IP-Se-06, a Selenylated Imidazo[1,2-a]pyridine, Modulates Intracellular Redox State and Causes Akt/mTOR/HIF-1 alpha and MAPK Signaling Inhibition, Promoting Antiproliferative Effect and Apoptosis in Glioblastoma Cells

Author(s)

dos Santos, Daniela C. ; Rafique, Jamal ; Saba, Sumbal ; Grinevicius, Valdelucia M. A. S. ; Filho, Danilo W. ; Zamoner, Ariane ; Braga, Antonio L. ; Pedrosa, Rozangela C. ; Ourique, Fabiana

• Document type: Journal article
• Source: OXIDATIVE MEDICINE AND CELLULAR LONGEVITY; v. 2022, p. 18-pg., 2022-03-22.

Abstract

Glioblastoma multiforme (GBM) is a notably lethal brain tumor associated with high proliferation rate and therapeutic resistance, while currently effective treatment options are still lacking. Imidazo[1,2-a]pyridine derivatives and organoselenium compounds are largely used in medicinal chemistry and drug development. This study is aimed at further investigating the antitumor mechanism of IP-Se-06 (3-((2-methoxyphenyl)selanyl)-7-methyl-2-phenylimidazol[1,2-a]pyridine), a selenylated imidazo[1,2a]pyridine derivative in glioblastoma cells. IP-Se-06 exhibited high cytotoxicity against A172 cells (IC50 = 1:8 mu M) and selectivity for this glioblastoma cell. The IP-Se-06 compound has pharmacological properties verified in its ADMET profile, especially related to blood-brain barrier (BBB) permeability. At low concentration (1 mu M), IP-Se-06 induced intracellular redox state modulation with depletion of TrxR and GSH levels as well as inhibition of NRF2 protein. IP-Se-06 also decreased mitochondrial membrane potential, induced cytochrome c release, and chromatin condensation. Furthermore, IP-Se-06 induced apoptosis by decreasing levels of Bcl-xL while increasing levels of gamma-H2AX and p53 proteins. Treatment with IP-Se-06 induced cell cycle arrest and showed antiproliferative effect by inhibition of Akt/mTOR/HIF-1 alpha and ERK 1/2 signaling pathways. In addition, IP-Se-06 displayed significant inhibition of p38 MAPK and p-p38, leading to inhibition of inflammasome complex proteins (NLRP3 and caspase-1) in glioblastoma cells. These collective findings demonstrated that IPSe-06 is a bioactive molecule that can be considered a candidate for the development of a novel drug for glioblastoma treatment. (AU)

• FAPESP's process: 14/50249-8 - Green chemistry: sustainable synthetic methods employing benign solvents, safer reagents, and bio-renewable feedstock
• Grantee: Arlene Gonçalves Corrêa
• Support Opportunities: Research Grants - Research Centers in Engineering Program