Siramesine

Siramesine（Lu 28-179）is a specific agonist of sigma (σ) receptor [1].

Siramesine（Lu 28-179）has been reported to specific bind to σ2 receptor in human cortical and rat brain homogenates with Kd values of 1.1±0.2nM, 2.2 ±0.4nM and moderate capacity Bmax values of 26±3 fmol mg tissue-1,50±12 fmol mg tissue-1, respectively. In addition, Siramesine has shown the ligand selectivity profile of [3H]Lu28-179 binding to rat and human brain membranes with Ki values of 4.4±1.7nM and 8.6±0.6 nM, respectively. Apart from these, Siramesine has been revealed to displace [3H]DTG binding with very high affinity and [3H](+)pentazocine binding of σ2-sites. The IC50 of Siramesine inhibited the [3H]DTG binding is 0.19nM [1].

References:
[1] Søby KK1, Mikkelsen JD, Meier E, Thomsen C. Lu 28-179 labels a sigma(2)-site in rat and human brain. Neuropharmacology. 2002 Jul;43(1):95-100.

Siramesine triggers cell death through destabilisation of mitochondria, but not lysosomes.[Pubmed:24091661]

Cell Death Dis. 2013 Oct 3;4:e818.

A sigma-2 receptor agonist Siramesine has been shown to trigger cell death of cancer cells and to exhibit a potent anticancer activity in vivo. However, its mechanism of action is still poorly understood. We show that Siramesine can induce rapid cell death in a number of cell lines at concentrations above 20 muM. In HaCaT cells, cell death was accompanied by caspase activation, rapid loss of mitochondrial membrane potential (MMP), cytochrome c release, cardiolipin peroxidation and typical apoptotic morphology, whereas in U-87MG cells most apoptotic hallmarks were not notable, although MMP was rapidly lost. In contrast to the rapid loss of MMP above 20 muM Siramesine, a rapid increase in lysosomal pH was observed at all concentrations tested (5-40 muM); however, it was not accompanied by lysosomal membrane permeabilisation (LMP) and the release of lysosomal enzymes into the cytosol. Increased lysosomal pH reduced the lysosomal degradation potential as indicated by the accumulation of immature forms of cysteine cathepsins. The lipophilic antioxidant alpha-tocopherol, but not the hydrophilic antioxidant N-acetyl-cysteine, considerably reduced cell death and destabilisation of mitochondrial membranes, but did not prevent the increase in lysosomal pH. At concentrations below 15 muM, Siramesine triggered cell death after 2 days or later, which seems to be associated with a general metabolic and energy imbalance due to defects in the endocytic pathway, intracellular trafficking and energy production, and not by a specific molecular event. Overall, we show that cell death in Siramesine-treated cells is induced by destabilisation of mitochondria and is independent of LMP and the release of cathepsins into the cytosol. Moreover, it is unlikely that Siramesine acts exclusively through sigma-2 receptors, but rather through multiple molecular targets inside the cell. Our findings are therefore of significant importance in designing the next generation of Siramesine analogues with high anticancer potential.

Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells.[Pubmed:27441659]

Cell Death Dis. 2016 Jul 21;7:e2307.

Ferroptosis is an iron-dependent, oxidative cell death, and is distinct from apoptosis, necrosis and autophagy. In this study, we demonstrated that lysosome disrupting agent, Siramesine and a tyrosine kinase inhibitor, lapatinib synergistically induced cell death and reactive oxygen species (ROS) in MDA MB 231, MCF-7, ZR-75 and SKBr3 breast cancer cells over a 24 h time course. Furthermore, the iron chelator deferoxamine (DFO) significantly reduced cytosolic ROS and cell death following treatment with Siramesine and lapatinib. Furthermore, we determined that FeCl3 levels were elevated in cells treated with Siramesine and lapatinib indicating an iron-dependent cell death, ferroptosis. To confirm this, we treated cells with a potent inhibitor of ferroptosis, ferrastatin-1 that effectively inhibited cell death following Siramesine and lapatinib treatment. The increase levels of iron could be due to changes in iron transport. We found that the expression of transferrin, which is responsible for the transport of iron into cells, is increased following treatment with lapatinib alone or in combination with Siramesine. Knocking down of transferrin resulted in decreased cell death and ROS after treatment. In addition, ferroportin-1 (FPN) is an iron transport protein, responsible for removal of iron from cells. We found its expression is decreased after treatment with Siramesine alone or in combination with lapatinib. Overexpression FPN resulted in decreased ROS and cell death whereas knockdown of FPN increased cell death after Siramesine and lapatinib treatment. This indicates a novel induction of ferroptosis through altered iron regulation by treating breast cancer cells with a lysosome disruptor and a tyrosine kinase inhibitor.

Siramesine causes preferential apoptosis of mast cells in skin biopsies from psoriatic lesions.[Pubmed:28117878]

Br J Dermatol. 2017 Jul;177(1):179-187.

BACKGROUND: Skin mast cells are implicated as detrimental effector cells in various inflammatory skin diseases such as contact eczema, atopic dermatitis and psoriasis. Selective reduction of cutaneous mast cells, e.g. by inducing targeted apoptosis, might prove a rational and efficient therapeutic strategy in dermatoses negatively influenced by mast cells. OBJECTIVES: The objective of the present study was to evaluate whether a lysosomotropic agent such as Siramesine can cause apoptosis of mast cells present in psoriatic lesions. MATERIALS AND METHODS: Punch biopsies were obtained from lesional and uninvolved skin in 25 patients with chronic plaque psoriasis. After incubation with Siramesine, the number of tryptase-positive mast cells and their expression of interleukin (IL)-6 and IL-17 was analysed. Skin biopsies were digested to allow flow cytometric analysis of the drug's effect on cutaneous fibroblasts and keratinocytes. RESULTS: Siramesine caused a profound reduction in the total number of mast cells in both lesional and uninvolved psoriatic skin biopsies without affecting the gross morphology of the tissue. The drug reduced the density of IL-6- and IL-17-positive mast cells, and showed antiproliferative effects on epidermal keratinocytes but had no apparent cytotoxic effect on keratinocytes or dermal fibroblasts. CONCLUSIONS: Considering the pathophysiology of psoriasis, the effects of Siramesine on cutaneous mast cells may prove favourable from the therapeutic aspect. The results encourage further studies to assess the usefulness of Siramesine and other lysosomotropic agents in the treatment of cutaneous mastocytoses and inflammatory skin diseases aggravated by dermal mast cells.

Effects of the lysosomal destabilizing drug siramesine on glioblastoma in vitro and in vivo.[Pubmed:28270132]

BMC Cancer. 2017 Mar 7;17(1):178.

BACKGROUND: Glioblastoma is the most frequent and most malignant brain tumor with the patients having a median survival of only 14.6 months. Although glioblastoma patients are treated with surgery, radiation and chemotherapy recurrence is inevitable. A stem-like population of radio- and chemoresistant brain tumor-initiating cells combined with the invasive properties of the tumors is believed to be critical for treatment resistance. In the present study, the aim was to investigate the effect of a novel therapeutic strategy using the lysosomotropic detergent Siramesine on glioblastomas. METHODS: Standard glioma cell lines and patient-derived spheroids cultures with tumor-initiating stem-like cells were used to investigate effects of Siramesine on proliferation and cell death. Responsible mechanisms were investigated by inhibitors of caspases and cathepsins. Effects of Siramesine on migrating tumor cells were investigated by a flat surface migration assay and by implanting spheroids into organotypic rat brain slice cultures followed by confocal time-lapse imaging. Finally the effect of Siramesine was investigated in an orthotopic mouse glioblastoma model. Results obtained in vitro and in vivo were confirmed by immunohistochemical staining of histological sections of spheroids, spheroids in brain slice cultures and tumors in mice brains. RESULTS: The results showed that Siramesine killed standard glioma cell lines in vitro, and loss of acridine orange staining suggested a compromised lysosomal membrane. Co-treatment of the cell lines with inhibitors of caspases and cathepsins suggested differential involvement in cell death. Siramesine caused tumor cell death and reduced secondary spheroid formation of patient-derived spheroid cultures. In the flat surface migration model Siramesine caused tumor cell death and inhibited tumor cell migration. This could not be reproduced in the organotypic three dimensional spheroid-brain slice culture model or in the mice xenograft model. CONCLUSIONS: In conclusion the in vitro results obtained with tumor cells and spheroids suggest a potential of lysosomal destabilizing drugs in killing glioblastoma cells, but Siramesine was without effect in the organotypic spheroid-brain slice culture model and the in vivo xenograft model.

Siramesine(Lu 28-179) is a selective sigma-2 receptor agonist, which has been shown to trigger cell death of cancer cells and to exhibit a potent anticancer activity in vivo.

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