Siramesine hydrochloride is an effective sigma-2 receptor agonist. Siramesine has an annanometer-level affinity for the sigma-2 receptor (IC50 = 0.12nM), and its selectivity for the sigma-2 receptor is 140 times that of the sigma-1 receptor (IC50 = 17nM) [1]. The sigma-2 receptor is highly expressed in various rapidly proliferating cancer cells and is considered a biomarker of cancer cells [2]. Siramesine triggers cell death through mitochondrial instability rather than lysosomes, showing effective anti-cancer activity [3].
In vitro, Siramesine (0-15μM) treatment of cultures containing glioblastoma stem cell-like spheres (GSS) for 24 hours reduced sphere formation, indicating its inhibitory effect on tumor stem cell properties [4]. The lysosomal destabilizing drug Siramesine (with a concentration higher than 20μM) can induce rapid cell death in many cell lines. In HaCaT cells, the concentration of Siramesine that induces significant cell death within 8 hours is within the range of 20-30μM, and 90% of the cells die after treatment with a concentration of 40-50μM of Siramesine. And Siramesine at concentrations greater than 25μM reduces the mitochondrial membrane potential (MMP) of HaCaT cells within 15 minutes [1].
In vivo, In C57 mice with cocaine-enhanced behavior, the sigma-2 receptor agonist Siramesine (0.1, 0.3, and 1mg/kg/d; i.p.) significantly reduced the dopamine release induced by cocaine in the striatum of freely moving mice, which may have therapeutic potential for treating cocaine relapse [5]. 24 hours before the test, Siramesine (1mg/kg/d; i.p.) combined with MEM (as well as AMA) administration could shorten the immobility time of rats. The combined treatment of Siramesine and AMA is not affected by progesterone nor by BD 1047 (a new sigma antagonist with preferential affinity for the sigma 1 site) [6].
References:
[1] Česen MH, Repnik U, Turk V, Turk B. Siramesine triggers cell death through destabilisation of mitochondria, but not lysosomes. Cell Death Dis. 2013 Oct 3;4(10):e818.
[2] Huang Y S, Lu H L, Zhang L J, et al. Sigma‐2 receptor ligands and their perspectives in cancer diagnosis and therapy[J]. Medicinal research reviews, 2014, 34(3): 532-566.
[3] Bhatti I. The lysosomotropic agent siramesine induces cell death in prostate cancer cells and synergizes with the tyrosine kinase inhibitor lapatinib[J]. 2024.
[4] Jensen S S, Petterson S A, Halle B, et al. Effects of the lysosomal destabilizing drug siramesine on glioblastoma in vitro and in vivo[J]. BMC cancer, 2017, 17: 1-16.
[5] Klawonn AM, Nilsson A, Rådberg CF, Lindström SH, Ericson M, Granseth B, Engblom D, Fritz M. The Sigma-2 Receptor Selective Agonist Siramesine (Lu 28-179) Decreases Cocaine-Reinforced Pavlovian Learning and Alters Glutamatergic and Dopaminergic Input to the Striatum. Front Pharmacol. 2017 Oct 10;8:714.
[6] Skuza G, et al. The synergistic effect of selective sigma receptor agonists and uncompetitive NMDA receptor antagonists in the forced swim test in rats. J Physiol Pharmacol. 2006 Jun;57(2):217-29.