Etoposide (ETS), topoisomerase-II inhibitor, is a first-line anticancer therapeutics used in diverse cancer types. However, the therapeutic potential of this molecule has mainly impeded due to its detrimental toxicity profile, unfavorable rejection by the cancer cells due to P-glycoprotein (P-gp) efflux activity, and rapid hepatic clearance through extensive metabolism by Cytochrome-P450. To increase the therapeutic potency without significant adverse effects, the implication of novel ETS-nanoformulation strategies have recommended mainly. Nanomedicine based nanoformulation approaches based on nanoparticles (NPs), dendrimers, carbon-nanotubes (CNTs), liposomes, polymeric micelles, emulsions, dendrimers, solid-lipid NPs, etc offers immense potential opportunities to improve the therapeutic potential of pharmaceutically problematic drugs. This review provides an up-to-date argument on the work done in the field of nanomedicine to resolve pharmacokinetic and pharmacodynamic issues associated with ETS. The review also expounds the progress in regards to the regulatory, patenting and clinical trials related to the innovative formulation aspects of ETS.
Matched MeSH terms: Topoisomerase II Inhibitors/metabolism; Topoisomerase II Inhibitors/chemistry*
The emergence of antimicrobial resistance due to the widespread and inappropriate use of antibiotics has now become the global health challenge. Flavonoids have long been reported to be a potent antimicrobial agent against a wide range of pathogenic microorganisms in vitro. Therefore, new antibiotics development based on flavonoid structures could be a potential strategy to fight against antibiotic-resistant infections. This research aims to screen the potency of flavonoids of the genus Erythrina as an inhibitor of bacterial ATPase DNA gyrase B. From the 378 flavonoids being screened, 49 flavonoids show potential as an inhibitor of ATPase DNA gyrase B due to their lower binding affinity compared to the inhibitor and ATP. Further screening for their toxicity, we identified 6 flavonoids from these 49 flavonoids, which are predicted to have low toxicity. Among these flavonoids, erystagallin B (334) is predicted to have the best pharmacokinetic properties, and therefore, could be further developed as new antibacterial agent.
Matched MeSH terms: Topoisomerase II Inhibitors/pharmacology; Topoisomerase II Inhibitors/chemistry
Conjunctival necrosis is a rare complication following periocular/intraocular triamcinolone acetonide injection and has been reported extensively in adults. We describe a child who developed conjunctival necrosis following subconjunctival injection of triamcinolone acetonide for severe chronic anterior uveitis. Prompt diagnosis and management of this uncommon condition is vital.
Matched MeSH terms: Topoisomerase II Inhibitors/therapeutic use
Chronic myeloid leukaemia (CML) is a form of leukaemia derived from the myeloid cell lineage. Imatinib mesylate, the breakpoint cluster region-abelson murine leukeamia kinase inhibitor, is a specific reagent used in the clinical treatment of CML. The DNA topoisomerase II inhibitor, etoposide, is also employed as a therapeutic, though it is used to a lesser extent. The present study aims to evaluate the effects of CML-targeted therapy, utilising imatinib mesylate and etoposide in the in vitro treatment of parental sensitive and adriamycin-resistant CML in the K562 and K562/ADM cell lines, respectively. Preliminary work involved the screening of multidrug resistant (MDR) gene expression, including MDR1, MRP1 and B-cell lymphoma 2 (BCL-2) at the mRNA levels. The sensitive and resistant CML cell lines expressed the MRP1 gene, though the sensitive K562 cells expressed low, almost undetectable levels of MDR1 and BCL-2 genes relative to the K562/ADM cells. Following treatment with imatinib mesylate or etoposide, the IC50 for imatinib mesylate did not differ between the sensitive and resistant cell lines (0.492±0.024 and 0.378±0.029, respectively), indicating that imatinib mesylate is effective in the treatment of CML regardless of cell chemosensitivity. However, the IC50 for etoposide in sensitive K562 cells was markedly lower than that of K562/ADM cells (50.6±16.5 and 194±8.46 µM, respectively), suggesting that the higher expression levels of MDR1 and/or BCL-2 mRNA in resistant cells may be partially responsible for this effect. This is supported by terminal deoxynucleotidyl transferase dUTP nick-end labeling data, whereby a higher percentage of apoptotic cells were found in the sensitive and resistant K562 cells treated with imatinib mesylate (29.3±0.2 and 31.9±16.7%, respectively), whereas etoposide caused significant apoptosis of sensitive K562 cells (18.3±8.35%) relative to K562/ADM cells (5.17±3.3%). In addition, the MDR genes in K562/ADM cells were knocked down by short interfering RNAs. The percentage knockdowns were 15.4% for MRP1, 17.8% for MDR and 30.7% for BCL-2, which resulted in a non-significant difference in the half maximal inhibitory concentration value of K562/ADM cells relative to K562 cells upon treatment with etoposide.
Glucocorticoids (GCs) and topoisomerase II inhibitors are used to treat acute lymphoblastic leukaemia (ALL) as they induce death in lymphoid cells through the glucocorticoid receptor (GR) and p53 respectively. Mechanisms underlying ALL cell death and the contribution of the bone marrow microenvironment to drug response/resistance remain unclear. The role of the microenvironment and the identification of chemoresistance determinants were studied by transcriptomic analysis in ALL cells treated with Dexamethasone (Dex), and Etoposide (Etop) grown in the presence or absence of bone marrow conditioned media (CM). The necroptotic (RIPK1) and the apoptotic (caspase-8/3) markers were downregulated by CM, whereas the inhibitory effects of chemotherapy on the autophagy marker Beclin-1 (BECN1) were reduced suggesting CM exerts cytoprotective effects. GCs upregulated the RIPK1 ubiquitinating factor BIRC3 (cIAP2), in GC-sensitive (CEM-C7-14) but not in resistant (CEM-C1-15) cells. In addition, CM selectively affected GR phosphorylation in a site and cell-specific manner. GR is recruited to RIPK1, BECN1 and BIRC3 promoters in the sensitive but not in the resistant cells with phosphorylated GR forms being generally less recruited in the presence of hormone. FACS analysis and caspase-8 assays demonstrated that CM promoted a pro-survival trend. High molecular weight proteins reacting with the RIPK1 antibody were modified upon incubation with the BIRC3 inhibitor AT406 in CEM-C7-14 cells suggesting that they represent ubiquitinated forms of RIPK1. Our data suggest that there is a correlation between microenvironment-induced ALL proliferation and altered response to chemotherapy.
Matched MeSH terms: Topoisomerase II Inhibitors/pharmacology*