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].
Siramesine HCl/西拉美新盐酸盐 细胞实验
Cell Line
Concentration
Treated Time
Description
References
DU145 cells
10-45 µM
24 hours
Induced cell death with LC50 of 35 μM
Cancers (Basel). 2022 Nov 8;14(22):5478
PC3 cells
10-50 µM
24 hours
Induced cell death with LC50 of 20 μM
Cancers (Basel). 2022 Nov 8;14(22):5478
ZR-75-1
10 µM
4 hours
Induced cell death
Cell Death Dis. 2016 Jul 21;7(7):e2307
MCF-7
10 µM
4 hours
Induced cell death
Cell Death Dis. 2016 Jul 21;7(7):e2307
SH-SY5Y cells
20-30 µM
8 hours
Induced cell death
Cell Death Dis. 2013 Oct 3;4(10):e818
MCF-7 cells
20-30 µM
8 hours
Induced cell death
Cell Death Dis. 2013 Oct 3;4(10):e818
SKBr3
10 µM
24 hours
Induced cell-death and reactive oxygen species (ROS)
Cell Death Dis. 2016 Jul 21;7(7):e2307
MDA MB-231
10 µM
24 hours
Induced cell-death and reactive oxygen species (ROS)
Cell Death Dis. 2016 Jul 21;7(7):e2307
HeLa cells
20-30 µM
8 hours
Induced cell death
Cell Death Dis. 2013 Oct 3;4(10):e818
Hsc-4 cells
20-30 µM
8 hours
Induced cell death
Cell Death Dis. 2013 Oct 3;4(10):e818
LNCaP cells
10-40 µM
24 hours
Induced cell death with LC50 of 40 μM
Cancers (Basel). 2022 Nov 8;14(22):5478
MDA-MB-435 human melanoma cells
10 µM
16 hours
To observe the formation of autophagosomes induced by Siramesine using electron microscopy, results showed that Siramesine induced the formation of autophagy-like vacuoles.
Br J Cancer. 2012 Feb 14;106(4):693-701
Human lung mast cells
20 µM
24 hours
To evaluate the effect of siramesine on human lung mast cells, results showed a significant reduction in mast cell numbers.
Front Immunol. 2017 Nov 27;8:1645
HS-5 stromal cells
1 µM
24 hours
To evaluate the effect of Siramesine on CLL cell death in the presence of HS-5 stromal cells. Results showed that Siramesine could overcome the protective effect of HS-5 and increase CLL cell death.
Cells. 2024 Jun 15;13(12):1041
Primary chronic lymphocytic leukemia (CLL) cells
1 µM
24 hours
To evaluate the effect of Siramesine on lysosome membrane permeabilization (LMP) and cell death in CLL cells. Results showed that Siramesine significantly increased LMP and cell death.
Cells. 2024 Jun 15;13(12):1041
Patient-derived TNBC tumor cells
5 µM
48 hours
To evaluate the effect of siramesine in combination with palbociclib on the proliferation of patient-derived TNBC tumor cells. Results showed that the combination of siramesine and palbociclib nearly completely arrested tumor cell proliferation.
Sci Adv. 2020 Jun 17;6(25):eabb2210
MDA-MB-435 human melanoma cells
10 µM
48 hours
To evaluate the effect of Siramesine on cell viability, results showed that Siramesine significantly reduced cell viability.
Br J Cancer. 2012 Feb 14;106(4):693-701
EMT-6 mouse breast cancer cells
10 µM
48 hours
To evaluate the effect of Siramesine on cell viability, results showed that Siramesine significantly reduced cell viability.
Br J Cancer. 2012 Feb 14;106(4):693-701
TNBC cells
3.5 µM (SUM159), 2 µM (HCC1806)
6 days
To evaluate the effect of siramesine in combination with palbociclib on the proliferation of TNBC cells. Results showed that the combination of siramesine and palbociclib significantly inhibited the proliferation of TNBC cells.
Sci Adv. 2020 Jun 17;6(25):eabb2210
U-87MG cells
20-30 µM
8 hours
Induced cell death, most apoptotic hallmarks were not notable, although MMP was rapidly lost
Cell Death Dis. 2013 Oct 3;4(10):e818
HaCaT cells
20-30 µM
8 hours
Induced cell death accompanied by caspase activation, rapid loss of mitochondrial membrane potential (MMP), cytochrome c release, cardiolipin peroxidation and typical apoptotic morphology
Cell Death Dis. 2013 Oct 3;4(10):e818
Siramesine HCl/西拉美新盐酸盐 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Male C57/bl6 mice
Cocaine-induced conditioned place preference (CPP) model
Intraperitoneal injection
0.1, 0.3, 1 mg/kg
Single administration, tested 60 minutes later
To investigate the effect of Siramesine on cocaine-induced conditioned place preference (CPP). Results showed that Siramesine significantly attenuated CPP acquisition and expression, and completely blocked cocaine-primed reinstatement.
Front Pharmacol. 2017 Oct 10;8:714
NU-Foxn1nu nude mice
PDAC1 and PDAC3 PDX models
Oral gavage
30 mg/kg
Twice a week for ~4 weeks
Evaluation of Siramesine's effects on tumor growth in PDAC1 and PDAC3 PDX models, showing that combination therapy with gemcitabine significantly reduced the CSC population.
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