Elsevier

Surgery

Volume 152, Issue 3, Supplement, September 2012, Pages S152-S156
Surgery

Therapeutic targeting of pancreatic cancer utilizing sigma-2 ligands

https://doi.org/10.1016/j.surg.2012.05.014Get rights and content

One major barrier in the development of pancreas cancer therapeutics is the selective delivery of the drugs to their cellular targets. We have previously developed several sigma-2 ligands and reported the discovery of a component of the receptor for these ligands. Several sigma-2 ligands have been shown to trigger apoptosis in pancreas cancer cells. More importantly, sigma-2 ligands are internalized rapidly by the cancer cells and are capable of delivering other small-molecule therapeutics. Here we review sigma-2 ligands and conjugates as a potential novel therapy suitable for investigation in patients with pancreatic cancer.

Section snippets

Sigma receptor background

Sigma receptors were identified initially as a subclass of opioid receptors; however, they had low binding affinity to the active stereoisomer of naloxone,11 a potent morphine antagonist, and were, thus, placed subsequently in their own family, consisting of sigma-1 and sigma-2 receptors. Because of the nature of the compounds that bind these receptors, early research focused primarily on neuropharmacology. Sigma-1 and -2 receptors were distinguished classically on the basis of their binding

PGRMC1/sigma-2 receptor in cancer

Identification and cloning of the sigma-2 receptor had remained elusive for many years despite more than a decade of investigation into this protein. Recently, PGRMC1 was identified as the putative sigma-2 receptor binding site by photoaffinity binding with a novel ligand, WC-21, as compared with the known PGRMC1 ligand AG-205.18, 19 This important finding set the stage for validation studies of overexpression of the PGRMC1/sigma-2 receptor and its function in pancreatic cancer, because PGRMC1

Specific uptake in pancreatic cancer cells

Sigma-2 receptor ligands are internalized preferentially by proliferating cancer cells, a characteristic that may limit systemic toxicity. Sigma-2 receptor ligands conjugated with the chromophore 4-chloro-7-nitrobenzo-2-oxa-1, 3-diazole (NBD) were first utilized to show subcellular uptake into proliferating breast cancer cells.10 This study was the first to reveal uptake of these compounds by receptor-mediated endocytosis. Further studies in pancreatic cancer cells with SW120, another

Evidence for sigma-2 ligands as therapy for pancreatic cancer

We first became interested in the use of sigma-2 receptors for pancreatic cancer when it was identified that agents selective for sigma-2 receptors are taken up specifically in tumor cells, as seen on positron emission tomography imaging,17, 48 and that they induce apoptosis.49 Because pancreatic cancer is poorly detected prior to advanced stages and has a poor overall response to chemotherapy, promising agents such as this deserve attention, and the rationale for evaluating selective sigma-2

Sigma-2 ligands augment apoptosis in pancreatic cancer

Drug resistance in pancreatic cancer occurs rapidly through both natural and acquired resistance. Resistance pathways to therapies such as gemcitabine are multiple and include adaptations to cell influx/efflux, nuclear translocation, nucleoside analog conversion by dUTPase, introduction into the DNA strand, DNA editing, cell checkpoint proteins, and further downstream apoptotic pathways.50, 51 Despite this, in our studies of cellular death by sigma-2 ligands in pancreatic cancer, we have

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