title: Resiniferatoxin induces death of bladder cancer cells associated with mitochondrial dysfunction and reduces tumor growth in a xenograft mouse model.
abstract: Bladder cancer (BC) is the fifth most common non-cutaneous malignancy and the most common form of BC in Western countries is transitional cell carcinoma. Resiniferatoxin (RTX) has found therapeutic usefulness for the treatment of bladder dysfunction but no data are available on its use as chemotherapeutic agent. The aim of this work is to evaluate the use of RTX as new anti-cancer drug in BC therapy. The effects of RTX on cell viability and cell death were evaluated on T24 and 5637 BC cell lines by MTT assay, cell cycle analysis, Annexin-V/PI staining and agarose gel electrophoresis of DNA. Mitochondrial depolarization and ROS production were assessed by flow cytometry. ADP/ATP ratio was measured by bioluminescence and caspase 3 cleavage by Western blot. For in vivo experiments, athymic nude mice, xenografted with T24 cells, received subcutaneous administrations of RTX. Tumor volumes were measured and immunohistochemistry was performed on tumor sections. Our data demonstrated that RTX influences cell cycle and induces necrotic cell death of BC cells by altering mitochondrial function, leading to depolarization, increase in ADP/ATP ratio and ROS production. Moreover, RTX is able to reduce tumor growth in a xenograft mouse model. Overall, we demonstrated that RTX induces necrotic cell death of BC cells and reduces tumor growth in a xenograft mouse model of BC, suggesting RTX as a new potential anti-cancer drug in BC chemotherapy.
authors.affiliation: School of Pharmacy, Experimental Medicine Section, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Farfariello
authors.affiliation: School of Pharmacy, Experimental Medicine Section, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Italy; Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Liberati
authors.affiliation: School of Pharmacy, Experimental Medicine Section, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Italy. Electronic address: beatricemorelli@hotmail.com.
authors.forename: Maria Beatrice
authors.initials: MB
authors.lastname: Morelli
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Tomassoni
authors.affiliation: Department of Medical Oncology, Polytechnic University of the Marche Region, Via Conca 71, 60126 Ancona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Santoni
authors.affiliation: School of Pharmacy, Experimental Medicine Section, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Nabissi
authors.affiliation: Department of Urology and Andrology, Uro-andrology and Tissue Engineering Laboratory, University of Perugia, Piazzale Menghini 1, 06129 Perugia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Giannantoni
authors.affiliation: School of Pharmacy, Experimental Medicine Section, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Santoni
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Amantini
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D017382:Reactive Oxygen Species; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C468130:iodoresiniferatoxin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; C024353:resiniferatoxin
keywords: Bladder cancer; Mitochondria; Necrosis; Resiniferatoxin; Xenograft