Antiproliferative and cytotoxic effects of some σ2 agonists and σ1 antagonists in tumour cell lines

To establish the activity of sigma ligands at sigma(1) and sigma(2) receptor, we chose two tumour cell lines, the human SK-N-SH neuroblastoma and the rat C6 glioma lines, which express sigma(2) receptors at a high density and sigma(1) receptors in their high-affinity or low-affinity state. We tested the sigma(2) receptor agonist PB28 and the sigma(2) antagonist AC927, and (+)-pentazocine and NE100 as agonist and antagonist, respectively, at sigma(1) receptors, with regard to antiproliferative and cytotoxic effects. In addition, 1,3-di(2-tolyl)guanidine (DTG) and haloperidol were tested as reference compounds displaying nearly equipotent sigma affinity (sigma(2)>sigma(1) and sigma(1)>sigma(2), respectively). In both SK-N-SH and C6 cells, PB28 and NE100 displayed the most potent results both in antiproliferative and cytotoxic assay while AC927 and (+)-pentazocine were inactive in both assays. The cytotoxic and antiproliferative effects of DTG and haloperidol reflected their sigma(1) antagonist activity and sigma(2) agonist activity. Moreover, our results in the tumour cell lines correlated well with those for sigma(2) activity found previously in a functional assay in the guinea-pig bladder. These findings establish a new model for evaluating both sigma(2) and sigma(1) receptor activity of sigma ligands, which could be useful for developing new ligands having mixed sigma(2) agonist/sigma(1) antagonist activity as potential antineoplastic agents.