Sigma‐2 Receptor Ligands and Their Perspectives in Cancer Diagnosis and Therapy

Abstract

The sigma-2 receptor is highly expressed in various rapidly proliferating cancer cells and regarded as a cancer cell biomarker. Selective sigma-2 ligands have been shown to specifically label the tumor sites, induce cancer cells to undergo apoptosis, and inhibit tumor growth. Sigma-2 ligands are potentially useful as cancer diagnostics, anticancer therapeutics, or adjuvant anticancer treatment agents. However, both the cloning of this receptor and the identification of its endogenous ligand have not been successful, and the lack of structural information has severely hindered the understanding of its physiological roles, its signaling pathways, and the development of more selective sigma-2 ligands. Recent data have implicated that sigma-2 binding sites are within the lipid rafts and that PGRMC1 (progesterone receptor membrane component 1) complex and sigma-2 receptor may be coupled with EGFR (epidermal growth factor receptor), mTOR (mammalian target of rapamycin), caspases, and ion channels. Due to its promising applications in cancer management, there are rapidly increasing research efforts that are being directed into this field. This review article updates the current understanding of sigma-2 receptor and its potential physiological roles, applications, interaction with other effectors, with special focuses on the development of sigma-2 ligands, their chemical structures, pharmacological profiles, applications in imaging and anticancer therapy.

Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands

“…[29][30][31][32][33] Thus sigma-2 receptor may provide a new therapeutic target for the development of novel anti-cancer agents. 4,7,34 The mechanism of action of sigma-2 ligands is not yet entirely clear. But increasing evidence indicated that the apoptotic effects of sigma-2 ligands may involve multiple pathways that include the activation of caspases, inhibition of mTOR activities, disruption of ion channels, and induction of oxidative stress.…”

“…The sigma-2/PGRMC1 receptor is likely coupled to various cellular kinase pathways and thus the activation or inhibition of this receptor may regulate the cellular signal transduction and the fate of the cell. 4 Previously, we discovered that 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 9-azabicyclo[3.3.1]nonane derivatives had high affinities for sigma-2 receptor and low or no affinities for sigma-1 receptor. [35][36][37] These two classes of analogs are still among the most selective sigma-2 ligands reported to date.…”

“…[15][16][17][18] Therefore, PGRMC1 protein and sigma-2 receptor may likely be the same molecule or within the same bio-molecular complex. 4,9 Because of its high expression in proliferating cancer cells compared to the corresponding non-proliferating cancer cells and non-cancerous cells, sigma-2 receptor has drawn significant attention in the society of oncology. 17 Sigma-2 receptor has been regarded as an endogenous biomarker for cell proliferation.…”

“…Common elements of the various binging models of the sigma-2 receptor binding region include one hydrogen bond or electrostatic interaction site and at least two hydrophobic pockets. 4 It is generally accepted that the binding region of sigma-2 receptor is more hydrophobic than that of sigma-1 receptor.…”

“…2,3 Though the exact physiological functions are not clear for both receptors and the endogenous ligands for these receptors are still unknown, evidences indicate that sigma-1 receptor may play important roles in central nervous system involved in cognition and movement, while sigma-2 receptor may play important roles in regulation of cell survival, morphology, and differentiation. [4][5][6] Sigma-1 receptor has been cloned in various cells of both human and rodent origin with a molecular weight of 25.3 KDa. 7 Sigma-2 receptor has not yet been cloned.…”