Targeting glioblastoma with hybrid H ₃ R antagonists with piperidinylpropoxy and trimethoxychalcone motifs results in broad oncosuppressive effects

Among the many emerging strategies in precision medicine, surface receptor-directed drugs offer a promising pathway for the targeted and effective delivery of a cure. Histamine receptor (H₃R) antagonists have been demonstrated to target and effectively suppress cancer cells that overexpress H₃R. The present study aimed to evaluate the anticancer potential of (E)-3-(3,4,5-trimethoxyphenyl)-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)prop-2-en-1-one (AR71), a hybrid H₃R antagonist/inverse agonist featuring a piperidinylpropoxy motif conjugated to trimethoxychalcone, which mimics colchicine and disrupts microtubule assembly. Following incubation with AR71, we observed significant inhibition of growth and cell cycle arrest at G2/M in glioblastoma and neuroblastoma cells, which correlated with their H₃R expression levels. AR71 treatment decreased the invasion potential of cancer cells by 60-80% along with a decrease in MMP-2 release. In-depth immunocytochemical investigations revealed dose-dependent impairment of microtubule organisation after treatment with AR71. Consequently, tubulin polymerisation and cytokinesis failure led to a greater incidence of aneuploid cells and tripolar mitotic events. We also observed an increase in mitochondrial reactive oxygen species in cancer cells following exposure to AR71. As a result, the mitochondrial membrane potential decreased significantly. In summary, targeting dual molecules with AR71 may create favourable conditions for the selective and synergistic action of combined anticancer compounds against glioblastoma and neuroblastoma.