title: Potential applications for sigma receptor ligands in cancer diagnosis and therapy.
abstract: Sigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g., progesterone) which bind to both sigma receptor subpopulations. The sigma-1 receptor is a ligand-regulated molecular chaperone with various ion channels and G-protein-coupled membrane receptors as clients. The sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1). Although sigma receptors are over-expressed in tumors and up-regulated in rapidly dividing normal tissue, their ligands induce significant cell death only in tumor tissue. Sigma ligands may therefore be used to selectively eradicate tumors. Multiple mechanisms appear to underlie cell killing after administration of sigma ligands, and the signaling pathways are dependent both on the type of ligand and the type of tumor cell. Recent evidence suggests that the sigma-2 receptor is a potential tumor and serum biomarker for human lung cancer and an important target for inhibiting tumor invasion and cancer progression. Current radiochemical efforts are focused on the development of subtype-selective radioligands for positron emission tomography (PET) imaging. Right now, the mostpromising tracers are [18F]fluspidine and [18F]FTC-146 for sigma-1 receptors and [11C]RHM-1 and [18F]ISO-1 for the sigma-2 subtype. Nanoparticles coupled to sigma ligands have shown considerable potential for targeted delivery of antitumor drugs in animal models of cancer, but clinical studies exploring this strategy in cancer patients have not yet been reported. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Electronic address: a.van.waarde@umcg.nl.
authors.forename: Aren
authors.initials: A
authors.lastname: van Waarde
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Rybczynska
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Nisha K
authors.initials: NK
authors.lastname: Ramakrishnan
authors.affiliation: Tokyo Metropolitan Institute of Gerontology, Research Team for Neuroimaging, 35-2 Sakae-Cho, Itabashi-Ku, Tokyo 173-0015, Japan.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; University of Ghent, University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Rudi A J O
authors.initials: RA
authors.lastname: Dierckx
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D003287:Contrast Media / Q000737:chemistry / Q000627:therapeutic use; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D049268:Positron-Emission Tomography; D011379:Prognosis; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003287:Contrast Media; D005462:Fluorine Radioisotopes; D008024:Ligands; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C106107:sigma-2 receptor
keywords: Antitumor agents; Chemotherapy; Drug targeting; Positron emission tomography; Sigma-1 receptor; Sigma-2 receptor