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

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

93 Citations (Scopus)

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 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 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).

Original languageEnglish
Pages (from-to)3519-3537
Number of pages19
JournalCurrent Pharmaceutical Design
Volume16
Issue number31
Publication statusPublished - 2010

Keywords

  • Sigma ligands
  • tumor imaging
  • proliferation markers
  • anti-tumor therapy
  • chemosensitizers
  • P-glycoprotein
  • apoptosis
  • multidrug resistance
  • POSITRON-EMISSION-TOMOGRAPHY
  • IN-VIVO EVALUATION
  • TUMOR-CELL-LINES
  • PHEOCHROMOCYTOMA PC12 CELLS
  • PRECLINICAL ACUTE TOXICITY
  • METABOLIC PET TRACERS
  • IMAGING BREAST-CANCER
  • HUMAN PROSTATE TUMORS
  • HIGH-AFFINITY BINDING
  • DOMAIN-LIKE-I

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