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Published on: February 17, 2019
Microsecond Pulsed Electric Fields: An Effective Way to Selectively Target and Radiosensitize Medulloblastoma Cancer
Mirella Tanori1, Arianna Casciati1, Alessandro Zambotti1
1Division of Health Protection Technologies, Italian National Agency for Energy New Technologies and Sustainable Economic Development (ENEA), Rome, Italy.
Purpose:
Cancer stem cells constitute an endless reserve for the maintenance and progression of tumors, and they could be the reason for conventional therapy failure. New therapeutic strategies are necessary to specifically target them. In this context, microsecond pulsed electric fields have been selected to expose D283Med cells, a human medulloblastoma cell line resulted to be rich in cancer stem cells, and normal human astrocytes.
Methods:
We analyzed in vitro different endpoints at different times after microsecond pulsed electric field exposure, such as permeabilization, reactive oxygen species generation, cell viability/proliferation, cell cycle, and clonogenicity, as well as the expression of different genes involved in cell cycle, apoptosis, and senescence. Furthermore, the response of D283Med cells exposed to microsecond pulsed electric fields was validated in vivo in a heterotopic mouse xenograft model.
Results:
Our in vitro results showed that a specific pulse protocol (ie, 0.3 MV/m, 40 μs, 5 pulses) was able to induce irreversible membrane permeabilization and apoptosis exclusively in medulloblastoma cancer stem cells. In the surviving cells, reactive oxygen species generation was observed, together with a transitory G2/M cell-cycle arrest with a senescence-associated phenotype via the upregulation of GADD45A. In vivo results, after pulsed electric field exposure, demonstrated a significant tumor volume reduction with no eradication of tumor mass. In conjunction, we verified the efficacy of electric pulse pre-exposure followed by ionizing irradiation in vivo to enable complete inhibition of tumor growth.
Conclusions:
Our data reveal novel therapeutic options for the targeting of medulloblastoma cancer stem cells, indicating nonionizing pulsed electric field pre-exposure as an effective means to overcome the radioresistance of cancer stem cells.
Insights
Microsecond pulsed electric fields selectively target medulloblastoma cancer stem cells, reducing tumor volume. Pre-exposure to pulsed electric fields enhances the efficacy of radiation therapy, overcoming radioresistance.
Area of Science:
- Oncology
- Biophysics
- Cell Biology
Background:
- Cancer stem cells (CSCs) drive tumor progression and therapy resistance.
- Medulloblastoma is a pediatric brain tumor with a significant CSC component.
- Novel therapeutic strategies are needed to target CSCs effectively.
Purpose of the Study:
- To investigate the efficacy of microsecond pulsed electric fields (µsPEFs) against medulloblastoma CSCs.
- To evaluate the potential of µsPEFs to overcome CSC radioresistance.
Main Methods:
- In vitro exposure of D283Med cells (medulloblastoma CSCs) and normal astrocytes to µsPEFs.
- Assessment of cell viability, apoptosis, cell cycle, and gene expression.
- In vivo validation using a mouse xenograft model.
Main Results:
- A specific µsPEF protocol induced apoptosis in medulloblastoma CSCs without affecting normal cells.
- µsPEFs caused transient cell cycle arrest and senescence in surviving CSCs.
- In vivo, µsPEFs reduced tumor volume and, when combined with irradiation, led to complete tumor growth inhibition.
Conclusions:
- µsPEFs offer a targeted approach to eliminate medulloblastoma CSCs.
- Pre-exposure to µsPEFs can sensitize CSCs to ionizing radiation, overcoming radioresistance.
