The antiproliferative effect of indomethacin-loaded lipid-core nanocapsules in glioma cells is mediated by cell cycle regulation, differentiation, and the inhibition of survival pathways

Abstract

Andressa Bernardi,1,* Rudimar L Frozza,2,* Juliana B Hoppe,2 Christianne Salbego,2 Adriana R Pohlmann,1,3 Ana Maria O Battastini,2 Sílvia S Guterres11Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brasil; 2Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS, Brasil; 3Departamento de Química Orgânica, Instituto de Química, UFRGS, Porto Alegre, RS, Brasil *Both authors contributed equally to this workAbstract: Despite recent advances in radiotherapy, chemotherapy, and surgical techniques, glioblastoma multiforme (GBM) prognosis remains dismal. There is an urgent need for new therapeutic strategies. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted intense interest in recent years because they can provide sustained, controlled, and targeted delivery. Here, we investigate the mechanisms involved in the antiproliferative effect of indomethacin-loaded lipid-core nanocapsules (IndOH-LNC) in glioma cells. IndOH-LNC were able to reduce cell viability by inducing apoptotic cell death in C6 and U138-MG glioma cell lines. Interestingly, IndOH-LNC did not affect the viability of primary astrocytes, suggesting that this formulation selectively targeted transformed cells. Mechanistically, IndOH-LNC induced inhibition of cell growth and cell-cycle arrest to be correlated with the inactivation of AKT and ß-catenin and the activation of GSK-3ß. IndOH-LNC also induced G0/G1 and/or G2/M phase arrest, which was accompanied by a decrease in the levels of cyclin D1, cyclin B1, pRb, and pcdc2 and an increase in the levels of Wee1 CDK inhibitor p21WAF1. Additionally, IndOH-LNC promoted GBM cell differentiation, observed as upregulation of glial fibrillary acidic protein (GFAP) protein and downregulation of nestin and CD133. Taken together, the crosstalk among antiproliferative effects, cell-cycle arrest, apoptosis, and cell differentiation should be considered when tailoring pharmacological interventions aimed at reducing glioma growth by using formulations with multiples targets, such as IndOH-LNC.Keywords: glioblastoma multiforme, PI3K/AKT, cell differentiation, indomethacin-loaded lipid core nanocapsules, cell cycle regulation