Tumor treating fields increases membrane permeability in glioblastoma cells
| Autor: | Caroline Young, Arutselvan Natarajan, Lydia-Marie Joubert, Thomas Flores, Edwin Chang, Christoph Pohling, Hamed Arami, Chirag B. Patel, Robert Sinclair, Jonathan Song, Yitian Zeng, Sanjiv S. Gambhir |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Membrane permeability medicine.medical_treatment Immunology lcsh:RC254-282 Article 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine medicine lcsh:QH573-671 Mitosis Chemotherapy Chemistry lcsh:Cytology Cell Biology medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Radiation therapy 030104 developmental biology Permeability (electromagnetism) 030220 oncology & carcinogenesis Cancer cell Cancer research Mitotic spindle assembly Glioblastoma |
| Zdroj: | Cell Death Discovery Cell Death Discovery, Vol 4, Iss 1, Pp 1-13 (2018) |
| ISSN: | 2058-7716 |
| Popis: | Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and chemotherapy) to treating glioblastoma; namely, tumor treating fields (TTFields). TTFields involves the delivery of alternating electric fields to the tumor but its mechanisms of action are not fully understood. Current theories involve TTFields disrupting mitosis due to interference with proper mitotic spindle assembly. We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics. Increased membrane permeability through the imposition of TTFields was shown by several approaches. For example, increased permeability was indicated through increased bioluminescence with TTFields exposure or with the increased binding and ingress of membrane-associating reagents such as Dextran-FITC or ethidium D or with the demonstration by scanning electron microscopy of augmented number and sizes of holes on the cellular membrane. Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24 h after cessation of alternating electric fields thus demonstrating that this phenomenom is reversible. Preliminary investigations showed that TTFields did not induce membrane holes in normal human fibroblasts thus suggesting that the phenomenom was specific to cancer cells. With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate tumor from normal tissue in glioblastoma patients. In addition, this mechanism helps to explain previous reports of additive and synergistic effects between TTFields and other chemotherapies. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies for these diseases. |
| Databáze: | OpenAIRE |
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