title: A protective effect after clearance of orthotopic rat hepatocellular carcinoma by nanosecond pulsed electric fields.
abstract: Strategies for treating liver cancer using radiation, chemotherapy combinations and tyrosine kinase inhibitors targeting specific mutations have provided longer survival times, yet multiple treatments are often needed and recurrences with new malignant phenotypes are not uncommon. New and innovative treatments are undoubtedly needed to successfully treat liver cancer. Over the last decade, nanosecond pulsed electric fields (nsPEFs) have shown promise in pre-clinical studies; however, these have been limited to treatment of skin cancers or xenographs in mice. In the present report, an orthotopic hepatocellular carcinoma (HCC) model is established in rats using N1-S1 HCC cells. Data demonstrate a response rate of 80-90% when 1000 pulses are delivered with 100ns durations, electric field strengths of 50kV/cm and repetition rates of 1Hz. N1-S1 tumours treated with nsPEFs expressed significant number of cells with active caspase-3 and caspase-9, but not caspase-8, indicating an intrinsic apoptosis mechanism(s) as well as caspase-independent mechanisms. Most remarkably, rats with successfully ablated tumours failed to re-grow tumours when challenged with a second injection of N1-S1 cells when implanted in the same or different liver lobe that harboured the original tumour. Given this protective effect, infiltration of immune cells and the presence of granzyme B expressing cells within days of treatment suggest the possibility of an anti-tumour adaptive immune response. In conclusion, NsPEFs not only eliminate N1-S1 HCC tumours, but also may induce an immuno-protective effect that defends animals against recurrences of the same cancer.
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, 4211 Monarch Way, IRP2, Suite 300, Norfolk, VA 23508, USA; Ethicon, 4545 Creek Road, Cincinnati, OH 45242, USA.
authors.forename: Ru
authors.initials: R
authors.lastname: Chen
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, 4211 Monarch Way, IRP2, Suite 300, Norfolk, VA 23508, USA.
authors.forename: Nova M
authors.initials: NM
authors.lastname: Sain
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, 4211 Monarch Way, IRP2, Suite 300, Norfolk, VA 23508, USA.
authors.forename: K Tyler
authors.initials: KT
authors.lastname: Harlow
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, 4211 Monarch Way, IRP2, Suite 300, Norfolk, VA 23508, USA.
authors.forename: Yeong-Jer
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Ethicon, 4545 Creek Road, Cincinnati, OH 45242, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Shires
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, 4211 Monarch Way, IRP2, Suite 300, Norfolk, VA 23508, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Heller
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, 4211 Monarch Way, IRP2, Suite 300, Norfolk, VA 23508, USA. Electronic address: sbeebe@odu.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Beebe
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D065840:Protective Factors; D061208:Pulsed Radiofrequency Treatment / Q000379:methods*; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D053804:Granzymes; D053148:Caspase 3; D053453:Caspase 9
keywords: Absence of recurrence; Apoptosis; Cancer ablation; Electroporation; Granzyme B; Hepatocellular carcinoma; Immunity; Nanosecond pulsed electric fields; Non-thermal; Orthotopic model