title: Sigma-2 receptor agonist derivatives of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) induce cell death via mitochondrial superoxide production and caspase activation in pancreatic cancer.
abstract: Despite considerable efforts by scientific research, pancreatic cancer is the fourth leading cause of cancer related mortalities. Sigma-2 receptors, which are overexpressed in several tumors, represent promising targets for triggering selective pancreatic cancer cells death.
  
  
  
  We selected five differently structured high-affinity sigma-2 ligands (PB28, PB183, PB221, F281 and PB282) to study how they affect the viability of diverse pancreatic cancer cells (human cell lines BxPC3, AsPC1, Mia PaCa-2, and Panc1 and mouse Panc-02, KCKO and KP-02) and how this is reflected in vivo in a tumor model.
  
  
  
  Important cytotoxicity was shown by the compounds in the aggressive Panc02 cells, where cytotoxic activity was caspase-3 independent for four of the five compounds. However, both cytotoxicity and caspase-3 activation involved generation of Reactive Oxygen Species (ROS), which could be partially reverted by the lipid antioxidant α-tocopherol, but not by the hydrophilic N-acetylcysteine (NAC) indicating crucial differences in the intracellular sites exposed to oxidative stress induced by sigma-2 receptor ligands. Importantly, all the compounds strongly increased the production of mitochondrial superoxide radicals except for PB282. Despite a poor match between in vitro and the in vivo efficacy, daily treatment of C57BL/6 mice bearing Panc02 tumors resulted in promising effects with PB28 and PB282 which were similar compared to the current standard-of-care chemotherapeutic gemcitabine without showing signs of systemic toxicities.
  
  
  
  Overall, this study identified differential sensitivities of pancreatic cancer cells to structurally diverse sigma-2 receptor ligands. Of note, we identified the mitochondrial superoxide pathway as a previously unrecognized sigma-2 receptor-activated process, which encourages further studies on sigma-2 ligand-mediated cancer cell death for the targeted treatment of pancreatic tumors.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125, Bari, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Pati
authors.affiliation: Department of Surgery, Division of Hepatobiliary, Pancreatic, and Gastrointestinal Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Hornick
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125, Bari, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125, Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.affiliation: Department of Surgery, Division of Hepatobiliary, Pancreatic, and Gastrointestinal Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Spitzer
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125, Bari, Italy. carmen.abate@uniba.it.
authors.forename: Carmen
authors.initials: C
authors.lastname: Abate
authors.affiliation: Department of Surgery, Division of Hepatobiliary, Pancreatic, and Gastrointestinal Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: William
authors.initials: W
authors.lastname: Hawkins
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000077489:Piperazine; D010879:Piperazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists*; D013481:Superoxides / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D010879:Piperazines; D017382:Reactive Oxygen Species; D017480:Receptors, sigma; C106107:sigma-2 receptor; D013481:Superoxides; D000077489:Piperazine; D053148:Caspase 3
keywords: Caspase-3 activity; Mitochondrial superoxide; Pancreatic cancer; Reactive oxygen species; Sigma-2 receptor