title: Conjugation to a SMAC mimetic potentiates sigma-2 ligand induced tumor cell death in ovarian cancer.
abstract: BACKGROUND
  Drug resistance is a significant problem in the treatment of ovarian cancer and can be caused by multiple mechanisms. Inhibition of apoptosis by the inhibitor of apoptosis proteins (IAPs) represents one such mechanism, and can be overcome by a mitochondrial protein called second mitochondria-derived activator of caspases (SMAC). We have previously shown that the ligands of sigma-2 receptors effectively induce tumor cell death. Additionally, because sigma-2 receptors are preferentially expressed in tumor cells, their ligands provide an effective mechanism for selective anti-cancer therapy.
  
  
  METHODS
  In the current work, we have improved upon the previously described sigma-2 ligand SW43 by conjugating it to a pro-apoptotic small molecule SMAC mimetic SW IV-52, thus generating the novel cancer therapeutic SW IV-134. The new cancer drug was tested for receptor selectivity and tumor cell killing activity in vitro and in vivo.
  
  
  RESULTS
  We have shown that SW IV-134 retained adequate sigma-2 receptor binding affinity in the context of the conjugate and potently induced cell death in ovarian cancer cells. The cell death induced by SW IV-134 was significantly greater than that observed with either SW43 or SW IV-52 alone and in combination. Furthermore, the intraperitoneal administration of SW IV-134 significantly reduced tumor burden and improved overall survival in a mouse xenograft model of ovarian cancer without causing significant adverse effects to normal tissues. Mechanistically, SW IV-134 induced degradation of cIAP-1 and cIAP-2 leading to NF-қB activation and TNFα-dependent cell death.
  
  
  CONCLUSIONS
  Our findings suggest that coupling sigma-2 ligands to SMAC peptidomimetics enhances their effectiveness while maintaining the cancer selectivity. This encouraging proof-of-principle preclinical study supports further development of tumor-targeted small peptide mimetics via ligands to the sigma-2 receptor for future clinical applications.
authors.forename: Gunjal
authors.initials: G
authors.lastname: Garg
authors.forename: Suwanna
authors.initials: S
authors.lastname: Vangveravong
authors.forename: Chenbo
authors.initials: C
authors.lastname: Zeng
authors.forename: Lynne
authors.initials: L
authors.lastname: Collins
authors.forename: Mary
authors.initials: M
authors.lastname: Hornick
authors.forename: Yassar
authors.initials: Y
authors.lastname: Hashim
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Powell
authors.forename: David G
authors.initials: DG
authors.lastname: Mutch
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.affiliation: Department of Surgery, Washington University School of Medicine, 660 S, Euclid Avenue, Campus Box 8109, St, Louis, MO 63110, USA. hawkinsw@wudosis.wustl.edu.
authors.forename: William G
authors.initials: WG
authors.lastname: Hawkins
authors.forename: Dirk
authors.initials: D
authors.lastname: Spitzer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D053961:Azabicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry; D008024:Ligands; D051379:Mice; D016513:Mice, SCID; D024101:Mitochondrial Proteins / Q000737:chemistry; D058990:Molecular Targeted Therapy / Q000379:methods; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D053961:Azabicyclo Compounds; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D024101:Mitochondrial Proteins; D009842:Oligopeptides; D017480:Receptors, sigma; C000591378:SW IV-134; C106107:sigma-2 receptor