-
Biomolecules & Therapeutics Mar 2023Despite the various medications used in clinics, the efforts to develop more effective treatments for depression continue to increase in the past decades mainly because...
Despite the various medications used in clinics, the efforts to develop more effective treatments for depression continue to increase in the past decades mainly because of the treatment-resistant population, and the testing of several hypotheses- and target-based treatments. Undesirable side effects and unresponsiveness to current medications fuel the drive to solve this top global health problem. In this study, we focused on neuroinflammatory response-mediated depression which represents a cluster of depression etiology both in animal models and humans. Several meta-analyses reported that proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were increased in major depressive disorder patients. Inflammatory mediators implicated in depression include type-I interferon and inflammasome pathways. To elucidate the molecular mechanisms of neuroinflammatory cascades underlying the pathophysiology of depression, we introduced hycanthone, an antischistosomal drug, to check whether it can counteract depressive-like behaviors and normalize the inflammation-induced changes . Lipopolysaccharide (LPS) treatment increased proinflammatory cytokine expression in the murine microglial cells as well as the stimulation of type I interferon-related pathways that are directly or indirectly regulated by Janus kinase-signal transducer and activator of transcription (JAK-STAT) activation. Hycanthone treatment attenuated those changes possibly by inhibiting the JAK-STAT pathway and inflammasome activation. Hycanthone also ameliorated depressive-like behaviors by LPS. Taken together, we suggest that the inhibitory action of hycanthone against the interferon pathway leading to attenuation of depressive-like behaviors can be a novel therapeutic mechanism for treating depression.
PubMed: 36203404
DOI: 10.4062/biomolther.2022.073 -
Memorias Do Instituto Oswaldo Cruz 1987Drug resistance associated with the treatment of human schistosomiasis appears to be an emerging problem requiring more attention from the scientific community than the... (Comparative Study)
Comparative Study Review
Drug resistance associated with the treatment of human schistosomiasis appears to be an emerging problem requiring more attention from the scientific community than the subject currently receives. Drug-resistant strains of Schistosoma mansoni have been isolated by various investigators as a result of laboratory experimentation or from a combination of field and laboratory studies. Review of this data appears to indicate that the lack of susceptibility observed for some of the isolated strains cannot be ascribed solely to previous administration of antischistosome drugs and thus further studies are required to elucidate this phenomena. Strains of S. mansoni have now been identified from Brazil which are resistant to oxamniquine, hycanthone and niridazole; from Puerto Rico which are resistant to hycanthone and oxamniquine; and from Kenya which are resistant to niridazole and probably oxamniquine. Strains derived by in vitro selection and resistant to oxamniquine and possibly to oltipraz are also available. All of these strains are currently maintained in the laboratory in snails and mice, thus providing for the first time an opportunity for indepth comparative studies. Preliminary data indicates that S. haematobium strains resistant to metrifonate may be occurring in Kenya. This problem could poise great difficulty in the eventual development of antischistosomal agents. Biomphalaria glabrata from Puerto Rico and Brazil were found to be susceptible to drug-resistant S. mansoni from each country.
Topics: Animals; Anthelmintics; Biomphalaria; Drug Resistance; Helminthiasis; Helminthiasis, Animal; Humans; Mice; Schistosoma mansoni; Schistosomiasis mansoni; Schistosomicides
PubMed: 3151088
DOI: 10.1590/s0074-02761987000800025 -
PloS One 2011Lucanthone and hycanthone are thioxanthenone DNA intercalators used in the 1980s as antitumor agents. Lucanthone is in Phase I clinical trial, whereas hycanthone was...
Lucanthone and hycanthone are thioxanthenone DNA intercalators used in the 1980s as antitumor agents. Lucanthone is in Phase I clinical trial, whereas hycanthone was pulled out of Phase II trials. Their potential mechanism of action includes DNA intercalation, inhibition of nucleic acid biosyntheses, and inhibition of enzymes like topoisomerases and the dual function base excision repair enzyme apurinic endonuclease 1 (APE1). Lucanthone inhibits the endonuclease activity of APE1, without affecting its redox activity. Our goal was to decipher the precise mechanism of APE1 inhibition as a prerequisite towards development of improved therapeutics that can counteract higher APE1 activity often seen in tumors. The IC(50) values for inhibition of APE1 incision of depurinated plasmid DNA by lucanthone and hycanthone were 5 µM and 80 nM, respectively. The K(D) values (affinity constants) for APE1, as determined by BIACORE binding studies, were 89 nM for lucanthone/10 nM for hycanthone. APE1 structures reveal a hydrophobic pocket where hydrophobic small molecules like thioxanthenones can bind, and our modeling studies confirmed such docking. Circular dichroism spectra uncovered change in the helical structure of APE1 in the presence of lucanthone/hycanthone, and notably, this effect was decreased (Phe266Ala or Phe266Cys or Trp280Leu) or abolished (Phe266Ala/Trp280Ala) when hydrophobic site mutants were employed. Reduced inhibition by lucanthone of the diminished endonuclease activity of hydrophobic mutant proteins (as compared to wild type APE1) supports that binding of lucanthone to the hydrophobic pocket dictates APE1 inhibition. The DNA binding capacity of APE1 was marginally inhibited by lucanthone, and not at all by hycanthone, supporting our hypothesis that thioxanthenones inhibit APE1, predominantly, by direct interaction. Finally, lucanthone-induced degradation was drastically reduced in the presence of short and long lived free radical scavengers, e.g., TRIS and DMSO, suggesting that the mechanism of APE1 breakdown may involve free radical-induced peptide bond cleavage.
Topics: Cell Line, Tumor; Circular Dichroism; DNA; DNA-(Apurinic or Apyrimidinic Site) Lyase; Glioblastoma; Humans; Hycanthone; Hydrogen Bonding; Indoles; Inhibitory Concentration 50; Lucanthone; Mutation; Oxidation-Reduction; Plasmids; Protein Binding; Recombinant Proteins; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 21935361
DOI: 10.1371/journal.pone.0023679 -
PloS One 2019Drug combinations are extensively used to treat cancer and are often selected according to complementary mechanisms. Here, we describe a cell-based high-throughput...
Drug combinations are extensively used to treat cancer and are often selected according to complementary mechanisms. Here, we describe a cell-based high-throughput screening assay for identification of synergistic combinations between broadly applied platinum-based chemotherapeutics and drugs from a library composed of 1280 chemically and pharmacologically diverse (mostly FDA approved) compounds. The assay was performed on chemoresistant cell lines derived from lung (A549) and pancreatic (PANC-1) carcinoma, where platinum-based combination regimens are currently applied though with limited success. The synergistic combinations identified during the screening were validated by synergy quantification using the combination index method and via high content fluorescent microscopy analysis. New promising synergistic combinations discovered using this approach include compounds currently not used as anticancer drugs, such as cisplatin or carboplatin with hycanthone and cisplatin with spironolactone in pancreatic carcinoma, and carboplatin and deferoxamine in non-small cell lung cancer. Strong synergy between cisplatin or carboplatin and topotecan in PANC-1 cells, compared to A549 cells, suggests that this combination, currently used in lung cancer treatment regimens, could be applied to pancreatic carcinoma as well. Several drugs used to treat diseases other than cancer, including pyrvinium pamoate, auranofin, terfenadine and haloprogin, showed strong cytotoxicity on their own and synergistic interactions with platinum drugs. This study demonstrates that non-obvious drug combinations that would not be selected based on complementary mechanisms can be identified via high-throughput screening.
Topics: A549 Cells; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Repositioning; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; High-Throughput Screening Assays; Humans; Lung Neoplasms; Microscopy, Fluorescence; Pancreatic Neoplasms; Platinum; Prognosis
PubMed: 30695050
DOI: 10.1371/journal.pone.0211268 -
Frontiers in Oncology 2021Lung adenocarcinoma (LUAD) is one of the most common and malignant cancer types. Abnormal cell proliferation, exemplified by cell cycle and cell division dysregulation,...
Lung adenocarcinoma (LUAD) is one of the most common and malignant cancer types. Abnormal cell proliferation, exemplified by cell cycle and cell division dysregulation, is one of the most prominent hallmarks of cancer and is responsible for recurrence, metastasis, and resistance to cancer therapy. However, LUAD-specific gene regulation and clinical significance remain obscure. Here, by using both tissues and cells from LUAD and normal lung samples, 434 increased and 828 decreased genes of biological significance were detected, including 127 cell cycle-associated genes (95 increased and 32 decreased), 66 cell division-associated genes (56 increased and 10 decreased), and 81 cell proliferation-associated genes (34 increased and 47 decreased). Among them, 12 increased genes (, , , , , , , , , , , and ) and 2 decreased genes ( and ) were associated with all the three above processes. Importantly, 2 ( and ) out of the 11 increased genes (except ) are previously uncharacterized ones in LUAD and can potentially be prognostic markers. Moreover, could be a promising therapeutic target for LUAD. Besides, protein-protein interaction network analysis showed that and were the hub genes, which might play crucial roles in cell proliferation of LUAD. Furthermore, transcriptional regulatory network analysis suggested that the transcription factor E2F1 could be a key regulator in controlling cell proliferation of LUAD expression modulation of most cell cycle-, cell division-, and cell proliferation-related DEGs. Finally, trichostatin A, hycanthone, vorinostat, and mebeverine were identified as four potential therapeutic agents for LUAD. This work revealed key regulators contributing to cell proliferation in human LUAD and identified four potential therapeutic agents for treatment strategy.
PubMed: 34650921
DOI: 10.3389/fonc.2021.737152 -
Memorias Do Instituto Oswaldo Cruz Oct 1989Genetic crosses between phenotypically resistant and sensitive schistosomes demonstrated that resistance to hycanthone and oxamniquine behaves like a recessive trait,...
Genetic crosses between phenotypically resistant and sensitive schistosomes demonstrated that resistance to hycanthone and oxamniquine behaves like a recessive trait, thus suggesting that resistance is due to the lack of some factor. We hypothesized that, in order to kill schistosomes, hycanthone and oxamniquine need to be converted into an active metabolite by some parasite enzyme which, if inactive, results in drug resistance. Esterification of the drugs seemed to be the most likely event as it would lead to the production of an alkylating agent upon dissociation of the ester. An artificial ester of hycanthone was indeed active even in resistant worms, thus indirectly supporting our hypothesis. In addition, several lines of evidence demonstrated that exposure to hycanthone and oxamniquine results in alkylation of worm macromolecules. Thus, radioactive drugs formed covalent bonds with the DNA of sensitive (but not of resistant) schistosomes; an antiserum raised against hycanthone detected the presence of the drug in the purified DNA fraction of sensitive (but not of resistant) schistosomes; a drug-DNA adduct was isolated from hycanthone-treated worms and fully characterized as hycanthone-deoxyguanosine.
Topics: Alkylation; Animals; Crosses, Genetic; DNA; Drug Resistance; Genes, Recessive; Hycanthone; Nitroquinolines; Oxamniquine; Schistosoma; Thioxanthenes
PubMed: 2638729
DOI: 10.1590/s0074-02761989000500005 -
Frontiers in Genetics 2014Schistosoma mansoni is a parasitic plathyhelminth responsible for intestinal schistosomiasis (or bilharzia), a disease affecting 67 million people worldwide and causing...
Schistosoma mansoni is a parasitic plathyhelminth responsible for intestinal schistosomiasis (or bilharzia), a disease affecting 67 million people worldwide and causing an important economic burden. The schistosomicides hycanthone, and its later proxy oxamniquine, were widely used for treatments in endemic areas during the twentieth century. Recently, the mechanism of action, as well as the genetic origin of a stably and Mendelian inherited resistance for both drugs was elucidated in two strains. However, several observations suggested early on that alternative mechanisms might exist, by which resistance could be induced for these two drugs in sensitive lines of schistosomes. This induced resistance appeared rapidly, within the first generation, but was metastable (not stably inherited). Epigenetic inheritance could explain such a phenomenon and we therefore re-analyzed the historical data with our current knowledge of epigenetics. In addition, we performed new experiments such as ChIP-seq on hycanthone treated worms. We found distinct chromatin structure changes between sensitive worms and induced resistant worms from the same strain. No specific pathway was discovered, but genes in which chromatin structure modifications were observed are mostly associated with transport and catabolism, which makes sense in the context of the elimination of the drug. Specific differences were observed in the repetitive compartment of the genome. We finally describe what types of experiments are needed to understand the complexity of heritability that can be based on genetic and/or epigenetic mechanisms for drug resistance in schistosomes.
PubMed: 25076965
DOI: 10.3389/fgene.2014.00207 -
Antibiotics (Basel, Switzerland) Sep 2015Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2-4 week antibiotic treatment,...
Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2-4 week antibiotic treatment, 10%-20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and reactive oxygen species production are more active against the B. burgdorferi persisters than the commonly used antibiotics that inhibit macromolecule biosynthesis. Future studies are needed to evaluate and optimize the promising active hits in drug combination studies in vitro and also in vivo in animal models. These studies may have implications for developing more effective treatments of Lyme disease.
PubMed: 27025631
DOI: 10.3390/antibiotics4030397 -
Memorias Do Instituto Oswaldo Cruz 1993The susceptibility of four isolates of Schistosoma mansoni (BH, MAP, MPR-1 and K) to four multiple doses of anti-schistosomal agents (hycanthone, niridazole,...
The susceptibility of four isolates of Schistosoma mansoni (BH, MAP, MPR-1 and K) to four multiple doses of anti-schistosomal agents (hycanthone, niridazole, oxamniquine, and praziquantel) were evaluated in infected female Swiss albino mice. These schistosomal isolates had been maintained in the laboratory without further drug pressure for 20 to 30 generations. Multiple dosage regimens were used for each drug against each isolate of S. mansoni to generate ED50 (effective dose 50%) values. Results demonstrated that the K isolate is resistant to niridazole, the MPR-1 isolate to oxamniquine, and the MAP isolate to both hycanthone and oxamniquine. The BH isolate was susceptible to all drugs and was used as the reference isolate. All isolates were susceptible to parziquantel. The significance of the difference in response of the MPR-1 and MAP isolates is discussed. These results confirm the resistance of these isolates of S. mansoni to three schistosomicides and demonstrate that the resistance of these isolates are stable over long periods of time without exposure to drugs.
Topics: Animals; Dose-Response Relationship, Drug; Drug Resistance; Female; Hycanthone; Male; Mice; Niridazole; Oxamniquine; Praziquantel; Schistosoma mansoni; Schistosomicides
PubMed: 8246759
DOI: 10.1590/s0074-02761993000100014 -
Bulletin of the World Health... 1971The absorption, distribution, and excretion of hycanthone were studied with rats and rhesus monkeys using tritiated materials at the therapeutic dose recommended for man...
The absorption, distribution, and excretion of hycanthone were studied with rats and rhesus monkeys using tritiated materials at the therapeutic dose recommended for man (3.0+/-0.5 mg/kg). Nine pairs of each species received single intramuscular doses of randomly tritiated (specific activity 193.7 mCi/mmol) hycanthone methanesulfonate and were then sacrificed at intervals between 15 min and 72 h after medication. Peak blood and tissue concentrations occurred 30-60 min after administration (plasma half-life-45 min). The highest concentrations were observed in the liver, spleen, kidneys and adrenals, but decreased rapidly (more than 80% of the dose was excreted in 48-72 hours). In monkeys a high concentration of the compound was found in the bile (hours 1-8), probably conjugated to glucuronic acid.Radiochromatography showed only unchanged drug in the blood and tissues, except in the liver where rapid conversion occurred to sulfoxide in the rat and to the deethyl analogue in the monkey.
Topics: Adrenal Glands; Animals; Anthelmintics; Bile; Ethylamines; Haplorhini; Kidney; Liver; Macaca; Male; Methanol; Rats; Rats, Inbred Strains; Species Specificity; Spleen; Tritium; Xanthenes
PubMed: 5004005
DOI: No ID Found