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.
Siramesine hydrochloride是一种有效的sigma-2受体激动剂。Siramesine对sigma-2受体具有亚纳摩尔亲和力 (IC50=0.12nM)，并且对sigma-2受体的选择性是sigma-1受体的140倍 (IC50=17nM) [1]。Sigma-2受体在各种快速增殖的癌细胞中高度表达，并被认为是癌细胞生物标志物[2]。Siramesine通过线粒体的不稳定而不是溶酶体触发细胞死亡，显示出有效的抗癌活性[3]。
在体外，Siramesine（0-15μM）处理含有胶质母细胞瘤干细胞样球状体（GSS）的培养物24小时，减少了球状体形成，这表明其对肿瘤干细胞性有抑制作用[4]。溶酶体失稳药物Siramesine（浓度高于20μM）可诱导许多细胞系的快速细胞死亡。在HaCaT细胞中，8小时内Siramesine诱导显著细胞死亡的浓度在20-30μM范围内，而用浓度为40-50μM的Siramesine处理后90%的细胞死亡。并且浓度大于25μM的Siramesine在15分钟内降低了HaCaT细胞的线粒体膜电位（MMP）[1]。
在体内，在可卡因强化行为的C57小鼠中，sigma-2受体激动剂Siramesine（0.1, 0.3, and 1mg/kg/d；i.p.）显著降低了自由活动小鼠纹状体中由可卡因引发的多巴胺释放量，其可能具有对抗可卡因复吸的治疗潜力[5]。在测试开始前24小时Siramesine(1mg/kg/d；i.p.)与MEM（以及AMA）联合给药可缩短大鼠的不动时间。Siramesine和AMA的联合治疗既不受孕酮也不受BD 1047（一种对sigma-1位点具有优先亲和力的新型sigma拮抗剂）的影响[6]。