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.