Nanosecond pulsed electric fields abolish orthotopic rat hepatocellular carcinoma and bypass cancer mutations that evade apoptosis induction

3^rd World Congress on Cancer Science & Therapy

October 21-23, 2013 DoubleTree by Hilton Hotel San Francisco Airport, CA, USA

Stephen J. Beebe

ScientificTracks: J Cancer Sci Ther

Abstract :

Pulse power using nanosecond pulsed electric fields (nsPEFs) induced cell death in N1-S1 hepatocellular carcinoma (HCC) and Jurkat cells. To induce cell death, nsPEFs disrupted the mitochondria membrane potential (ΔΨm), which is independent of nanoporation and Ca 2+ -dependent, and induced an influx of calcium through nanopores in the plasma membrane. This follows the ?two hit? hypothesis where Ca 2+ overload and another pathological stimulus, dissipation of ΔΨm, must be present to cause loss of cell viability. Effects of nsPEFs on Jurkat cells with deficiencies in FADD or caspase-8 had no effects on cytochrome c release or cell death, indicating oncogenic mechanisms for apoptosis evasion through death receptor pathways are readily surmountable by nsPEFs. Using Jurkat cells with deficiencies in APAF-1, nsPEF-induced cell death was caspase-dependent at lower electric fields and caspase-independent at higher electric fields. Thus, nsPEFs induce multiple forms of intrinsic cell death. Unlike apoptosis induced by heat or genotoxic stress, over expression of Bcl-xl (8-fold) in Jurkat cells had no effect on nsPEF-induced dissipation of ΔΨm or viability. Thus, nsPEFs can bypass cancer mechanisms that protect mitochondrial function. In vivo nsPEFs ablated 90% of orthotopic HCC. Caspase-9 and caspase-3, but not caspase-8, were activated. For rats with N1-S1 HCC tumors that were eliminated, a challenge injection of the same HCC cells in the same or adjacent liver lobes failed to establish tumors, while age- matched naïve control rats readily grew tumors. These results suggest a host-mediated immune response after clearance of rat N1-S1 HCC with nsPEFs.

Biography :

Stephen J. Beebe received his Ph.D. at the Medical College of Ohio, now The University of Toledo College of Medicine. He was as post-doctoral fellow in the Howard Hughes Medical Institute in the Department of Molecular Physiology and Biophysics at Vanderbilt University. He then was a Fulbright Scholar in Oslo Norway before serving as an Assistant and Associate Professor at the Eastern Virginia Medical School in Departments of Physiological Sciences. He is now a Professor in the Frank Reidy Research Center for Bioelectrics at Old Dominion University, Norfolk Virginia. He is the author of over 100 peer reviewed published manuscripts.