Sigma Receptors in Oncology: Therapeutic and Diagnostic Applications of Sigma Ligands

Abstract

Sigma receptors (subtypes sigma-1 and sigma-2) are a unique class of binding sites expressed throughout the mammalian body. The endogenous ligand for these sites has not been identified, but steroid hormones (particularly progesterone), sphingolipid-derived amines and N,N-dimethyltryptamine can bind with fairly high affinity. Sigma receptors are overexpressed in rapidly proliferating cells, like cancer cells. Particularly the sigma-2 subtype is upregulate when cells divide and down regulated when they become quiescent. Sigma ligands, especially sigma-2 agonists, can inhibit proliferation and induce apoptosis by a mechanism involving changes in cytosolic Ca(2+), ceramide and sphingolipid levels. Tumor cells are much more sensitive to such treatment than cells from their tissue of origin. Sigma ligands induce apoptosis not only in drug-sensitive but also in drug-resistant cancer cells (e.g., cells with p53 mutations, or caspase dysfunction). Moreover, sigma ligands may abrogate P-glycoprotein-mediated drug resistance and at subtoxic doses, they can potentiate the effect of conventional cytostatics. Thus, sigma-2 agonists may be developed as antineoplastic agents for the treatment of drug-resistant tumors. A large number of radiolabeled sigma ligands has been prepared for SPECT (single-photon emission computed tomography) and PET (positron emission tomography) imaging. Such radiopharmaceuticals can be used for tumor detection, tumor staging, and evaluation of anti-tumor therapy. There is still a need for the development of ligands with (1) high selectivity for the sigma-2 subtype, (2) defined action (agonist or antagonist) and (3) optimal pharmacokinetics (low affinity for P-glycoprotein, high and specific tumor uptake, and rapid washout from non-target tissues).

Evaluation of 4′-[Methyl-11C]Thiothymidine in a Rodent Tumor and Inflammation Model

“…More specific information on the in vivo status of tumors may be acquired by the use of a radiopharmaceutical that is a proliferation marker, as proliferative activity is one of the key factors of malignant disease. Various approaches toward tumor-specific visualization have been described in the literature, including the use of radiolabeled amino acids (7), nucleosides (8)(9)(10), choline (11)(12)(13), and various receptor ligands (14)(15)(16)(17). Strictly speaking, only labeled nucleosides that are incorporated into DNA are true proliferation markers, but the tissue kinetics of radiopharmaceuticals tracing amino acid transport, membrane metabolism, enzyme activity, or receptor expression can be used as a surrogate marker of cellular proliferation if the activity of such processes is increased in rapidly dividing cells.…”

Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics

“…Several cancers, including pancreatic cancer, are sensitive to s-2 agonists, which inhibit proliferation and induce apoptosis by various mechanisms with little effect on normal tissues (Bem et al, 1991;Vilner et al, 1995). A possible mechanism for the action of s-2 agonists is by eliminating P-glycoprotein-mediated drug resistance and at subtoxic doses (van Waarde et al, 2010). A large number of radiolabeled s-2 ligands have been prepared for PET imaging (Abate et al, 2011;Dehdashti et al, 2013).…”

A non-replicating oncolytic vector as a novel therapeutic tool against cancer

“…The anti-CD19 antibody targets B cell lymphoma (48), and immunotoxin therapy has been developed (49). Sigma receptors are known to be enriched in cancers (50). Its ligand is used for cancer-targeting drug delivery by conjugating with liposomes (51).…”