bims-stacyt Biomed news on
Starvation pathways leading to cytokine regulation
Issue of 2018‒03‒11
two papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Cell Mol Life Sci. 2018 Mar 03. doi: 10.1007/s00018-018-2784-1
    Abstract:  In the last decade, metabolism has been recognized as a major determinant of immunological processes. During an inflammatory response, macrophages undergo striking changes in their metabolism. This metabolic reprogramming is governed by a complex interplay between metabolic enzymes and metabolites of different pathways and represents the basis for proper macrophage function. It is now evident that these changes go far beyond the well-known Warburg effect and the perturbation of metabolic targets is being investigated as a means to treat infections and auto-immune diseases. In the present review, we will aim to provide an overview of the metabolic responses during proinflammatory macrophage activation and show how these changes modulate the immune response.
    Keywords:  Infection; Inflammation; Itaconate; Macrophage; Metabolism; Succinate
  2. J Control Release. 2018 Feb 28. doi: 10.1016/j.jconrel.2018.02.034276
    Abstract:  We report for the first time on a nano-drug delivery system based on glucosylated polymeric nanomicelles to actively target the second-generation tyrosine kinase inhibitor dasatinib to glucose-avid pediatric sarcomas by the intravenous route. After a comprehensive physicochemical characterization that confirmed the substantially lower critical micellar concentration and the higher encapsulation capacity of the glucosylated amphiphilic nanocarrier with respect to the pristine counterpart, we showed a 9-fold decrease of the half maximal inhibitory concentration of dasatinib in a rhabdomyosarcoma cell line, Rh30, in vitro. In immunodeficient mice bearing the glucose-avid Rh30 xenograft, we revealed that the glucosylated polymeric nanomicelles increased the delivery of dasatinib in the tumor parenchyma. Conversely, the exposure of off-target tissues and organs to the drug was substantially reduced. Upon experimental confirmation that most patient-derived xenograft (PDX) models of pediatric sarcomas overexpress glucose transporter 1 (GLUT-1), we demonstrated the selective accumulation of dasatinib in a patient-derived rhabdomyosarcoma model in vivo. Conversely, the reference dose administered by the oral route was not tumor-selective. Finally, the improved nanocarrier pharmacokinetics led to prolonged median survival of mice bearing a clinically relevant PDX model of alveolar rhabdomyosarcoma from 19 days for the untreated controls to 27 days for the targeted therapy.
    Keywords:  Dasatinib; Glucose-avid pediatric sarcomas; Glucosylated polymeric nanomicelles; Patient-derived xenografts; Rhabdomyosarcoma; Tumor targeting