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

Aren      van Waarde; Anna      A. Rybczynska; Nisha      K. Ramakrishnan; Kiichi      Ishiwata; Philip      H. Elsinga; Rudi      A.J.O. Dierckx

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), sphingolipidderived 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 upregulated 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 Ca2+, 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).

Keywords: Sigma ligands, tumor imaging, proliferation markers, anti-tumor therapy, chemosensitizers, P-glycoprotein, apoptosis, multidrug resistance, Sigma Receptors, Oncology, steroid hormones, progesterone, sphingolipid-, N,N-dimethyltryptamine, sigma-2 subtype, cy-tosolic Ca2+, ceramide, caspase dysfunction, P-glycoprotein-mediated drug resistance, cytostatics, antineoplastic agents, radiolabeled sigma ligands, single-photon emission computed tomography, positron emission tomography, multidrug, SKF 10,047, psychiatric disorders, endogenous ligand, veratradine, neuropeptide Y, peptide YY, pregnenolone, testosterone, D-erythro-sphingosine, sphingamine, 3H-pentazocine, Meningioma, Neuroblastoma SK-N-MC, SPECT, malignant melanoma xenografts, 99mTc-labeled sigma ligand, Pentazocine, blood-brain barrier, CNS, benzamide analogues