Characterization of the Normalization, Differentiation, and Growth Arrest Effects of Small, Novel Anticancer Molecule AKS7 on Glioblastoma

Human glioblastoma is a devastating, difficult to treat disease with a poor prognosis. Contemporary chemotherapy regiments are systemically damaging and non-specific. Therefore, the development of targeted therapy is critical for the treatment of glioblastoma. In our current study, the efficacy of the small, novel molecule, AKS7, was characterized, in vitro, against the human glioblastoma cell line, U87-MG.;Our investigation, which utilized next generation sequencing and molecular wet-lab techniques, demonstrates that AKS7-treated U87 cells are growth-arrested, normalized, and show profound morphological changes. Both a 48-hour post-treatment cell cycle analysis and bioinformatics analysis reveal that AKS7-treated cells are arrested in the G2/M phase of the cell cycle. AKS7-treated U87 cells also resulted in an astrocytic or neuronal phenotype, as well as possible transdifferentiation into endothelial-like cells. The astrocytic, star-like phenotype is characterized by a large, flat cell body with multiple projections while the neuronal phenotype is characterized by a small, round cell body with two long projections on either end. Our investigation focused on the astrocytic phenotype due to the origin of U87, which is an astrocytoma. Analysis of the next generation transcriptomic sequencing data of AKS7-treated U87 cells showed upregulated response in synapse genes and differentiation markers along with upregulated inflammatory product production. Additionally, it was found that AKS7 induces extreme vacuolization at high concentrations. The vacuoles are of intracellular origin, yet their production and origin remain an enigma. Our investigation also showed that AKS7 chelates iron (III), localizes within mitochondria, and interferes with mitochondrial function. AKS7-treated cells show an increase in mitochondrial ?? as well as an increase in ATP production followed by cell death characterized by massive vacuolization.;The implications of normalization and differentiation of astrocytoma necessitates future studies conducted on the mechanism of action of AKS7. AKS7-induced cell cycle arrest and differentiation in U87 cells makes AKS7 a promising candidate for the treatment of glioblastoma.