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Tumor treating fields increases membrane permeability in glioblastoma cells.

Al's Comment:

 This show a different possible method of action for Optune.

Posted on: 12/13/2018

  Cell Death Discov. 2018 Dec 5;4:113. doi: 10.1038/s41420-018-0130-x. eCollection 2018.
Tumor treating fields increases membrane permeability in glioblastoma cells.
Chang E#1, Patel CB#1,2, Pohling C1, Young C1, Song J1, Flores TA3, Zeng Y4, Joubert LM5, Arami H1, Natarajan A1, Sinclair R4, Gambhir SS1,4,6.
Author information:
1. 1Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Room E150, 318 Campus Drive West, Stanford, CA 94305 USA.
2. 2Division of Neuro-Oncology, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305 USA.
3. 3Department of Applied Physics, Stanford University School of Medicine, Stanford, CA 94305 USA.
4. 4Department of Materials Science & Engineering, Stanford University School of Medicine, Stanford, CA 94305 USA.
5. 5Electron Microscopy Unit, Stellenbosch University, Stellenbosch, South Africa.
6. 6Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305 USA.
#. Contributed equally
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.
PMCID: PMC6281619
PMID: 30534421
Conflict of interest statement


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