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

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[1,2-a]pyridine derivative in glioblastoma cells. IP-Se-06 exhibited high cytotoxicity against A172 cells ( I C 50 = 1.8 μ 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 μM), 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 γ-H2AX and p53 proteins. Treatment with IP-Se-06 induced cell cycle arrest and showed antiproliferative effect by inhibition of Akt/mTOR/HIF-1α 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 IP-Se-06 is a bioactive molecule that can be considered a candidate for the development of a novel drug for glioblastoma treatment.

Selenylated Imidazo[1,2-a]pyridine Induces Cell Senescence and Oxidative Stress in Chronic Myeloid Leukemia Cells

“…The results obtained corroborated those of Santos and collaborators who, through the analysis of a compound derived from selenylated imidazopyridine, obtained a significant reduction in cell counts when compared to cells not treated with the compound; that is, they reported that imidazopyridine derivatives have an antiproliferative potency in the cells of glioblastoma [ 30 ]. Another study by Almeida and collaborators using the same imidazopyridine-derived compound demonstrated an inhibition of cell growth in 90% of breast cancer cell lines when compared to untreated controls [ 13 ].…”

Glutathione S-Transferases S1, Z1 and A1 Serve as Prognostic Factors in Glioblastoma and Promote Drug Resistance through Antioxidant Pathways

“…The GSH redox system plays an important role in cell survival and apoptosis [ 52 , 53 , 54 ], and inhibition of HPGDS was found to result in a downregulation of the GSH levels and a reduction in cellular drug resistance. Considering that the JNK pathway plays an important role in promoting apoptosis in glioma, and a variety of GSTs can regulate the activation of the JNK signaling pathway [ 42 , 55 , 56 ], we speculate that the resistance-promoting function of HPGDS is partly attributable to the inhibition of apoptosis resulting from downregulated activation of the JNK pathway.…”

Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis

“…These methodologies generally require high-cost equipment, result in low yield, and use toxic solvents, which reduces the sustainability of the process. In line with our interest in discovering and developing a new sustainable, efficient methodologies for biologically active compounds and patient-compliant alternative for leishmaniasis treatment [10][11][12][13][14][15][16][17], our research group aimed to yield natural-based bioactive compounds with multitarget properties. To achieve this purpose, we designed a scalable, easy-to-replicate, and inexpensive synthetic route to obtain flavonol and chalcone analogs.…”