4-IBP: A s1 Receptor Agonist Decreases the Migration of Human Cancer Cells Including Glioblastoma Cells In Vitro and Sensitizes Them In Vitro and In Vivo to the Cytotoxic Insults of Pro-Apoptotic and Pro-Autophagic Drugs

Mégalizzi V, Mathieu V, Mijatovic T, Gailly P, Debeir O, De Neve N, Van Damme M, Bontempi G, Haibe-Kains B, Decaestecker C, Kondo Y, Kiss R and Lefranc F

Although the molecular function of σ receptors has not been fully defined and the natural ligand(s) still not known, there is increasing evidence that these receptors and their ligands might play a significant role in cancer biology. 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), a selective σ1 agonist has been used to investigate whether this compound is able to modify i) in vitro the migration and proliferation of human cancer cells, ii) in vitro the sensitivity of human glioblastoma cells to cytotoxic drugs and iii) in vivo in orthotopic glioblastoma and NSCLC models, the survival of mice co-administered cytotoxics.

4-IBP has revealed weak anti-proliferative effects on human U373-MG glioblastoma and C32 melanoma cells but induced marked concentration-dependent decreases in the growth of human A549 NSCLC and PC3 prostate cancer cells. The compound was also significantly anti-migratory in all four cancer cell lines. This may result, at least in U373-MG cells from modifications to the actin cytoskeleton. 4-IBP modified the sensitivity of U373-MG cells in vitro to pro-apoptotic lomustin and pro-autophagic temozolomide and markedly decreased the expression of two proteins involved in drug resistance: glucosylceramide synthase and Rho GDI. In vivo, 4-IBP increased the anti-tumor effects of temozolomide and irinotecan in immunodeficient mice orthotopically grafted with invasive cancer cells, respectively human U373-MG glioblastoma and A549 NSCLC.