A cell-penetrating MARCKS mimetic selectively triggers cytolytic death in glioblastoma
Autor: | Zeel Patel, Hayley Widden, Hasan Alrefai, Anita B. Hjelmeland, Patricia H. Hicks, Jason M. Warram, Rune T. Pedersen, G. Yancey Gillespie, Christopher D. Willey, William J. Placzek, Nicholas Eustace, Joshua C. Anderson |
---|---|
Rok vydání: | 2020 |
Předmět: |
MARCKS
0301 basic medicine Cancer Research Programmed cell death patient-derived xenograft Cell Membrane Permeability Cell Apoptosis Article Mice 03 medical and health sciences 0302 clinical medicine Protein Domains Cell Line Tumor effector domain Genetics medicine Animals Humans Tissue Distribution Myristoylated Alanine-Rich C Kinase Substrate Cytotoxicity Molecular Biology peptide therapeutic Caspase Temozolomide biology Brain Neoplasms glioblastoma phosphoinositides Xenograft Model Antitumor Assays Peptide Fragments nervous system diseases Cytolysis 030104 developmental biology medicine.anatomical_structure Blood-Brain Barrier Drug Resistance Neoplasm Cell culture Astrocytes Caspases 030220 oncology & carcinogenesis Cancer research biology.protein Signal Transduction medicine.drug |
Zdroj: | Oncogene |
ISSN: | 1476-5594 0950-9232 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |