Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma

The prognosis of metastatic melanoma remains poor due to de novo or acquired resistance to immune and targeted therapies. Previous studies have shown that melanoma cells have perturbed metabolism and that cellular metabolic pathways represent potential therapeutic targets. To support the discovery of new drug candidates for melanoma, we examined 180 metabolic modulators, including phytochemicals and anti-diabetic compounds, for their growth-inhibitory activities against melanoma cells, alone and in combination with the BRAF inhibitor vemurafenib. Two positive hits from this screen, 4-methylumbelliferone (4-MU) and ursolic acid (UA), were subjected to validation and further characterization. Metabolic analysis showed that 4-MU affected cellular metabolism through inhibition of glycolysis and enhanced the effect of vemurafenib to reduce the growth of melanoma cells. In contrast, UA reduced mitochondrial respiration, accompanied by an increase in the glycolytic rate. This metabolic switch potentiated the growth-inhibitory effect of the pyruvate dehydrogenase kinase inhibitor dichloroacetate. Both drug combinations led to increased production of reactive oxygen species, suggesting the involvement of oxidative stress in the cellular response. These results support the potential use of metabolic modulators for combination therapies in cancer and may encourage preclinical validation and clinical testing of such treatment strategies in patients with metastatic melanoma

Probing the Chemistry of Adhesion between a 316L Substrate and Spin-on-Glass Coating

Hydrogen silsesquioxane ([HSiO_3/2]_<i>n</i>)-based “spin-on-glass” has been deposited on a 316L substrate and cured in Ar/H₂ gas atmosphere at 600 °C to form a continuous surface coating with submicrometer thickness. The coating functionality depends primarily on the adhesion to the substrate, which is largely affected by the chemical interaction at the interface between the coating and the substrate. We have investigated this interface by transmission electron microscopy and electron energy loss spectroscopy. The analysis identified a 5–10 nm thick interaction zone containing signals from O, Si, Cr, and Fe. Analysis of the energy loss near edge structure of the present elements identified predominantly signal from [SiO₄]^4– units together with Fe²⁺, Cr²⁺, and traces of Cr³⁺. High-resolution transmission electron microscopy images of the interface region confirm a crystalline Fe₂SiO₄ interfacial region. In agreement with computational thermodynamics, it is proposed that the spin-on-glass forms a chemically bonded silicate-rich interaction zone with the substrate. It was further suggested that this zone is composed of a corundum-type oxide at the substrate surface, followed by an olivine-structure intermediate phase and a spinel-type oxide in the outer regions of the interfacial zone