title: Use of multifunctional sigma-2 receptor ligand conjugates to trigger cancer-selective cell death signaling.
abstract: One major challenge in the development of cancer therapeutics is the selective delivery of the drugs to their cellular targets. In the case of pancreatic cancer, the σ-2 receptor is a unique target that triggers apoptosis upon activation. We have previously developed a series of chemical compounds with high affinity for the σ-2 receptor and showed rapid internalization of the ligands. One particular specific ligand of the σ-2 receptor, SV119, binds to pancreatic cancer cells and induces target cell death in vitro and in vivo. In this study, we characterized the ability of SV119 to selectively deliver other death-inducing cargos to augment the cytotoxic properties of SV119 itself. When conjugated to SV119, small molecules that are known to interfere with intracellular prosurvival pathways retained their ability to induce cell death, the efficiency of which was enhanced by the combinatorial effect of SV119 delivered with its small molecule cargo. Our findings define a simple platform technology to increase the tumor-selective delivery of small molecule therapeutics via σ-2 ligands, permitting chemotherapeutic synergy that can optimize efficacy and patient benefit.
authors: Department of Surgery, Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: Dirk
authors: D
authors: Spitzer
authors: Peter O
authors: PO
authors: Simon
authors: Hiroyuki
authors: H
authors: Kashiwagi
authors: Jinbin
authors: J
authors: Xu
authors: Chenbo
authors: C
authors: Zeng
authors: Suwanna
authors: S
authors: Vangveravong
authors: Dong
authors: D
authors: Zhou
authors: Katherine
authors: K
authors: Chang
authors: Jonathan E
authors: JE
authors: McDunn
authors: John R
authors: JR
authors: Hornick
authors: Peter
authors: P
authors: Goedegebuure
authors: Richard S
authors: RS
authors: Hotchkiss
authors: Robert H
authors: RH
authors: Mach
authors: William G
authors: WG
authors: Hawkins
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D005260:Female; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D017480:Receptors, sigma / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; D017480:Receptors, sigma; C106107:sigma-2 receptor