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

Abstract

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.

Sigma-2 Receptor—A Potential Target for Cancer/Alzheimer’s Disease Treatment via Its Regulation of Cholesterol Homeostasis

“…In addition, a high dose of PB221 induced cell death of ALTS1C1 cells; these effects all involved mitochondrial oxidative stress. Consistent with this notion, PB221 effectively retarded tumor growth in tumor models [19]. Using CRISPR/Cas9 technology to remove TMEM97 in HeLa cells, one recent study has found that TMEM97 does not mediate cytotoxicity induced by the sigma-2 ligand [25].…”

PB28, the Sigma-1 and Sigma-2 Receptors Modulator With Potent Anti–SARS-CoV-2 Activity: A Review About Its Pharmacological Properties and Structure Affinity Relationships

“…This green emitter compound was successfully used in flow cytometry and confocal microscopy analyses to visualize sigma-2 receptors ( Abate et al, 2014 ; Niso et al, 2015 ; Pati et al, 2017a ; Pati et al, 2018a ). Importantly, using this same strategy, also sigma-2 versus sigma-1 (and vice versa), selective ligands were obtained starting from the diverse pharmacophores identified through the years, such that fluorescent tracers to selectively study one sigma subtype at a time are also available ( Niso et al, 2015 ; Abate et al, 2016 ; Liu et al, 2019 ; Cantonero et al, 2020 ). In order to expand the fluorescent properties, the same scaffold adopted for F412 was used to decorate inorganic quantum dots (QDs) generating nanoparticles with superior fluorescent properties able to visualize sigma receptors ( Figure 5 ) ( Pati et al, 2018a ).…”

Modeling human pediatric and adult gliomas in immunocompetent mice through costimulatory blockade

“…Mice were sacrificed when they deteriorated neurologically (failure to ambulate, lethargy) or after weight loss >20%. 31 Following transcardial perfusion with 5% sucrose and 4% paraformaldehyde in PBS, brain tissues were post-fixed with 4% paraformaldehyde overnight at 4°C and then transferred to 30% sucrose for dehydration. Brains were cryosectioned into 30-μm-thick slices.…”