Sigma Receptor (σR) Ligands with Antiproliferative and Anticancer Activity

Georgiadis, Markos‐Orestis; Karoutzou, Olga; Foscolos, Angeliki‐Sofia; Papanastasiou, Ioannis

doi:10.3390/molecules22091408

Cited by 39 publications

(26 citation statements)

References 122 publications

(175 reference statements)

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“…Interest in SRs has increased substantially over the years, as documented by the high number of research papers and reviews published, patents registered ( Bowen, 2000 ; Bourrie et al, 2004 ; Collina et al, 2013 , 2017a ; Georgiadis et al, 2017 ), as well as by the presence of SR modulators in the pipelines of pharmaceutical industries 1 , 2 , 3 ( Accuronix Therapeutics, 2018 ; Anavex Pipeline, 2018 ; Context Therapeutics, 2018 ).…”

Section: Er Stress and Srsmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Er Stress and Srsmentioning

confidence: 99%

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

et al. 2018

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“…The overexpression of the sigma-2 receptor in various types of cancers, including breast carcinoma, melanoma, prostate cancer, pancreatic tumors, and brain tumors [14, 27], has caused sigma-2 receptor ligands to be potential drugs for monitoring and treating cancer [18, 28]. Previous studies have shown that several derivatives of the high affinity sigma-2 receptor agonist PB28 (1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine), have the ability to inhibit the growth of pancreatic cancer [20, 25] and the neuroblastoma SK-N-SH cell line [19].…”

Section: Resultsmentioning

confidence: 99%

“…The overexpression of the sigma-2 receptor by cancer cells has been reported in several types of tumors, including breast, pancreatic, and brain tumors [14, 18]. This has led to the discovery of sigma-2 receptor ligands as potential compounds in cancer diagnosis and therapy [28]. Among the many sigma-2 receptor ligands, serial analogues of PB28 have been developed and their potential for cancer imaging and therapy, addressed [15, 16, 18–20, 24, 25, 30].…”

Section: Discussionmentioning

confidence: 99%

Sigma-2 receptor/TMEM97 agonist PB221 as an alternative drug for brain tumor

Liu

Wang

et al. 2019

BMC Cancer

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Background There are limited effective drugs that can reach the brain to target brain tumors, in particular glioblastoma, which is one of the most difficult cancers to be cured from. Because the overexpression of the sigma-2 receptor is frequently reported in glioma clinical samples and associated with poor prognosis and malignancy, we herein studied the anti-tumor effect of the sigma-2 receptor agonist PB221 (4-cyclohexyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperidine) on an anaplastic astrocytoma tumor model based on previous encouraging results in pancreatic cancer and neuroblastoma SK-N-SH cells. Methods The expression of the sigma-2 receptor, transmembrane protein 97 (TMEM97), in ALTS1C1 and UN-KC6141 cell lines was measured by RT-PCR and quantitative RT-PCR. The binding of sigma-2 receptor fluorescent ligands PB385 (6-[5-[3-(4-cyclohexylpiperazin-1-yl)propyl]-5,6,7,8-tetrahydronaphthalen-5-yloxy]-N-(7-nitro-2,1,3-benzoxadiazol-4-yl)hexanamine) and NO1 (2-{6-[2-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H )-yl)propyl)-3,4-dihydroisoquinolin-1(2 H )-one-5-yloxy]hexyl}-5-(dimethylamino)isoindoline-1,3-dione) was examined by flow cytometry and the fluorescent plate reader. The antitumor activity of PB221 was initially examined in the murine brain tumor cell line ALTS1C1 and then in the murine pancreatic cell line UN-KC6141. The potential therapeutic efficacy of PB221 for murine brain tumors was examined by in vitro migration and invasion assays and in vivo ectopic and orthotopic ALTS1C1 tumor models. Results: The IC 50 of PB221 for ALTS1C1 and UN-KC6141 cell lines was 10.61 ± 0.96 and 13.13 ± 1.15 μM, respectively. A low dose of PB221 (1 μM) significantly repressed the migration and invasion of ALTS1C1 cells, and a high dose of PB221 (20 μM) resulted in the apoptotic cell death of ALTS1C1 cells. These effects were reduced by the lipid antioxidant α-tocopherol, but not by the hydrophilic N-acetylcysteine, suggesting mitochondrial oxidative stress is involved. The in vivo study revealed that PB221 effectively retarded tumor growth to 36% of the control tumor volume in the ectopic intramuscular tumor model and increased the overall survival time by 20% (from 26 to 31 days) in the orthotopic intracerebral tumor model. Conclusions This study demonstrates that the sigma-2 receptor agonist PB221 has the potential to be an alternative chemotherapeutic drug for brain tumors with comparable side effects as the current standard-of-care drug, temozolomide. Electronic supplementary material The online version of this article (10.1186/s12885-019-5700-7) contains supplementary material, which is available to authorized users.

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“…Although clinical trials failed to show satisfactory efficacy in the treatment of psychiatric disorders, the drug was well-tolerated and non-toxic in humans. The lack of side-effects; the strong and immediate effects of siramesine on lysosome acidification, trafficking, and autophagy activation; and its predicted capacity to target the nsp16/nsp10 interface might open new avenues for the therapeutic consideration of this lysosomotropic agent and/or closely related sigma-2-receptor-targeting drugs [66,[90][91][92].…”

Section: Siramesinementioning

confidence: 99%

Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA

Encinar

Menendez

2020

Viruses

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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 respiratory disease pandemic utilizes unique 2′-O-methyltransferase (2′-O-MTase) capping machinery to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the 2′-O-MTase is unusual in its requirement for a stimulatory subunit (nsp10) to catalyze the ribose 2′-O-methylation of the viral RNA cap. Here we provide a computational basis for drug repositioning or de novo drug development based on three differential traits of the intermolecular interactions of the SARS-CoV-2-specific nsp16/nsp10 heterodimer, namely: (1) the S-adenosyl-l-methionine-binding pocket of nsp16, (2) the unique “activating surface” between nsp16 and nsp10, and (3) the RNA-binding groove of nsp16. We employed ≈9000 U.S. Food and Drug Administration (FDA)-approved investigational and experimental drugs from the DrugBank repository for docking virtual screening. After molecular dynamics calculations of the stability of the binding modes of high-scoring nsp16/nsp10–drug complexes, we considered their pharmacological overlapping with functional modules of the virus–host interactome that is relevant to the viral lifecycle, and to the clinical features of COVID-19. Some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine, bemcentinib, itacitinib, or phthalocyanine) might be suitable for repurposing to pharmacologically reactivate innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 2′-O-methylation.

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Sigma Receptor (σR) Ligands with Antiproliferative and Anticancer Activity

Cited by 39 publications

References 122 publications

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

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

Sigma-2 receptor/TMEM97 agonist PB221 as an alternative drug for brain tumor

Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA

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