ABSTRACT
Malignant melanoma is still a serious medical problem. Relatively high mortality, a still-growing number of newly diagnosed cases, and insufficiently effective methods of therapy necessitate melanoma research. Tetracyclines are compounds with pleiotropic pharmacological properties. Previously published studies on melanotic melanoma cells ascertained that minocycline and doxycycline exerted an anti-melanoma effect. The purpose of the study was to assess the anti-melanoma potential and mechanisms of action of minocycline and doxycycline using A375 and C32 human amelanotic melanoma cell lines. The obtained results indicate that the tested drugs inhibited proliferation, decreased cell viability, and induced apoptosis in amelanotic melanoma cells. The treatment caused changes in the cell cycle profile and decreased the intracellular level of reduced thiols and mitochondrial membrane potential. The exposure of A375 and C32 cells to minocycline and doxycycline triggered the release of cytochrome c and activated initiator and effector caspases. The anti-melanoma effect of analyzed drugs appeared to be related to the up-regulation of ERK1/2 and MITF. Moreover, it was noticed that minocycline and doxycycline increased the level of LC3A/B, an autophagy marker, in A375 cells. In summary, the study showed the pleiotropic anti-cancer action of minocycline and doxycycline against amelanotic melanoma cells. Considering all results, it could be concluded that doxycycline was a more potent drug than minocycline.
Subject(s)
Antineoplastic Agents/pharmacology , Doxycycline/pharmacology , Minocycline/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Biomarkers, Tumor , Caspases/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Melanoma, Amelanotic , Membrane Potential, Mitochondrial/drug effectsABSTRACT
BACKGROUND: The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified at the end of 2019. Despite growing understanding of SARS-CoV-2 in virology as well as many molecular studies, except remdesivir, no specific anti-SARS-CoV-2 drug has been officially approved. METHODS: In the present study molecular docking technique was applied to test binding affinity of ciprofloxacin and levofloxacin-two commercially available fluoroquinolones, to SARS-CoV-2 S-, E- and TMPRSS2 proteins, RNA-dependent RNA polymerase and papain-like protease (PLPRO). Chloroquine and dexamethasone were used as reference positive controls. RESULTS: When analyzing the molecular docking data it was noticed that ciprofloxacin and levofloxacin possess lower binding energy with S protein as compared to the references. In the case of TMPRSS2 protein and PLPRO protease the best docked ligand was levofloxacin and in the case of E proteins and RNA-dependent RNA polymerase the best docked ligands were levofloxacin and dexamethasone. Moreover, a molecular dynamics study also reveals that ciprofloxacin and levofloxacin form a stable complex with E- and TMPRSS2 proteins, RNA polymerase and papain-like protease (PLPRO). CONCLUSIONS: The revealed data indicate that ciprofloxacin and levofloxacin could interact and potentially inhibit crucial SARS-CoV-2 proteins.
Subject(s)
Anti-Infective Agents/chemistry , Ciprofloxacin/chemistry , Levofloxacin/chemistry , Viral Proteins/antagonists & inhibitors , Binding Sites , Computer Simulation , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2 , Serine Endopeptidases , COVID-19 Drug TreatmentABSTRACT
BACKGROUND: A large body of research has focused on fluoroquinolones. It was shown that this class of synthetic antibiotics could possess antiviral activity as a broad range of anti-infective activities. Based on these findings, we have undertaken in silico molecular docking study to demonstrate, for the first time, the principle for the potential evidence pointing ciprofloxacin and moxifloxacin ability to interact with COVID-19 Main Protease. METHODS: In silico molecular docking and molecular dynamics techniques were applied to assess the potential for ciprofloxacin and moxifloxacin interaction with COVID-19 Main Protease (Mpro). Chloroquine and nelfinavir were used as positive controls. RESULTS: We revealed that the tested antibiotics exert strong capacity for binding to COVID-19 Main Protease (Mpro). According to the results obtained from the GOLD docking program, ciprofloxacin and moxifloxacin bind to the protein active site more strongly than the native ligand. When comparing with positive controls, a detailed analysis of the ligand-protein interactions shows that the tested fluoroquinolones exert a greater number of protein interactions than chloroquine and nelfinavir. Moreover, lower binding energy values obtained from KDEEP program were stated when compared to nelfinavir. CONCLUSIONS: Here, we have demonstrated for the first time that ciprofloxacin and moxifloxacin may interact with COVID-19 Main Protease (Mpro).