Understanding the role of calcium-mediated cell death in high-frequency irreversible electroporation

Wasson, Elisa M.; Alinezhadbalalami, Nastaran; Brock, Rebecca M.; Allen, Irving C.; Verbridge, Scott S.; Davalos, Rafael V.

doi:10.1016/j.bioelechem.2019.107369

Cited by 38 publications

(24 citation statements)

References 67 publications

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“…It was also shown that calcium electroporation cannot be effectively improved by the increase of calcium concentration above the threshold. The result is in agreement with the study 23 by Wasson et al During study design we speculated that the ultrashort pulses will result in lower electrotransfer of calcium compared to the conventional procedures, thus increase of the concentration will allow to compensate for the loss. Partially it was true and the difference in treatment efficiency between 2 mM and 5 mM calcium concentrations was more profound in sub-microsecond range compared to the ESOPE protocol (Refer to Fig.…”

Section: Discussionsupporting

confidence: 92%

Effects of extracellular medium conductivity on cell response in the context of sub-microsecond range calcium electroporation

Novickij

Rembiałkowska

Staigvila

et al. 2020

Sci Rep

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In the present study, we report the effects of extracellular medium conductivity on cell response in the context of sub-microsecond range (100 ns-900 ns) electroporation, calcium electroporation and cell size. The effects of 25 ns and microsecond range (100 μs) pulses were also covered. As a model, three different cancer cell lines of various size (C32, MCF-7/DX and MC38/0) were used and the results indicated different size-dependent susceptibility patterns to the treatment. The applied pulsed electric field (PEF) protocols revealed a significant decrease of cell viability when calcium electroporation was used. The dependence of calcium ion transport and finally the anticancer effect on the external medium conductivity was determined. It was shown that small differences in conductivity do not alter viability significantly, however, mostly affect the permeabilization. At the same, MC38/0 cell line was the least susceptible to calcium electroporation, while the C32 line the most. In all cases calcium electroporation was mostly dependent on the sensitivity of cells to electroporation and could not be effectively improved by the increase of CaCl 2 concentration from 2 mM to 5 mM. Lastly, sub-microsecond PEF stimulated aquaporin-4 and VDAC1/Porin immunoreactions in all treated cells lines, which indicated that cell water balance is affected, ions exchange is increased and release of mitochondrial products is occurrent.Electroporation is a phenomenon of pulsed electric field (PEF) initiated permeabilization of biological cell plasma membrane, which serves as a basepoint of many successful biomedical and biotechnological methodologies 1,2 . The mechanism of electroporation is dependent on cell polarization in PEF and transient charge accumulation on the cell membrane (known as transmembrane potential, TMP) 3,4 . When a threshold TMP is reached, the permeability of cell membrane is increased due to occurrence of transient hydrophilic pores 5 . It is believed that oxidative effects can be a separate mechanism responsible for the formation of pores during electroporation 6,7 , nevertheless, polarization of the cell is a primary trigger.Polarization of the cell depends on the parameters of PEF, however, also on the permittivity and conductivity of both the cells and the medium 3,8 . Therefore, the effects of extracellular medium conductivity on electroporation efficiency have been focused for decades 9-12 . Absolute majority of the scientific works focus the micro-millisecond range of pulses, while a new modality of shorter (nanosecond range) pulses was introduced and is gaining popularity 13,14 . Currently, there are two contributions 10,11 experimentally focusing the 12-102 ns range of pulses in the context of extracellular medium conductivity, while the sub-microsecond range is not covered in literature. Both papers are published by the same group Silve et al., however the upmost interest lies in the peculiar cell response to 12 ns pulses. According to these studies, the same DC3-F cell line indicated an opposite respons...

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Section: Discussionsupporting

confidence: 92%

Effects of extracellular medium conductivity on cell response in the context of sub-microsecond range calcium electroporation

Novickij

Rembiałkowska

Staigvila

et al. 2020

Sci Rep

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“…By modifying the pulsing parameters and the electrode configuration, HFE can be used to selectively open the BBB with spatiotemporal control of the therapeutic window. Ultimately, we foresee a treatment regimen wherein high-frequency pulses are used to ablate a tumor core, while the tumor margins are subjected to a combination of H-FIRE selective cell kill and HFE-BBBD-mediated exposure to precisely targeted chemical, biomolecular, or immunological agents centimeters from the solid mass [56]. HFE-induced BBBD alone is a promising development for the prospect of improved patient outcomes from those suffering from glioblastoma multiforme.…”

Section: Discussionmentioning

confidence: 99%

Temporal Characterization of Blood–Brain Barrier Disruption with High-Frequency Electroporation

Lorenzo

Thomas

Kani

et al. 2019

Cancers

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Treatment of intracranial disorders suffers from the inability to accumulate therapeutic drug concentrations due to protection from the blood–brain barrier (BBB). Electroporation-based therapies have demonstrated the capability of permeating the BBB, but knowledge of the longevity of BBB disruption (BBBD) is limited. In this study, we quantify the temporal, high-frequency electroporation (HFE)-mediated BBBD in an in vivo healthy rat brain model. 40 male Fisher rats underwent HFE treatment; two blunt tipped monopolar electrodes were advanced into the brain and 200 bursts of HFE were delivered at a voltage-to-distance ratio of 600 V/cm. BBBD was verified with contrast enhanced T1W MRI (gadopentetate dimeglumine) and pathologically (Evans blue dye) at time points of 1, 24, 48, 72, and 96 h after HFE. Contrast enhanced T1W scans demonstrated BBBD for 1 to 72 h after HFE but intact BBB at 96 h. Histologically, tissue damage was restricted to electrode insertion tracks. BBBD was induced with minimal muscle contractions and minimal cell death attributed to HFE. Numerical modeling indicated that brief BBBD was induced with low magnitude electric fields, and BBBD duration increased with field strength. These data suggest the spatiotemporal characteristics of HFE-mediated BBBD may be modulated with the locally applied electric field.

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“…Irreversible electroporation is a method where very high electric fields and a higher number of pulses are used, resulting in irreversible permeabilisation of the plasma membrane. This method has been studied in vitro, in vivo, and in patients for treatment of tumors, without addition of drugs [96][97][98]; however, recent studies show enhanced efficacy of irreversible electroporation when combined with calcium [99][100][101][102]. Calcium has been used to eliminate tumors when combined with another permeabilisation method, sonoporation [79].…”

Section: Cell Deathmentioning

confidence: 99%

“…In the clinical studies described in this review, the European Standard Operating Procedure on Electrochemotherapy (ESOPE) was followed; however, it has been shown that ESOPE-equivalent or comparable pulsing protocols can be used with calcium electroporation with similar effect [104,105,127]. Furthermore, calcium may also enhance the effect of treatments using irreversible electroporation [99][100][101][102], nanosecond pulse electric fields (nsPEF) [89,90] and sonoporation [79].…”

Section: Perspectivesmentioning

confidence: 99%

A Comprehensive Review of Calcium Electroporation—A Novel Cancer Treatment Modality

Frandsen

Vissing

Gehl

2020

Cancers

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Calcium electroporation is a potential novel anti-cancer treatment where high calcium concentrations are introduced into cells by electroporation, a method where short, high voltage pulses induce transient permeabilisation of the plasma membrane allowing passage of molecules into the cytosol. Calcium is a tightly regulated, ubiquitous second messenger involved in many cellular processes including cell death. Electroporation increases calcium uptake leading to acute and severe ATP depletion associated with cancer cell death. This comprehensive review describes published data about calcium electroporation applied in vitro, in vivo, and clinically from the first publication in 2012. Calcium electroporation has been shown to be a safe and efficient anti-cancer treatment in clinical studies with cutaneous metastases and recurrent head and neck cancer. Normal cells have been shown to be less affected by calcium electroporation than cancer cells and this difference might be partly induced by differences in membrane repair, expression of calcium transporters, and cellular structural changes. Interestingly, both clinical data and preclinical studies have indicated a systemic immune response induced by calcium electroporation. New cancer treatments are needed, and calcium electroporation represents an inexpensive and efficient treatment with few side effects, that could potentially be used worldwide and for different tumor types.

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Understanding the role of calcium-mediated cell death in high-frequency irreversible electroporation

Cited by 38 publications

References 67 publications

Effects of extracellular medium conductivity on cell response in the context of sub-microsecond range calcium electroporation

Effects of extracellular medium conductivity on cell response in the context of sub-microsecond range calcium electroporation

Temporal Characterization of Blood–Brain Barrier Disruption with High-Frequency Electroporation

A Comprehensive Review of Calcium Electroporation—A Novel Cancer Treatment Modality

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