A novel heat shock protein inhibitor KU757 with efficacy in lenvatinib-resistant follicular thyroid cancer cells overcomes up-regulated glycolysis in drug-resistant cells in vitro.

BACKGROUND: Patients with advanced differentiated thyroid cancer develop resistance to lenvatinib treatment from metabolic dysregulation. Heat shock protein 90 is a molecular chaperone that plays an important role in glycolysis and metabolic pathway regulation. We hypothesize that lenvatinib-resistant differentiated thyroid cancer cells will have an increased dependency on glycolysis and that a novel C-terminal heat shock protein 90 inhibitor (KU757) can effectively treat lenvatinib-resistant cells by targeting glycolysis. METHODS: Inhibitory concentration 50 values of thyroid cancer cells were determined by CellTiter-Glo assay (Promega Corp, Madison, WI). Glycolysis was measured through Seahorse experiments. Reverse transcription-polymerase chain reaction and Western blot evaluated glycolytic pathway genes/proteins. Exosomes were isolated/validated by nanoparticle tracking analysis and Western blot. Differentially expressed long non-coding ribonucleic acids in exosomes and cells were evaluated using quantitative polymerase chain reaction. RESULTS: Extracellular acidification rate demonstrated >2-fold upregulation of glycolysis in lenvatinib-resistant cells versus parent cells and was downregulated after KU757 treatment. Lenvatinib-resistant cells showed increased expression of the glycolytic genes lactic acid dehydrogenase, pyruvate kinase M1/2, and hexokinase 2. KU757 treatment resulted in downregulation of these genes and proteins. Several long non-coding ribonucleic acids associated with glycolysis were significantly upregulated in WRO-lenvatinib-resistant cells and exosomes and downregulated after KU757 treatment. CONCLUSION: Lenvatinib resistance leads to increased glycolysis, and KU757 effectively treats lenvatinib-resistant cells and overcomes this increased glycolysis by targeting key glycolytic genes, proteins, and long non-coding ribonucleic acids.

Revisiting aminocoumarins for the treatment of melioidosis.

Burkholderia pseudomallei causes melioidosis, a potentially lethal disease that can establish both chronic and acute infections in humans. It is inherently recalcitrant to many antibiotics, there is a paucity of effective treatment options and there is no vaccine. In the present study, the efficacies of selected aminocoumarin compounds, DNA gyrase inhibitors that were discovered in the 1950s but are not in clinical use for the treatment of melioidosis were investigated. Clorobiocin and coumermycin were shown to be particularly effective in treating B. pseudomallei infection in vivo. A novel formulation with dl-tryptophan or l-tyrosine was shown to further enhance aminocoumarin potency in vivo. It was demonstrated that coumermycin has superior pharmacokinetic properties compared with novobiocin, and the coumermycin in l-tyrosine formulation can be used as an effective treatment for acute respiratory melioidosis in a murine model. Repurposing of existing approved antibiotics offers new resources in a challenging era of drug development and antimicrobial resistance.

7-Diethylamino-3(2'-benzoxazolyl)-coumarin is a novel microtubule inhibitor with antimitotic activity in multidrug resistant cancer cells.

Microtubules are a proven target for anticancer drug development because they are critical for mitotic spindle formation and the separation of chromosomes at mitosis. We here report a novel synthetic microtubule inhibitor 7-diethylamino-3(2'-benzoxazolyl)-coumarin (DBC). DBC causes destabilization of microtubules, leading to a cell cycle arrest at G(2)/M stage. In addition, human cancer cells are more sensitive to DBC (IC(50) 44.8-475.2nM) than human normal fibroblast (IC(50) 7.9microM), and DBC induces apoptotic cell death of cancer cells. Furthermore, our data show that DBC is a poor substrate of drug efflux pumps and effective against multidrug resistant (MDR) cancer cells. Taken together, these results describe a novel pharmacological property of DBC as a microtubule inhibitor, which may make it an attractive new agent for treatment of MDR cancer.