Cytotoxic activities of hydroxyethyl piperazine-based σ receptor ligands on cancer cells alone and in combination with melphalan, PB28 and haloperidol.

Abstract σ Receptor ligands are attracting interest as possible anti-cancer agents because of their ability to induce cell death by different mechanisms. In this study we investigated the cytotoxic effects of 12 recently developed σ-receptor ligands in a panel of eight different human tumor cell lines by either the crystal violet or MTT assays. The results show that σ ligands have broad cytotoxic activity on a number of human cancer cell lines with IC50 values in the low μM range. In addition, apoptosis was observed by the annexin-V/PI double staining method when RPMI 8226 human multiple myeloma cells were treated with a representative σ ligand, (R)-2b. Combination of (R)-2b with melphalan led to a higher apoptotic rate than with the drug alone. Likewise, combined treatment of (R)-2b with the known high affinity σ2-agonist PB28 showed an additive effect on the induction of apoptosis in the RPMI 8226 line. In contrast, combinations of (R)-2b with the known σ1-antagonist haloperidol lead to a significant reduction in the cytotoxic activity of (R)-2b. These results support the idea that (R)-2b acts as a σ-agonist to cause the death of RPMI 8226 cells.