Melania Elettra Vaccari
| Evaluation of the Anticancer Activity of the Pan-Sigma Modulator RC-106 in a 3D Glioblastoma Model |
| Vaccari Melania E.1, Salvi Sara1,Tosca Elena2, Aiello Ludovica2, Magni Paolo2 and Collina Simona1 1 Department of Drug Sciences, MedChemLab, University of Pavia, Pavia, Italy 2 Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy |
| Abstract Sigma receptors comprise two subtypes, namely Sigma-1 (S1R) and Sigma-2 (S2R) receptors, which are involved in a variety of biological processes. S1R agonists have been associated with neuroprotective effects, whereas S1R antagonists have shown promising potential in cancer treatment. S2R agonists have demonstrated anticancer activity across different tumor models[1–2]. The story of MedChemLab is closely linked to SRs, and led to the identification of several novel SRs ligands. Among these, RC-106 emerged as a pan-sigma modulator with promising anticancer activity[3-4]. Specifically, RC-106 exhibits a dual pharmacological profile, acting as an S1R antagonist and an S2R agonist, and has demonstrated cytotoxic activity in three pancreatic cancer cell lines (PANC-1, Capan-1, and Capan-2), all of which express SRs. Moreover, RC-106 disrupted PANC-1 spheroids within 48 hours of treatment and induced cell death in all cell lines tested[3]. Encouraged by these promising findings, we investigated the potential anticancer activity of RC-106 in the glioblastoma (GBM) cell line U87. GBM represents the most aggressive primary brain tumor in adults, with a median survival of 14 months, due to therapeutic resistance and limited efficacy of current treatment options[4]. In this context, RC-106 was first evaluated in 2D cultures to assess its cytotoxic effects, and subsequently in a 3D model to better mimic tumor architecture and microenvironmental conditions. These experiments aimed to determine RC-106 ability to inhibit spheroid growth and to promote spheroid disaggregation, thereby providing further insight into its therapeutic potential in GBM. Moreover, to gain deeper insight into the internal structure of the spheroids beyond size measurements, spheroids were embedded in paraffin and sectioned to obtain histological slices. These sections were stained using the hematoxylin and eosin technique to evaluate cell viability and density within the spheroid core. These data further confirm the anticancer activity of RC-106 and will contribute to the development of a mathematical model aimed at predicting the in vivo efficacy of the compound. |
| References [1] Listro, R. et al. Sigma Receptor And Aquaporin Modulators: Chiral Resolution, Configurational Assignment, and Preliminary Biological Profile of RC-752 Enantiomers. J. Pharm. Biomed Anal. 2024, doi:10.1016 [2] Oyer, H. M. et al. Small-Molecule Modulators of Sigma1 and Sigma2/TMEM97 in the Context of Cancer: Foundational Concepts and Emerging Themes. Front. Pharmacol. 2019. doi:10.3389 [3] Tesei, A. et al. Anti-tumor Efficacy Assessment of the Sigma Receptor Pan Modulator RC-106. A Promising Therapeutic Tool for Pancreatic Cancer. Front Pharmacol. 2019. doi: 10.3389 [4] Marino, N et al. Glitches in the brain: the dangerous relationship between radiotherapy and brain fog. Front. Cell. Neurosci. 2024. doi: 10.3389 |