Use of multifunctional sigma-2 receptor ligand conjugates to trigger cancer-selective cell death signaling

Dirk Spitzer, Peter O. Simon, Hiroyuki Kashiwagi, Jinbin Xu, Chenbo Zeng, Suwanna Vangveravong, Dong Zhou, Katherine Chang, Jonathan E. McDunn, John R. Hornick, Peter Goedegebuure, Richard S. Hotchkiss, Robert H. Mach, William G. Hawkins

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish
Pages (from-to)201-209
Number of pages9
JournalCancer research
Volume72
Issue number1
DOIs
StatePublished - Jan 1 2012

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