Sigma receptors are ubiquitously expressed in mammals with high levels found in the central nervous system (CNS) and in cancer. There are two subtypes of sigma receptors, sigma-1 and sigma-2. Although sigma-1 receptors promote cell growth and thus inhibit cell death, activation of sigma-2 receptors was reported to trigger cell death[3]. Siramesine hydrochloride is a selective sigma receptors agonist with IC50s of 17 and 0.12 nM for sigma-1 and sigma-2 receptors, respectively[4]. In all cell lines tested, the siramesine concentration found to induce significant cell death within 8 h was in the range of 20 -30 μM, whereas 90% of cells were dead after treatment with 40–50 μM siramesine. Six hours post treatment with 25 or 40 μM siramesine, HaCaT cells exhibited characteristic apoptotic morphology with chromatin condensation and apoptotic body formation. In HaCaT cells, significant accumulation of the proforms of cysteine cathepsin L and cathepsins B and C was observed upon treatment with siramesine concentrations ≤15 μM[3].
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