PMID- 35931323 OWN - NLM STAT- MEDLINE DCOM- 20230501 LR - 20230513 IS - 2090-1224 (Electronic) IS - 2090-1232 (Print) IS - 2090-1224 (Linking) VI - 47 DP - 2023 May TI - Medical gas plasma augments bladder cancer cell toxicity in preclinical models and patient-derived tumor tissues. PG - 209-223 LID - S2090-1232(22)00166-7 [pii] LID - 10.1016/j.jare.2022.07.012 [doi] AB - INTRODUCTION: Medical gas plasma therapy has been successfully applied to several types of cancer in preclinical models. First palliative tumor patients suffering from advanced head and neck cancer benefited from this novel therapeutic modality. The gas plasma-induced biological effects of reactive oxygen and nitrogen species (ROS/RNS) generated in the plasma gas phase result in oxidation-induced lethal damage to tumor cells. OBJECTIVES: This study aimed to verify these anti-tumor effects of gas plasma exposure on urinary bladder cancer. METHODS: 2D cell culture models, 3D tumor spheroids, 3D vascularized tumors grown on the chicken chorion-allantois-membrane (CAM) in ovo, and patient-derived primary cancer tissue gas plasma-treated ex vivo were used. RESULTS: Gas plasma treatment led to oxidation, growth retardation, motility inhibition, and cell death in 2D and 3D tumor models. A marked decline in tumor growth was also observed in the tumors grown in ovo. In addition, results of gas plasma treatment on primary urothelial carcinoma tissues ex vivo highlighted the selective tumor-toxic effects as non-malignant tissue exposed to gas plasma was less affected. Whole-transcriptome gene expression analysis revealed downregulation of tumor-promoting fibroblast growth factor receptor 3 (FGFR3) accompanied by upregulation of apoptosis-inducing factor 2 (AIFm2), which plays a central role in caspase-independent cell death signaling. CONCLUSION: Gas plasma treatment induced cytotoxicity in patient-derived cancer tissue and slowed tumor growth in an organoid model of urinary bladder carcinoma, along with less severe effects in non-malignant tissues. Studies on the potential clinical benefits of this local and safe ROS therapy are awaited. CI - Copyright (c) 2023. Production and hosting by Elsevier B.V. FAU - Gelbrich, Nadine AU - Gelbrich N AD - Clinic and Policlinic for Urology, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany; ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany. FAU - Miebach, Lea AU - Miebach L AD - ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany; Clinic and Policlinic for General, Visceral, Thoracic, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany. FAU - Berner, Julia AU - Berner J AD - ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany; Clinic and Policlinic for Oral, Maxillofacial, and Plastic Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany. FAU - Freund, Eric AU - Freund E AD - ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany; Clinic and Policlinic for General, Visceral, Thoracic, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany. FAU - Saadati, Fariba AU - Saadati F AD - ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany; Clinic and Policlinic of Dermatology and Venerology, Rostock University Medical Center, Stempelstr. 13, 18057 Rostock, Germany. FAU - Schmidt, Anke AU - Schmidt A AD - ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany. FAU - Stope, Matthias AU - Stope M AD - Department of Gynecology and Gynecological Oncology, University Hospital Bonn, 53127 Bonn, Germany. FAU - Zimmermann, Uwe AU - Zimmermann U AD - Clinic and Policlinic for Urology, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany. FAU - Burchardt, Martin AU - Burchardt M AD - Clinic and Policlinic for Urology, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany. FAU - Bekeschus, Sander AU - Bekeschus S AD - ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany. Electronic address: sander.bekeschus@inp-greifswald.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220803 PL - Egypt TA - J Adv Res JT - Journal of advanced research JID - 101546952 RN - 0 (Reactive Oxygen Species) SB - IM MH - Humans MH - Reactive Oxygen Species/metabolism MH - *Carcinoma, Transitional Cell MH - *Urinary Bladder Neoplasms/drug therapy/genetics MH - Apoptosis MH - Cell Death PMC - PMC10173201 OTO - NOTNLM OT - Apoptosis OT - Cancer OT - Cold physical plasma OT - Oncology OT - Reactive oxygen and nitrogen species OT - Urology COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/08/06 06:00 MHDA- 2023/05/01 06:42 PMCR- 2022/08/03 CRDT- 2022/08/05 19:26 PHST- 2021/11/30 00:00 [received] PHST- 2022/06/08 00:00 [revised] PHST- 2022/07/29 00:00 [accepted] PHST- 2023/05/01 06:42 [medline] PHST- 2022/08/06 06:00 [pubmed] PHST- 2022/08/05 19:26 [entrez] PHST- 2022/08/03 00:00 [pmc-release] AID - S2090-1232(22)00166-7 [pii] AID - 10.1016/j.jare.2022.07.012 [doi] PST - ppublish SO - J Adv Res. 2023 May;47:209-223. doi: 10.1016/j.jare.2022.07.012. Epub 2022 Aug 3.