Sigma receptors in oncology: therapeutic and diagnostic applications of sigma ligands.
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).
Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. a.van.waarde@ngmb.umcg.nl
Aren
A
van Waarde
Anna A
AA
Rybczynska
Nisha
N
Ramakrishnan
Kiichi
K
Ishiwata
Philip H
PH
Elsinga
Rudi A J O
RA
Dierckx
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals; D017480:Receptors, sigma / Q000819:agonists / Q000378:metabolism* / Q000502:physiology*; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
D000970:Antineoplastic Agents; D008024:Ligands; D019275:Radiopharmaceuticals; D017480:Receptors, sigma