Contribution of Prostaglandin E2-Induced Neuronal Excitation to Drug Resistance in Glioblastoma Countered by a Novel Blood-Brain Barrier Crossing Celecoxib Derivative

Glioblastoma (GBM) is a highly aggressive brain tumor. Its poor prognosis is primarily due to recurrence and resistance to standard therapies, such as temozolomide (TMZ). Emerging evidence suggests that neuronal excitation within the tumor microenvironment contributes to the progression and chemoresistance of GBM. This study identifies prostaglandin E2 (PGE2) as a key regulator of neuronal activity that promotes tumor resistance. It is demonstrated that PGE2 activates neurons via the prostaglandin E1 (EP1) receptor, leading to intracellular calcium influx and phosphorylation of calcium/calmodulin dependent protein kinase II (CaMKII), which enhances synaptic plasticity. Neuronal excitation results in upregulation of synaptic proteins and neurotransmitter alterations, notably increasing glutamine and asparagine levels, which correlate with heightened chemoresistance. Co-culture experiments confirmed that PGE2-stimulated neurons induce resistance in adjacent GBM cells, highlighting a neuron-tumor interaction that facilitates recurrence. To overcome this resistance mechanism, compound 11 is developed, a novel blood-brain barrier (BBB)-permeable celecoxib derivative that effectively inhibits PGE2 signaling. Treatment with compound 11 significantly reduces GBM growth, impairs neuronal excitation, and improves survival outcomes in preclinical models. These findings underscore PGE2-induced neuronal excitation as a critical driver of drug resistance in GBM, and implicate compound 11 as a promising therapeutic agent to counteract PGE2-driven tumor recurrence.