Are Sigma Receptor Modulators a Weapon Against Multiple Sclerosis Disease?

Collina, Simona; Rui, Marta; Stotani, Silvia; Bignardi, Emanuele; Rossi, Daniela; Curti, Daniela; Giordanetto, Fabrizio; Malacrida, Alessio; Scuteri, A; Cavaletti, Guido

doi:10.4155/fmc-2017-0122

Cited by 16 publications

(10 citation statements)

References 157 publications

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“…Over the past few decades, SRs, have been widely associated with aging- and mitochondria-associated disorders, such as Parkinson’s and Alzheimer’s disease and cancer (Martin et al, 1976; Su, 1982; Vaupel, 1983; Quirion et al, 1987; Maurice and Lockhart, 1997; Skuza, 2003; Peviani et al, 2014; Collina et al, 2017a,b). Moreover, although no endogenous SRs ligands have ever been found, and the specific role played by this orphan receptor family in cell biology has yet to be clarified, SRs are considered as potential therapeutic targets for neurodegenerative diseases and cancer.…”

Section: Introductionmentioning

confidence: 99%

Anti-tumor Efficacy Assessment of the Sigma Receptor Pan Modulator RC-106. A Promising Therapeutic Tool for Pancreatic Cancer

et al. 2019

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Introduction: Pancreatic cancer (PC) is one of the most lethal tumor worldwide, with no prognosis improvement over the past 20-years. The silent progressive nature of this neoplasia hampers the early diagnosis, and the surgical resection of the tumor, thus chemotherapy remains the only available therapeutic option. Sigma receptors (SRs) are a class of receptors proposed as new cancer therapeutic targets due to their over-expression in tumor cells and their involvement in cancer biology. The main localization of these receptors strongly suggests their potential role in ER unfolded protein response (ER-UPR), a condition frequently occurring in several pathological settings, including cancer. Our group has recently identified RC-106 , a novel pan-SR modulator with good in vitro antiproliferative activities toward a panel of different cancer cell lines. In the present study, we investigated the in vitro properties and pharmacological profile of RC-106 in PC cell lines with the aim to identify a potential lead candidate for the treatment of this tumor. Methods: Pancreatic cancer cell lines Panc-1, Capan-1, and Capan-2 have been used in all experiments. S1R and TMEM97/S2R expression in PC cell lines was quantified by Real-Time qRT-PCR and Western Blot experiments. MTS assay was used to assess the antiproliferative effect of RC-106 . The apoptotic properties of RC-106 was evaluated by TUNEL and caspase activation assays. GRP78/BiP, ATF4, and CHOP was quantified to evaluate ER-UPR. Proteasome activity was investigated by a specific fluorescent-based assay. Scratch wound healing assay was used to asses RC-106 effect on cell migration. In addition, we delineated the in vivo pharmacokinetic profile and pancreas distribution of RC-106 in male CD-1 mice. Results: Panc-1, Capan-1, and Capan-2 express both SRs. RC-106 exerts an antiproliferative and pro-apoptotic effect in all examined cell lines. Cells exposure to RC-106 induces the increase of the expression of ER-UPR related proteins, and the inhibition of proteasome activity. Moreover, RC-106 is able to decrease PC cell lines motility. The in vivo results show that RC-106 is more concentrated in pancreas than plasma. Conclusion: Overall, our data evidenced that the pan-SR modulator RC-106 is an optimal candidate for in vivo studies in animal models of PC.

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Section: Introductionmentioning

confidence: 99%

Anti-tumor Efficacy Assessment of the Sigma Receptor Pan Modulator RC-106. A Promising Therapeutic Tool for Pancreatic Cancer

et al. 2019

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“…(Mishina et al, 2005; Hashimoto, 2009; Furuse and Hashimoto, 2010; Mavlyutov et al, 2015; Vavers et al, 2017; Tesei et al, 2018). Moreover, S1R agonists enhanced neuroplasticity, and may be effective in amyotrophic lateral sclerosis (Peviani et al, 2014) and multiple sclerosis (Collina et al, 2017b).…”

Section: Introductionmentioning

confidence: 99%

Docking, Interaction Fingerprint, and Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR) of Sigma1 Receptor Ligands, Analogs of the Neuroprotective Agent RC-33

et al. 2019

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The human Sigma1 receptor (S1R), which has been identified as a target with an important role in neuropsychological disorders, was first crystallized 3 years ago. Since S1R structure has no relation with another previous crystallized structures, the presence of the new crystal is an important hallmark for the design of agonists and antagonists against this important target. Some years ago, our group identified RC-33, a potent and selective S1R agonist, endowed with neuroprotective properties. In this work, drawing on new structural information, we studied the interactions of RC-33 and its analogs with the S1R binding site by using computational methods such as docking, interaction fingerprints, and receptor-guided alignment three dimensional quantitative structure–activity relationship (3D-QSAR). We found that RC-33 and its analogs adopted similar orientations within S1R binding site, with high similitude with orientations of the crystallized ligands; such information was used for identifying the residues involved in chemical interactions with ligands. Furthermore, the structure-activity relationship of the studied ligands was adequately described considering classical QSAR tests. All relevant aspects of the interactions between the studied compounds and S1R were covered here, through descriptions of orientations, binding interactions, and features that influence differential affinities. In this sense, the present results could be useful in the future design of novel S1R modulators.

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“…Over the past few decades, sigma receptors (SRs), including sigma 1 and sigma 2 receptor subtypes (S1R and S2R, respectively) have been widely associated with aging- and mitochondria-associated disorders, such as Parkinson’s and Alzheimer’s disease, multiple sclerosis and amyotrophic lateral sclerosis ( Martin et al, 1976 ; Su, 1982 ; Vaupel, 1983 ; Quirion et al, 1987 ; Maurice and Lockhart, 1997 ; Skuza, 2003 ; Peviani et al, 2014 ; Collina et al, 2017b ). Although no endogenous SR ligand has ever been found, progesterone has been identified as a potential candidate ( Su, 1991 ; Monnet et al, 1995 ).…”

Section: Introductionmentioning

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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Are Sigma Receptor Modulators a Weapon Against Multiple Sclerosis Disease?

Cited by 16 publications

References 157 publications

Anti-tumor Efficacy Assessment of the Sigma Receptor Pan Modulator RC-106. A Promising Therapeutic Tool for Pancreatic Cancer

Anti-tumor Efficacy Assessment of the Sigma Receptor Pan Modulator RC-106. A Promising Therapeutic Tool for Pancreatic Cancer

Docking, Interaction Fingerprint, and Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR) of Sigma1 Receptor Ligands, Analogs of the Neuroprotective Agent RC-33

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

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