Cellular apoptosis by nanosecond, high-intensity electric pulses: model evaluation of the pulsing threshold and extrinsic pathway
ABSTRACT A simple, bistable rate-equation based model is used to predict trends of cellular apoptosis following electric pulsing. The caspase-8 extrinsic pathway with inherent delays in its activation, cytochrome c release, and an internal feedback mechanism between caspase-3 and cleavage of Bid are incorporated. Results obtained were roughly in keeping with the experimental cell-survival data and include an electrical pulse-number threshold followed by a near-exponential fall-off. The extrinsic caspase-8 mechanism is predicted to be more sensitive than the mitochondrial intrinsic pathway for electric pulse induced cell apoptosis. Also, delays of about an hour are predicted for detectable molecular concentration increases following electrical pulsing. Finally, our results suggest that multi-needle electrode systems with adjustable field orientations would likely enhance apoptosis in the context of pulsed voltage-induced inactivation of tumor cells.
- SourceAvailable from: Caleb C. Roth
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- "While these effects have all been observed after nsPEF exposures                , the relationship between nsPEF stimulation and lipid signaling pathways has never been studied. "
ABSTRACT: Exposure to nanosecond pulsed electrical fields (nsPEFs) results in a myriad of observable effects in mammalian cells. While these effects are often attributed to the direct permeabilization of both the plasma and organelle membranes, the underlying mechanism(s) are not well understood. We hypothesize that nsPEF-induced membrane disturbance will initiate complex intracellular lipid signaling pathways, which ultimately lead to the observed multifarious effects. In this article, we show activation of one of these pathways - phosphoinositide signaling cascade. Here we demonstrate that nsPEF initiates phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) hydrolysis or depletion from the plasma membrane, accumulation of inositol-1,4,5-trisphosphate (IP3) in the cytoplasm and increase of diacylglycerol (DAG) on the inner surface of the plasma membrane. All of these events are initiated by a single 16.2kV/cm, 600ns pulse exposure. To further this claim, we show that the nsPEF-induced activation mirrors the response of M1-acetylcholine Gq/11-coupled metabotropic receptor (hM1). This demonstration of PIP2 hydrolysis by nsPEF exposure is an important step toward understanding the mechanisms underlying this unique stimulus for activation of lipid signaling pathways and is critical for determining the potential for nsPEFs to modulate mammalian cell functions.Bioelectrochemistry (Amsterdam, Netherlands) 05/2013; 94C:23-29. DOI:10.1016/j.bioelechem.2013.05.002 · 3.87 Impact Factor
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ABSTRACT: Two new cancer therapies apply bioelectric principles. These methods target tumor structures locally and function by applying millisecond electric fields to deliver plasmid DNA encoding cytokines using electrogene transfer (EGT) or by applying rapid rise-time nanosecond pulsed electric fields (nsPEFs). EGT has been used to locally deliver cytokines such as IL-12 to activate an immune response, resulting in bystander effects. NsPEFs locally induce apoptosis-like effects and affect vascular networks, both promoting tumor demise and restoration of normal vascular homeostasis. EGT with IL-12 is in melanoma clinical trials and nsPEFs are used in models with B16F10 melanoma in vitro and in mice. Applications of bioelectrics, using conventional electroporation and extensions of it, provide effective alternative therapies for melanoma.09/2010; 2(3):1731-1770. DOI:10.3390/cancers2031731
- Treatment of Metastatic Melanoma, 10/2011; , ISBN: 978-953-307-574-7