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Oncogene ; 39(46): 6961-6974, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33077834

RESUMO

Glioblastoma (GBM) is an aggressive malignancy with limited effectiveness of standard of care therapies including surgery, radiation, and temozolomide chemotherapy necessitating novel therapeutics. Unfortunately, GBMs also harbor several signaling alterations that protect them from traditional therapies that rely on apoptotic programmed cell death. Because almost all GBM tumors have dysregulated phosphoinositide signaling as part of that process, we hypothesized that peptide mimetics derived from the phospholipid binding domain of Myristoylated alanine-rich C-kinase substrate (MARCKS) could serve as a novel GBM therapeutic. Using molecularly classified patient-derived xenograft (PDX) lines, cultured in stem-cell conditions, we demonstrate that cell permeable MARCKS effector domain (ED) peptides potently target all GBM molecular classes while sparing normal human astrocytes. Cell death mechanistic testing revealed that these peptides produce rapid cytotoxicity in GBM that overcomes caspase inhibition. Moreover, we identify a GBM-selective cytolytic death mechanism involving plasma membrane targeting and intracellular calcium accumulation. Despite limited relative partitioning to the brain, tail-vein peptide injection revealed tumor targeting in intracranially implanted GBM PDX. These results indicate that MARCKS ED peptide therapeutics may overcome traditional GBM resistance mechanisms, supporting further development of similar agents.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Substrato Quinase C Rico em Alanina Miristoilada/genética , Fragmentos de Peptídeos/farmacologia , Animais , Astrócitos , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/patologia , Caspases/metabolismo , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/patologia , Humanos , Camundongos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/uso terapêutico , Domínios Proteicos/genética , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
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