4-IBP, a σ1 Receptor Agonist, Decreases the Migration of Human Cancer Cells, Including Glioblastoma Cells, In Vitro and Sensitizes Them In Vitro and In Vivo to Cytotoxic Insults of Proapoptotic and Proautophagic Drugs

Abstract

Although the molecular function of sigma receptors has not been fully defined and the natural ligand(s) is 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 sigma1 agonist, has been used to investigate whether this compound is able to modify: 1) in vitro the migration and proliferation of human cancer cells; 2) in vitro the sensitivity of human glioblastoma cells to cytotoxic drugs; and 3) in vivo in orthotopic glioblastoma and non-small cell lung carcinoma (NSCLC) models the survival of mice co-administered cytotoxic agents. 4-IBP has revealed weak antiproliferative 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 antimigratory 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 proapoptotic lomustin and proautophagic temozolomide, and markedly decreased the expression of two proteins involved in drug resistance: glucosylceramide synthase and Rho guanine nucleotide dissociation inhibitor. In vivo, 4-IBP increased the antitumor effects of temozolomide and irinotecan in immunodeficient mice that were orthotopically grafted with invasive cancer cells.

Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines

“…Both drugs also showed no effect on the migration of MDA-MB-231 and MDA-MB-468 cells suggesting that sigma-1 receptors do not play a significant role in cellular motility. This result was rather surprising and would require further exploration in light of the fact that 4-IBP, another sigma-1 receptor agonist, was found to decrease the migration of glioblastoma cells (Megalizzi et al 2007). Previously, SKF10047 was found to promote the detachment of MDA-MB-231 cells plated on collagen in a 'single cell' adhesion assay (Palmer et al 2007(Palmer et al , 2008.…”

Ion Channels as Promising Therapeutic Targets for Melanoma

“…Treatments of c-Myc siRNA in the targeted nanoparticles also showed significant inhibition on the growth of MDA-MB-435 tumour (Chen et al, 2010). Last, the sigma1 ligand 4-IBP decreases melanoma cell migration in vitro (Megalizzi et al, 2007). These data raise the question of the function of sigma receptors in cancer cells.…”

Quercetin inhibits a large panel of kinases implicated in cancer cell biology

“…The direct visualisation of the effects of quercetin on human T98G glioblastoma cells was carried out by computer-assisted phase contrast microscopy (quantitative video-microscopy), as detailed elsewhere (13,(18)(19)(20)(21). T98G glioblastoma cells were monitored for 72 h in the absence (control) or presence of 30 μM quercetin, which is the IC 50 in vitro growth-inhibitory concentration as calculated by the MTT colorimetric assay (Fig.…”

“…1Ab). Movies were created from the time-lapse image sequences, which enabled a detailed screen for cell viability to determine whether the compound induced cytostatic or cytotoxic effects (13,(18)(19)(20)(21). Each experimental condition was performed in triplicate.…”