ABSTRACT
OBJECTIVE: Vorinostat is a drug used to treat cutaneous T cell lymphoma whose action mechanism is based on Histone Deacetylase inhibition. Histone Deacetylases are a family of enzymes that remove acetyl groups from histone and non-histone proteins that control many crucial processes, such as gene regulation, cell cycle progression, differentiation, and apoptosis. Histone Deacetylase homologues are also expressed in parasites of the genus Plasmodium, Leishmania, Cryptosporidium, Schistosoma, Entamoeba, and others. In this way, antiparasitic properties of Vorinostat have been explored. The aim of this review is to report the current state knowledge of Vorinostat as antiparasitic drug against Plasmodium, Leishmania, Cryptosporidium, Schistosoma and Entamoeba in order to support future investigation in this field. MATERIALS AND METHODS: The authors revised the recent and relevant literature concerning the topic and discussed advances and limitations of studies on Vorinostat as potential drug to treat human parasitic diseases. RESULTS: Vorinostat has been efficient in vitro and, in some cases, in vivo, against parasites that cause parasitic diseases, such as malaria, leishmaniasis, cryptosporidiosis, amoebiasis, and schistosomiasis. CONCLUSIONS: In vitro and in vivo models have demonstrated the antiparasitic activity of Vorinostat, however, the challenge is to assay its activity in animal models and to evaluate if Vorinostat is safe for humans as new alternative to treat human parasitic infections.
Subject(s)
Antiparasitic Agents/therapeutic use , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylases , Parasites/drug effects , Parasitic Diseases/drug therapy , Protozoan Proteins/antagonists & inhibitors , Vorinostat/therapeutic use , Animals , Antiparasitic Agents/adverse effects , Drug Repositioning , Histone Deacetylase Inhibitors/adverse effects , Histone Deacetylases/metabolism , Host-Parasite Interactions , Humans , Parasites/enzymology , Parasites/pathogenicity , Parasitic Diseases/diagnosis , Parasitic Diseases/parasitology , Protozoan Proteins/metabolism , Vorinostat/adverse effectsABSTRACT
AbbreviationsSAHAsuberoylanilide hydroxamic acidEhHDACHistone Deacetylase from Entamoeba histolyticaRgRadius of gyrationRMSDroot-mean-square deviationRMSFroot-mean-square fluctuationMDSmolecular dynamics simulationVMDVisual Molecular DynamicsNAMDNanoscale Molecular DynamicsPBCperiodic boundary conditionsPMEParticle Mesh Ewald3Dthree-dimensionalCαalpha carbonFDAFood and Drug AdministrationnsnanosecondsGPU CUDAGraphics Processing Unit Compute Unified Device ArchitectureCommunicated by Ramaswamy H. Sarma.
Subject(s)
Amebiasis/drug therapy , Amebiasis/parasitology , Entamoeba histolytica/physiology , Metronidazole/therapeutic use , Vorinostat/therapeutic use , Entamoeba histolytica/drug effects , Entamoeba histolytica/enzymology , Histone Deacetylases/chemistry , Metronidazole/chemistry , Metronidazole/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Phylogeny , Structural Homology, Protein , Trophozoites/drug effects , Trophozoites/physiology , Vorinostat/chemistry , Vorinostat/pharmacologyABSTRACT
OBJECTIVE: Metronidazole is an antibiotic widely used in different medical conditions such as trichomoniasis, amoebiasis, and giardiasis among others. Its use has been associated with toxicity; however, it is not well characterized. In this review, we discuss the different therapeutic uses of metronidazole and its side effects in order to aid future investigation in this field. MATERIALS AND METHODS: Relevant information, original research articles, clinical trials, and reviews were collected from PubMed to know the state of the art of the different therapeutic uses of metronidazole and the reported side effects. RESULTS: Metronidazole was used by the first time in 1959, to treat an infection caused by Trichomonas vaginalis; subsequently, new therapeutic properties were discovered. Nowadays, Metronidazole is used to treat infections caused by Bacteroides, Fusobacteria and Clostridia, rosacea, oral and dental infections, bone and joint infections, gynecologic infections, endocarditis, septicemia, and respiratory tract infections. It also can be used to treat Crohn´s disease or even like prophylaxis, before surgical procedures. Metronidazole is well tolerated with mild to moderate side effects such as nausea, abdominal pain, and diarrhea. Nevertheless, serious neurotoxicity, optic neuropathy, peripheral neuropathy, and encephalopathy have been reported in rare cases. Their genotoxic effects observed in animal models are controversial in humans. CONCLUSIONS: The therapeutic use of metronidazole had increased worldwide. Even though it is widely used, metronidazole has been associated with neurotoxicity and genotoxicity; however, its side effects are not well established. Conversely, its veterinary use is restricted in some countries because of its tumor association. Subsequently, further studies are needed to discover the secure use of metronidazole and describe new usages for this drug.
Subject(s)
Antiprotozoal Agents/adverse effects , Metronidazole/adverse effects , Neurotoxicity Syndromes/etiology , Protozoan Infections, Animal/drug therapy , Protozoan Infections/drug therapy , Animals , Carcinogenesis/drug effects , DNA Damage/drug effects , Disease Models, Animal , Drug Utilization/statistics & numerical data , Humans , Legislation, Veterinary , Veterinary Drugs/adverse effectsABSTRACT
Cytoskeleton remodeling can be regulated, among other mechanisms, by lysine acetylation. The role of acetylation on cytoskeletal and other proteins of Entamoeba histolytica has been poorly studied. Dynamic rearrangements of the actin cytoskeleton are crucial for amebic motility and capping formation, processes that may be effective means of evading the host immune response. Here we report the possible effect of acetylation on the actin cytoskeleton dynamics and in vivo virulence of E. histolytica. Using western blot, immunoprecipitation, microscopy assays, and in silico analysis, we show results that strongly suggest that the increase in Aspirin-induced cytoplasm proteins acetylation reduced cell movement and capping formation, likely as a consequence of alterations in the structuration of the actin cytoskeleton. Additionally, intrahepatic inoculation of Aspirin-treated trophozoites in hamsters resulted in severe impairment of the amebic virulence. Taken together, these results suggest an important role for lysine acetylation in amebic invasiveness and virulence.
Subject(s)
Actin Cytoskeleton/metabolism , Entamoeba histolytica/metabolism , Entamoeba histolytica/pathogenicity , Lysine/metabolism , Acetylation/drug effects , Actin Cytoskeleton/drug effects , Actins/metabolism , Amino Acid Sequence , Animals , Aspirin/pharmacology , Binding Sites , Cricetinae , Cytochalasin D/pharmacology , Entamoeba histolytica/growth & development , Entamoeba histolytica/ultrastructure , Male , Molecular Docking Simulation , Molecular Sequence Data , Movement/drug effects , Parasites/drug effects , Parasites/growth & development , Polymerization/drug effects , Trophozoites/drug effects , Trophozoites/growth & development , Trophozoites/ultrastructure , VirulenceABSTRACT
Protein kinases (PKs) of parasitic protozoa are being evaluated as drug targets. A large number of protein kinases within the protein kinome of Entamoeba histolytica strongly suggest that protein phosphorylation is a key component of pathogenesis regulation by this parasite. PI3 K and Src are kinases previously described in this parasite, but their role is poorly understood. Here, the effect of Src-1-inhibitor and PI3 K inhibitor (Wortmannin) on the virulence factors of E. histolytica was evaluated. Results show that both inhibitors affect the actin cytoskeleton and the amoebic movement. Also, the proteolytic activity is diminished by Wortmannin, but not by Src-inhibitor-1; however, the phagocytic capacity is diminished by Wortmannin and Src-1-inhibitor. Finally, we found that the virulence in vivo of E. histolytica is affected by Wortmannin but not by Src-1-inhibitor. This study opens the way for the design of anti-amoebic drugs based on kinase inhibition.
