhibitors and their DAT affinities, a number of compounds bind to the DAT and inhibit dopamine uptake but do not share cocaine-like effects. Such atypical behavior, depending on the compound, may be related to slow DAT association, combined sigma-receptor actions, or bias for cytosol-facing DAT. Some structures are sterically small enough to serve as DAT substrates but large enough to also inhibit transport. Such compounds may display partial DA releasing effects, and may be combined with release or uptake inhibition at other monoamine transporters.
CONCLUSIONS
Mechanisms of atypical DAT inhibitors may serve as targets for the development of treatments for stimulant abuse. These mechanisms are novel and their further exploration may produce compounds with unique therapeutic potential as treatments for stimulant abuse.
Topics: Animals; Benzhydryl Compounds; Benztropine; Central Nervous System Stimulants; Cocaine; Dopamine Plasma Membrane Transport Proteins; Drug Delivery Systems; Humans; Ligands; Modafinil; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary
PubMed: 25548026
DOI: 10.1016/j.drugalcdep.2014.12.005 -
Postgraduate Medical Journal Aug 1974Priapism following the administration of the tranquillizer pericyazine (Neulactil) is reported. No other aetiology was found after full investigation. The condition...
Priapism following the administration of the tranquillizer pericyazine (Neulactil) is reported. No other aetiology was found after full investigation. The condition resolved during treatment with intravenous benztropine (Cogentin). An attempt has been made to explain the aetiology and rationalize the treatment given.
Topics: Adult; Benztropine; Humans; Male; Priapism; Tranquilizing Agents
PubMed: 4464521
DOI: 10.1136/pgmj.50.586.523 -
Frontiers in Molecular Neuroscience 2021Cannabidiol, a compound of , has been proposed as an alternative treatment of schizophrenia. Preclinical and clinical data have suggested that cannabidiol shares more...
Cannabidiol, a compound of , has been proposed as an alternative treatment of schizophrenia. Preclinical and clinical data have suggested that cannabidiol shares more similarity with atypical antipsychotics than typical, both of which are customarily used to manage schizophrenia symptoms. While oligodendrocytes are known to be relevant targets of antipsychotics, the biochemical knowledge in this regard is still limited. Here we evaluated the molecular pathways modulated by cannabidiol compared to the antipsychotics clozapine (atypical) and haloperidol (typical), additionally evaluating the effects of benztropine, a muscarinic receptor antagonist that displays a protective effect in oligodendrocytes and myelination. For this purpose, we employed nano-chromatography coupled with mass spectrometry to investigate the proteomic response to these drugs both in healthy oligodendrocytic cells and in a cuprizone-based toxicity model, using the human oligodendrocyte precursor cell line MO3.13. Cannabidiol shares similarities of biochemical pathways with clozapine and benztropine, in agreement with other studies that indicated an atypical antipsychotic profile. All drugs tested affected metabolic and gene expression pathways and cannabidiol, benztropine, and clozapine modulated cell proliferation and apoptosis when administered after cuprizone-induced toxicity. These general pathways are associated with cuprizone-induced cytotoxicity in MO3.13 cells, indicating a possible proteomic approach when acting against the toxic effects of cuprizone. In conclusion, although modeling oligodendrocytic cytotoxicity with cuprizone does not represent the entirety of the pathophysiology of oligodendrocyte impairments, these results provide insight into the mechanisms associated with the effects of cannabidiol and antipsychotics against cuprizone toxicity, offering new directions of study for myelin-related processes and deficits.
PubMed: 34122009
DOI: 10.3389/fnmol.2021.673144 -
Biomolecules Jan 2022Despite the progressive research and recent advances in drug therapy to treat solid tumours, the number of cases and deaths in patients with cancer is still a major...
Despite the progressive research and recent advances in drug therapy to treat solid tumours, the number of cases and deaths in patients with cancer is still a major health problem. Drug repurposing coupled to drug combination strategies has been gaining interest among the scientific community. Recently, our group proposed novel drug combinations for breast and colon cancer using repurposed drugs from different classes (antimalarial and central nervous system (CNS)) and chemotherapeutic agents such as 5-fluorouracil (5-FU), paclitaxel (PTX), and found promising results. Here, we proposed a novel drug combination using different CNS drugs and doxorubicin (DOX), an antineoplastic used in breast cancer therapy, and studied their anticancer potential in MCF-7 breast cancer cells. Cells were treated with each drug alone and combined with increasing concentrations of DOX and cell viability was evaluated by MTT and SRB assays. Studies were also complemented with morphological evaluation. Assessment of drug interaction was performed using the CompuSyn and SynergyFinder software. We also compiled our previously studied drug pairs and selected the most promising ones for evaluation of the expression of EMT biomarkers (E-cadherin, P-cadherin, vimentin, and β-catenin) by immunohistochemistry (IHC) to assess if these drug combinations affect the expression of these proteins and eventually revert EMT. These results demonstrate that combination of DOX plus fluoxetine, benztropine, and thioridazine at their IC can improve the anticancer effect of DOX but to a lesser degree than when combined with PTX (previous results), resulting in most of the drug interactions being antagonist or additive. This suggests that the choice of the antineoplastic drug influences the success of the drug combination. Collectively, these results also allow us to conclude that antimalarial drugs as repurposed drugs have enhanced effects in MCF-7 breast cancer cells, while combination with CNS drugs seems to be more effective in HT-29 colon cancer cells. The IHC results demonstrate that combination treatments increase E-cadherin expression while reducing P-cadherin, vimentin, and β-catenin, suggesting that these treatments could induce EMT reversal. Taken together, these results could provide promising approaches to the design of novel drug combinations to treat breast and colon cancer patients.
Topics: Breast Neoplasms; Cell Line, Tumor; Colonic Neoplasms; Drug Combinations; Drug Repositioning; Epithelial-Mesenchymal Transition; Female; Humans; MCF-7 Cells; Paclitaxel
PubMed: 35204691
DOI: 10.3390/biom12020190 -
Biological Psychiatry Jul 1990
Topics: Anti-Anxiety Agents; Arousal; Benzodiazepines; Benztropine; Catatonia; Female; Humans; Middle Aged; Tropanes
PubMed: 1974151
DOI: 10.1016/0006-3223(90)90639-j -
Archives of Disease in Childhood Oct 2003Drooling frequently occurs in children with multiple handicaps; application of anticholinergic drugs is a potential strategy to treat drooling. A computer aided search... (Review)
Review
Drooling frequently occurs in children with multiple handicaps; application of anticholinergic drugs is a potential strategy to treat drooling. A computer aided search of original studies concerning the treatment of drooling was carried out. The methodological and statistical integrity of the identified studies were assessed with previously defined criteria. The articles were weighed for their separate contribution to the evidence. The search resulted in 64 reports, of which seven studies passed the screening and were subjected to further assessment and discussion by three referees. Because of the small number of reports and the methodological restriction within the studies, no meta-analysis could be performed. No general conclusion could be made about the efficacy of anticholinergic drugs in treatment of drooling in children with multiple handicaps. There was some evidence that three anticholinergic drugs (benztropine, glycopyrrolate, and benzhexol hydrochloride) are effective in the treatment of drooling, but it could not be concluded that one drug is preferable.
Topics: Child; Cholinergic Antagonists; Disabled Children; Humans; Randomized Controlled Trials as Topic; Research Design; Sialorrhea; Treatment Outcome
PubMed: 14500313
DOI: 10.1136/adc.88.10.911 -
British Journal of Pharmacology Jul 19881. The effect of benztropine, atropine and ketamine on veratridine-induced efflux of K+, membrane depolarization and release of amino acid neurotransmitters was...
Interactions of benztropine, atropine and ketamine with veratridine-activated sodium channels: effects on membrane depolarization, K+-efflux and neurotransmitter amino acid release.
1. The effect of benztropine, atropine and ketamine on veratridine-induced efflux of K+, membrane depolarization and release of amino acid neurotransmitters was investigated in the preparation of rat brain synaptosomes. 2. All three drugs inhibited in a concentration-dependent manner the processes measured: the most effective compound was benztropine which exhibited an approximate Kd of 2 microM. The inhibition was not competitive in nature. 3. The veratridine titration curves in the presence of drugs were sigmoid with Hill coefficients of about 1.4. 4. At higher concentrations, benztropine, atropine and ketamine blocked uptake of amino acid neurotransmitters into synaptosomes. 5. It is postulated that benztropine, atropine and ketamine interfere with the veratridine-activated influx of sodium into synaptosomes through voltage-dependent channels by acting at the same site as local anaesthetics. Interactions at this site alter allosterically binding and action of veratridine. In addition, at higher concentrations the drugs interact with the carrier proteins for amino acid neurotransmitters and block their transport.
Topics: Amino Acids; Animals; Atropine; Benztropine; Body Water; In Vitro Techniques; Ketamine; Male; Membrane Potentials; Nerve Tissue Proteins; Neurotransmitter Agents; Potassium; Rats; Rats, Inbred Strains; Sodium Channels; Synaptosomes; Tropanes; Veratridine; Veratrine; gamma-Aminobutyric Acid
PubMed: 2902895
DOI: 10.1111/j.1476-5381.1988.tb11599.x -
Journal of Pharmacy & Pharmaceutical... 1999Anticholinergic drugs were the first pharmacological agents used in the treatment of Parkinson"s disease. Although levodopa and other centrally acting dopaminergic... (Review)
Review
Anticholinergic drugs were the first pharmacological agents used in the treatment of Parkinson"s disease. Although levodopa and other centrally acting dopaminergic agonists have largely supplanted their use, they still have a place in treatment of the disease. As a therapeutic class, there is little pharmacokinetic information available for these drugs, which is inclusive of benztropine, biperiden, diphenhydramine, ethopropazine, orphenadrine, procyclidine and trihexyphenidyl. Pharmacokinetic information is largely restricted to studies involving young health volunteers given single doses. In general, this class of drugs is rapidly absorbed after oral administration to humans. Oral bioavailability is variable between the different drugs, ranging from 30% to over 70%. Each of the drugs appears to possess a large Vd in humans and animals, and distribution to tissues is rapid. The drugs are all characterized by relatively low clearance relative to hepatic blood flow, and appear to be extensively metabolized, primarily to N-dealkylated and hydroxylated metabolites. The available information suggests that excretion of parent drug and metabolite is via the urine and bile. Although the existence of a plasma concentration vs. therapeutic effect relationship has not been explored, there is some evidence suggesting a relationship between concentration and peripheral side effects. Elderly tolerate the drugs less well than do younger patients. There is a notable lack of pharmacokinetic information for these drugs in the elderly. The lack of pharmacokinetic information for multiple dose administration and in the elderly may be a possible hindrance in the safe and effective use of these drugs in patients with Parkinson"s disease.
Topics: Animals; Cholinergic Antagonists; Humans; Parkinson Disease
PubMed: 10952768
DOI: No ID Found -
Journal of Molecular Graphics &... Sep 2017The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain...
The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward-facing DAT conformation. The 3β-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward-facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2β- and 2α-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design.
Topics: Animals; Benztropine; Binding Sites; Cocaine; Dopamine; Dopamine Plasma Membrane Transport Proteins; Molecular Dynamics Simulation; Protein Binding; Protein Conformation
PubMed: 28734204
DOI: 10.1016/j.jmgm.2017.07.003