1 research outputs found
Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors
New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that
the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent
ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this
combination led to durable and complete radiological and pathological response, with extended disease-free survival in
an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular
sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO)
and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration
into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor)
phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits
consideration for early evaluation in clinical trials.Fondo de Desarrollo Regional (FEDER). Programa Operativo Epiro 2014-2020National Strategic Reference Frameworks de la Unión Europea. NSRF 2014-2020-5033092Ministerio de Ciencia, Innovación y Universidades de España y fondos FEDER. RTI2018-098645-B-100Consejería de Economía y Conocimiento de la Junta de Andalucía y fondos FEDER. P18- RT-1372Universidad de Sevilla. US-126480