Antiangiogenic Effect of (±)-Haloperidol Metabolite II Valproate Ester [(±)-MRJF22] in Human Microvascular Retinal Endothelial Cells

Olivieri, Melania; Amata, Emanuele; Vinciguerra, Shila; Fiorito, Jole; Giurdanella, Giovanni; Drago, Filippo; Caporarello, Nunzia; Prezzavento, Orazio; Arena, Elena; Salerno, Loredana; Rescifina, Antonio; Lupo, Gabriella; Anfuso, Carmelina Daniela; Marrazzo, Agostino

doi:10.1021/acs.jmedchem.6b01039

Cited by 38 publications

(44 citation statements)

References 44 publications

(73 reference statements)

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“…In particular, previous reports suggested that σ 1 may serve a chaperone molecule, possesses various oligomerization states and different intracellular localization compared to σ 2 receptor [ 36 , 37 ]. As far as concern cell migration, our data are consistent with previous reports showing that both sigma receptor ligands significantly reduces cell migration under various experimental conditions [ 28 , 38 , 39 ].…”

Section: Discussionsupporting

confidence: 92%

Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma

et al. 2017

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Uveal melanoma is the most common primary intraocular tumor in adults, with about 1200-1500 new cases occurring per year in the United States. Metastasis is a frequent occurrence in uveal melanoma, and outcomes are poor once distant spread occurs and no clinically significant chemotherapeutic protocol is so far available. The aim of the present study was to test the effect of various σ 1 and σ 2 receptor ligands as a possible pharmacological strategy for this rare tumor. Human uveal melanoma cells (92.1) were treated with various concentrations of different σ 2 ligands (haloperidol and haloperidol metabolite II) and σ 1 ligand ((+)-pentazocine) at various concentrations (1, 10 and 25 μM) and time points (0, 4 h, 8 h, 24 h and 48 h). Cell proliferation and migration were evaluated respectively by continuous cell monitoring by xCELLigence analysis, clonogenic assay and wound healing. Apoptosis and autophagy were also measured by cytofluorimetric and microscopy analysis. Our results showed that σ 2 receptor ligands significantly reduced cell proliferation whereas (+)-pentazocine exhibited opposite results. All tested ligands showed significant decrease in cell migration. Interestingly, both σ 1 and σ 2 receptor ligands showed significant increase of autophagy and apoptosis at all concentrations. Taken all together these results suggest that sigma receptors mediates opposite biological effects but they also share common pharmacological effect on apoptosis and autophagy in uveal melanoma. In conclusion, these data provide the first evidence that sigma receptors may represent a "druggable" target to develop new chemotherapic agent for uveal melanoma.

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Section: Discussionsupporting

confidence: 92%

Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma

et al. 2017

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“…The inhibitory effect of NO1 on SOCE was consistent with its effect impairing STIM1/Orai1 interaction, and probably, by promoting the dissociation of the complex between σ2R/TMEM97 and STIM1. As a result, NO1 administration to MDA-MB-231 cells evoked a reduction in cell proliferation and migration that agrees with previous investigations reported in the literature using other ligands of σ2R/TMEM97 [17,18,36,61]. In line with our observations, σ2R/TMEM97 was shown to be overexpressed in different cancer types, and even in patients with breast cancer [31,62,63].…”

Section: Discussionsupporting

confidence: 92%

“…This demonstrates that the σ2R/TMEM97 ligand, NO1, reduced cell migration; meanwhile, SM21 has the opposite effect in migration. Altogether, these results reveal a relevant functional role σ2R/TMEM97 on triple negative MDA-MB-231 breast cancer cells which agrees with previous results obtained in other cell models, as well as with different σ2R/TMEM97 agonists [35,36].…”

Section: σ2r/tmem97 Ligands Alter Tnbc Cell Proliferation and Migrationsupporting

confidence: 91%

NO1, a New Sigma 2 Receptor/TMEM97 Fluorescent Ligand, Downregulates SOCE and Promotes Apoptosis in the Triple Negative Breast Cancer Cell Lines

Cantonero

Camello

Abate

et al. 2020

Cancers

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(1) Background: The structure of the Sigma 2 receptor/TMEM97 (σ2RTMEM97) has recently been reported. (2, 3) Methods and results: We used genetic and biochemical approaches to identify the molecular mechanism downstream of σ2R/TMEM97. The novel σ2R/TMEM97 fluorescent ligand, NO1, reduced the proliferation and survival of the triple negative breast cancer cell lines (TNBC: MDA-MB-231 and MDA-MB-468 cell lines), due to NO1-induced apoptosis. Greater bioaccumulation and faster uptake of NO1 in MDA-MB-231 cells compared to MCF10A or MCF7 cell lines were also shown. Accordingly, elevated σ2R/TMEM97 expression was confirmed by Western blotting. In contrast to NO1, other σ2R/TMEM97 ligands, such as SM21 and PB28, enhanced MDA-MB-231 cell proliferation and migration. Store-operated calcium entry (SOCE) is crucial for different cancer hallmarks. Here, we show that NO1, but not other σ2R/TMEM97 ligands, reduced SOCE in MDA-MB-231 cells. Similarly, TMEM97 silencing in MDA-MB-231 cells also impaired SOCE. NO1 administration downregulated STIM1-Orai1 interaction, probably by impairing the positive regulatory effect of σ2R/TMEM97 on STIM1, as we were unable to detect interaction with Orai1. (4) Conclusion: σ2R/TMEM97 is a key protein for the survival of triple negative breast cancer cells by promoting SOCE; therefore, NO1 may become a good pharmacological tool to avoid their proliferation.

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“…The design and synthesis of bi-functional molecules is a field extensively studied [ 22 , 23 , 24 ] and has the aim to obtain an improvement of pharmacological effect compared to a two-drug administration, a reduction of dosage and side effects, and a better patient compliance.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Antioxidant Activity of Idebenone Derivative-Loaded Solid Lipid Nanoparticles

et al. 2017

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Idebenone (IDE) has been proposed for the treatment of neurodegenerative diseases involving mitochondria dysfunctions. Unfortunately, to date, IDE therapeutic treatments have not been as successful as expected. To improve IDE efficacy, in this work we describe a two-step approach: (1) synthesis of IDE ester derivatives by covalent linking IDE to other two antioxidants, trolox (IDETRL) and lipoic acid (IDELIP), to obtain a synergic effect; (2) loading of IDE, IDETRL, or IDELIP into solid lipid nanoparticles (SLN) to improve IDE and its esters’ water solubility while increasing and prolonging their antioxidant activity. IDE and its derivatives loaded SLN showed good physico-chemical and technological properties (spherical shape, mean particle sizes 23–25 nm, single peak in the size distribution, ζ potential values −1.76/−2.89 mV, and good stability at room temperature). In vitro antioxidant activity of these SLN was evaluated in comparison with free drugs by means of oxygen radical absorbance capacity (ORAC) test. IDETRL and IDELIP showed a greater antioxidant activity than IDE and encapsulation of IDE and its derivatives into SLN was able to prolong their antioxidant activity. These results suggest that loading IDETRL and IDELIP into SLN could be a useful strategy to improve IDE efficacy.

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Antiangiogenic Effect of (±)-Haloperidol Metabolite II Valproate Ester [(±)-MRJF22] in Human Microvascular Retinal Endothelial Cells

Cited by 38 publications

References 44 publications

Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma

Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma

NO1, a New Sigma 2 Receptor/TMEM97 Fluorescent Ligand, Downregulates SOCE and Promotes Apoptosis in the Triple Negative Breast Cancer Cell Lines

In Vitro Antioxidant Activity of Idebenone Derivative-Loaded Solid Lipid Nanoparticles

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