title: The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer.
abstract: Pancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspases (SMAC) mimetics selectively to cancer cells employing the sigma-2 ligand/receptor interaction. The intrinsic death pathway agonist SMAC offers an excellent opportunity to counteract the anti-apoptotic activity of IAPs. SMAC mimetics have been used to sensitize several cancer types to chemotherapeutic agents but cancer-selective delivery and appropriate cellular localization have not yet been considered. In our current study, we tested the ability of the sigma-2/SMAC drug conjugate SW IV-134 to sensitize pancreatic cancer cells to gemcitabine.
  
  
  
  Using the targeted SMAC mimetic SW IV-134, inhibition of the X-linked inhibitor of apoptosis proteins (XIAP) was induced pharmacologically and its impact on cell viability was studied alone and in combination with gemcitabine. Pathway analyses were performed by assessing caspase activation, PARP cleavage and membrane blebbing (Annexin-V), key components of apoptotic cell death. Single-agent treatment regimens were compared with combination therapy in a preclinical mouse model of pancreatic cancer.
  
  
  
  The sensitizing effect of XIAP interference toward gemcitabine was confirmed via pharmacological intervention using our recently designed, targeted SMAC mimetic SW IV-134 across a wide range of commonly used pancreatic cancer cell lines at concentrations where the individual drugs showed only minimal activity. On a mechanistic level, we identified involvement of key components of the apoptosis machinery during cell death execution. Furthermore, combination therapy proved superior in decreasing the tumor burden and extending the lives of the animals in a preclinical mouse model of pancreatic cancer.
  
  
  
  We believe that the strong sensitizing capacity of SW IV-134 in combination with clinically relevant doses of gemcitabine represents a promising treatment option that warrants clinical evaluation.
authors.affiliation: Department of Surgery, Barnes-Jewish Hospital and Washington University School of Medicine St. Louis, 660 S. Euclid Ave, Box 8109, Saint Louis, MO, 63110, USA.|Present Address: Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8215-NT, Los Angeles, CA, 90048, USA.
authors.forename: Yassar M
authors.initials: YM
authors.lastname: Hashim
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Suwanna
authors.initials: S
authors.lastname: Vangveravong
authors.affiliation: Department of Surgery, Barnes-Jewish Hospital and Washington University School of Medicine St. Louis, 660 S. Euclid Ave, Box 8109, Saint Louis, MO, 63110, USA.
authors.forename: Narendra V
authors.initials: NV
authors.lastname: Sankpal
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Pratibha S
authors.initials: PS
authors.lastname: Binder
authors.affiliation: Department of Surgery, Barnes-Jewish Hospital and Washington University School of Medicine St. Louis, 660 S. Euclid Ave, Box 8109, Saint Louis, MO, 63110, USA.|Division of Public Health Sciences, Section of Oncologic Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Surgery, Barnes-Jewish Hospital and Washington University School of Medicine St. Louis, 660 S. Euclid Ave, Box 8109, Saint Louis, MO, 63110, USA.|Alvin J. Siteman Cancer Center, St. Louis, MO, USA.
authors.forename: S Peter
authors.initials: SP
authors.lastname: Goedegebuure
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.affiliation: Department of Surgery, Barnes-Jewish Hospital and Washington University School of Medicine St. Louis, 660 S. Euclid Ave, Box 8109, Saint Louis, MO, 63110, USA.|Alvin J. Siteman Cancer Center, St. Louis, MO, USA.
authors.forename: Dirk
authors.identifier: 0000-0003-3949-1815
authors.initials: D
authors.lastname: Spitzer
authors.affiliation: Department of Surgery, Barnes-Jewish Hospital and Washington University School of Medicine St. Louis, 660 S. Euclid Ave, Box 8109, Saint Louis, MO, 63110, USA. hawkinsw@wudosis.wustl.edu.|Alvin J. Siteman Cancer Center, St. Louis, MO, USA. hawkinsw@wudosis.wustl.edu.
authors.forename: William G
authors.initials: WG
authors.lastname: Hawkins
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage* / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D053961:Azabicyclo Compounds; D009842:Oligopeptides; C000591378:SW IV-134; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Combination therapy; Gemcitabine; Pancreatic cancer; Sigma-2 receptors; Sigma-2/SMAC drug conjugate