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Review
.2018 Jul 10:9:711.
doi: 10.3389/fphar.2018.00711. eCollection 2018.

Sigma Receptors as Endoplasmic Reticulum Stress "Gatekeepers" and their Modulators as Emerging New Weapons in the Fight Against Cancer

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Review

Sigma Receptors as Endoplasmic Reticulum Stress "Gatekeepers" and their Modulators as Emerging New Weapons in the Fight Against Cancer

Anna Tesei et al. Front Pharmacol..

Abstract

Despite the interest aroused by sigma receptors (SRs) in the area of oncology, their role in tumor biology remains enigmatic. The predominant subcellular localization and main site of activity of SRs are the endoplasmic reticulum (ER). Current literature data, including recent findings on the sigma 2 receptor subtype (S2R) identity, suggest that SRs may play a role as ER stress gatekeepers. Although SR endogenous ligands are still unknown, a wide series of structurally unrelated compounds able to bind SRs have been identified. Currently, the identification of novel antiproliferative molecules acting via SR interaction is a challenging task for both academia and industry, as shown by the fact that novel anticancer drugs targeting SRs are in the preclinical-stage pipeline of pharmaceutical companies (i.e., Anavex Corp. and Accuronix). So far, no clinically available anticancer drugs targeting SRs are still available. The present review focuses literature advancements and provides a state-of-the-art overview of SRs, with emphasis on their involvement in cancer biology and on the role of SR modulators as anticancer agents. Findings from preclinical studies on novel anticancer drugs targeting SRs are presented in brief.

Keywords: anticancer targeted therapies; cancer cell proliferation; chaperone activity; endoplasmic reticulum stress; sigma receptors.

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Figures

FIGURE 1
FIGURE 1
Structures of(A) compounds co-crystallized with S1R;(B) SR ligands targeting other receptor classes;(C) putative SR endogenous ligands. The Ki values showed are consistent with those previously reported from literature for Dextromethorphan (Werling et al., 2007), Cocaine (Sharkey et al., 1988), Haloperidol (Cobos et al., 2007), Fluoxetine (Albayrak and Hashimoto, 2017), Quetiapine (Schotte et al., 1996), Clemastine (Gregori-Puigjané et al., 2012), and Chloroquine (Schmidt et al., 2016), respectively.
FIGURE 2
FIGURE 2
S1R ligands and their ability to change the oligomerization status of the receptor.
FIGURE 3
FIGURE 3
S1R acts as a chaperone protein to restore the correct folding of misfolded proteins.
FIGURE 4
FIGURE 4
The correlation between ER stress and cancer conditions. The role played by S1R and S2R in modulating ER stress.
FIGURE 5
FIGURE 5
S1R chaperone modulates the activity of numerous ion channels in cancer cells.
FIGURE 6
FIGURE 6
S1R and/or S2R modulators in preclinical or clinical trials.
See this image and copyright information in PMC

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References

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