In the central nervous system, σ receptors have been shown to be involved in the regulation of neurotransmitter release, the modulation of the neurotransmitter receptor function, learning and memory, and the regulation of movement and posture. Additional functions of σ receptors in connection with the motor, endocrine, and immune systems are also suggested. Although the molecular function of the σ receptors has not yet been fully defined and the natural ligand(s) is/are still not known, there is increasing evidence that σ receptors might play a significant role in cancer biology by modifying growth rates of human cancer cells lines in vitro and in vivo (for review see Aydar et al., Cancer Res 2004). Indeed, sigma and/or sigma-1 receptor drugs could produce anticancerous effects by modulating ion channels such as high-voltage-activated Ca2+ channels including N-, L, P/Q- and R-type Ca2+ channels, and the voltage-gated K+ ones.

The present study shows that activating the σ1 receptor with non-cytotoxic doses of the 4-IBP σ1 receptor agonist decreases the levels of migration of various types of cancer cells, including C32 melanoma, U373-MG glioblastoma (GBM), A549 NSCLC and PC3 prostate cancer cells. The 4-IBP-induced decrease in cancer cell migration occurs through modifications in the organization of the actin cytoskeleton. The activation of the σ1 receptor by 4-IBP in U373-MG GBM cells displaying the σ1 receptor V1 transcript variant sensitizes them to pro-apoptotic or pro-autophagic cytotoxic insults, a process in which RhoGDI and glucosylceramide synthase seem to be involved. In vivo, 4-IBP increases the anti-tumor effects of temozolomide and irinotecan in immunodeficient mice orthotopically grafted with either human U373-MG glioblastoma or A549 NSCLC cells.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA