ABSTRACT
Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defective (HRD) cancers rely on oxidative metabolism to supply NAD+ and ATP for poly(ADP-ribose) polymerase (PARP)-dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD+ concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient-derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors.
Subject(s)
Ovarian Neoplasms , Poly(ADP-ribose) Polymerase Inhibitors , Carcinoma, Ovarian Epithelial , Female , Homologous Recombination , Humans , Ovarian Neoplasms/drug therapy , Oxidative Stress , Poly(ADP-ribose) Polymerase Inhibitors/pharmacologyABSTRACT
In this work, the relationship between surface properties and drug release mechanism from binary composition tablets formed by quetiapine fumarate and biopolymer materials was studied. The biopolymers correspond to xanthan and tragacanth gums, which are projected as modified drug release systems. The surface studies were carried out by the sessile drop method, while the surface free energy (SFE) was determinate through Young-Dupree and OWRK semi-empirical models. On the other hand, the drug release studies were performed by in vitro dissolution tests, where the data were analyzed through kinetic models of zero order, first order, Higuchi, and Korsmeyer-Peppas. The results showed that depending on the type and the proportion of biopolymer, surface properties, and the drug release processes are significantly affected, wherein tragacanth gum present a usual erosion mechanism, while xanthan gum describes a swelling mechanism that controls the release of the drug.
Subject(s)
Biopolymers/chemistry , Plant Gums/chemistry , Polysaccharides, Bacterial/chemistry , Drug Carriers/chemistry , Drug Liberation , Quetiapine Fumarate/chemistryABSTRACT
La maca (lepidium meyenii Walp) es una alternativa para la nutrición de la población en los países en vías de desarrollo. Se utilizó la "maca sancochada" en la producción de pan y cachitos de manjar blanco con mantequilla, los cuales presentaron cualidades positivas de textura, excelente apariencia y, por consiguiente, buena aceptación. Las condiciones del proceso tecnológico para elaborar panes y pasteles fueron de 175°C temperatura de cocción y de 13 minutos tiempo de cocción. Se sustituyó el 12 por ciento de "maca sancochada" por harina de trigo. Mediante el control de calidad de constató la mayor retención de humedad que prolonga considerablemente la vida útil de ambos productos.
