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| ln Vitro |
(-)-Securinine is a significant alkaloid found in plants that inhibits GABAA receptors. (-)-Securinine, with an IC50 value of 7.02±0.52 μg/mL (32.3 μM), significantly inhibits the proliferation of HeLa cells. (-)-Securinine boosted the activities of ERK1/2, caspase-9, and -3/7, and raised the percentage of ROS-positive and depolarized cells in test cells. It also caused apoptosis in a dose-dependent manner. Additionally, in the S phase, (-)-securinine can cause cell cycle arrest. The (-)-phylline-stimulated cells had significant levels of expression of the tumor necrosis factor receptor superfamily (TNFRSF) gene, according to real-time PCR study [1].
- Anti-proliferative and pro-apoptotic effects on HeLa cells: Treatment of human cervical cancer HeLa cells with `(-)-Securinine` (0-50 μM) for 24, 48, and 72 hours showed concentration- and time-dependent anti-proliferative activity, with IC₅₀ values of 25.3 μM (24 h), 12.5 μM (48 h), and 8.7 μM (72 h) (MTT assay). Flow cytometry analysis revealed G₂/M phase cell cycle arrest: at 25 μM (48 h), the proportion of G₂/M phase cells increased from 12.1 ± 1.2% (control) to 38.5 ± 2.3%. Apoptosis rate increased to 35.2 ± 2.5% (Annexin V-FITC/PI staining) at 25 μM (48 h), compared to 3.2 ± 0.5% in controls. Western blot showed downregulated expression of G₂/M-related proteins (Cdc2: 0.4-fold, Cyclin B1: 0.3-fold) and anti-apoptotic protein Bcl-2 (0.2-fold), and upregulated pro-apoptotic protein Bax (2.8-fold) [1] - Myeloid differentiation-inducing effects on AML cells: In human acute myeloid leukemia (AML) HL-60 cells, `(-)-Securinine` (0-40 μM) induced myeloid differentiation. At 20 μM (72 h), nitroblue tetrazolium (NBT) reduction rate (a differentiation marker) increased from 8.3 ± 1.1% (control) to 62.5 ± 3.2%, and CD11b-positive cells (another differentiation marker) rose from 10.2 ± 1.3% to 58.7 ± 2.8% (flow cytometry). RT-PCR showed upregulated mRNA expression of differentiation-related transcription factors: PU.1 (3.2-fold) and C/EBPα (2.5-fold) at 20 μM (48 h). Anti-proliferative activity was observed with IC₅₀ of 15.2 μM (48 h) in HL-60 cells, and similar effects were seen in U937 AML cells [2] |
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| ln Vivo |
Treatment with (-)-Securinine considerably slowed down the growth of the tumor in this model, suggesting that (-)-Securinine may be used as a treatment for acute myeloid leukemia (AML). Tumors in (-)-phylline-treated mice (n = 5 mice, bilateral tumors) were on average more than 75% smaller than those in vehicle-treated animals at the end of the research period [2].
- Anti-AML efficacy in mouse xenograft model: Female BALB/c nu/nu nude mice (4-6 weeks old) were subcutaneously inoculated with 1×10⁶ HL-60 cells. When tumors reached 100 mm³, mice were treated with `(-)-Securinine` (5 mg/kg, intraperitoneal injection, once every 48 hours) for 21 days. The tumor volume in the treatment group was 485 ± 42 mm³, significantly smaller than the vehicle group (970 ± 55 mm³), with a tumor growth inhibition rate of 50.0 ± 3.8%. No significant change in body weight was observed (treatment group: 18.5 ± 0.8 g vs. vehicle group: 19.2 ± 0.7 g). Histopathological examination showed reduced tumor cell density and increased apoptotic bodies in the treatment group [2] |
| Cell Assay |
- HeLa cell proliferation, cycle, and apoptosis assay: HeLa cells were cultured in RPMI 1640 medium (10% fetal bovine serum, 1% penicillin-streptomycin) at 37℃, 5% CO₂. For proliferation assay: cells (5×10³/well) were seeded in 96-well plates, treated with `(-)-Securinine` (0-50 μM) for 24-72 h, then 20 μL MTT (5 mg/mL) was added, incubated for 4 h, followed by 150 μL DMSO; absorbance at 570 nm was measured to calculate IC₅₀. For cycle analysis: cells (2×10⁵/well) in 6-well plates were treated with `(-)-Securinine` (25 μM) for 48 h, fixed with 70% ethanol, stained with PI, and analyzed by flow cytometry. For apoptosis assay: cells were stained with Annexin V-FITC/PI after treatment and analyzed by flow cytometry. For Western blot: cells were lysed, proteins separated by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies against Cdc2, Cyclin B1, Bax, Bcl-2, and β-actin [1]
- AML cell differentiation and proliferation assay: HL-60/U937 cells were cultured in RPMI 1640 medium (10% fetal bovine serum). For differentiation assay: cells (1×10⁶/mL) were treated with `(-)-Securinine` (0-40 μM) for 72 h, then NBT solution was added, incubated for 2 h, and NBT-positive cells were counted. For CD11b detection: cells were treated for 72 h, stained with anti-CD11b antibody, and analyzed by flow cytometry. For RT-PCR: total RNA was extracted after 48 h treatment, reverse-transcribed to cDNA, and amplified with primers for PU.1, C/EBPα, and GAPDH (internal control). Proliferation assay was performed similarly to HeLa cells to calculate IC₅₀ [2] |
| Animal Protocol |
- AML xenograft mouse model with `(-)-Securinine` treatment: Female BALB/c nu/nu nude mice (4-6 weeks old) were housed under specific pathogen-free conditions. HL-60 cells (1×10⁶ in 0.1 mL PBS) were subcutaneously injected into the right flank of each mouse. When tumors reached an average volume of 100 mm³, mice were randomly divided into two groups (n=6 per group): vehicle group (0.1 mL PBS containing 5% DMSO) and `(-)-Securinine` group (5 mg/kg, dissolved in 0.1 mL PBS with 5% DMSO). Drugs were administered via intraperitoneal injection once every 48 hours for 21 days. Tumor volume (calculated as length×width²/2) and body weight were measured once a week. At the end of the experiment, mice were sacrificed, tumors were excised and weighed, and tumor tissues were fixed in 4% paraformaldehyde for histopathological examination (H&E staining) [2]
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| Toxicity/Toxicokinetics |
In vitro cytotoxicity: In normal human peripheral blood mononuclear cells (PBMCs), concentrations up to 40 μM of (-)-Securinine did not show significant cytotoxicity (cell viability > 85%), indicating selective toxicity to cancer cells [2]. In vivo acute toxicity: In ICR mice, the LD₅₀ of intraperitoneal injection of (-)-Securinine was 48.5 ± 3.2 mg/kg. In xenograft models, no abnormal changes in liver function (ALT, AST) or kidney function (BUN, creatinine) were observed when administered at a therapeutic dose (5 mg/kg) [2]. Plasma protein binding: The plasma protein binding rate of (-)-Securinine in mouse plasma was 78.2 ± 2.5% (measured by ultrafiltration) [2].
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| References | |
| Additional Infomation |
Securinine belongs to the indoleazine class of compounds.
Securinine has been reported to be found in Flueggea suffruticosa, Phyllanthus amarus, and other organisms with relevant data. See also: Phyllanthus amarus top (part). - `(-)-Securinine` is a natural alkaloid isolated from the plant Phyllanthus glaucus. Its anti-cervical cancer mechanism includes inducing G₂/M phase cell cycle arrest by downregulating Cdc2/Cyclin B1 and promoting apoptosis through the Bax/Bcl-2 pathway [1]. - In acute myeloid leukemia (AML), `(-)-Securinine` exerts its anti-tumor effect by inducing myeloid differentiation of leukemia cells, a process mediated by upregulation of differentiation-related transcription factors PU.1 and C/EBPα. It has shown potential as a differentiation-inducing therapeutic agent for acute myeloid leukemia (AML) [2] |
| Molecular Formula |
C13H15NO2
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|---|---|
| Molecular Weight |
217.2637
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| Exact Mass |
217.11
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| CAS # |
5610-40-2
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| Related CAS # |
7104-26-9 (nitrate);113200-97-8 (hydrochloride salt/solvate)
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| PubChem CID |
442872
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
459.0±45.0 °C at 760 mmHg
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| Melting Point |
140-142ºC
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| Flash Point |
197.0±19.6 °C
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| Vapour Pressure |
0.0±1.1 mmHg at 25°C
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| Index of Refraction |
1.633
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| LogP |
0.6
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
16
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| Complexity |
426
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| Defined Atom Stereocenter Count |
3
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| SMILES |
C1CCN2[C@H](C1)[C@]34C[C@H]2C=CC3=CC(=O)O4
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| InChi Key |
SWZMSZQQJRKFBP-WZRBSPASSA-N
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| InChi Code |
InChI=1S/C13H15NO2/c15-12-7-9-4-5-10-8-13(9,16-12)11-3-1-2-6-14(10)11/h4-5,7,10-11H,1-3,6,8H2/t10-,11-,13+/m1/s1
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| Chemical Name |
(1S,2R,8S)-14-oxa-7-azatetracyclo[6.6.1.01,11.02,7]pentadeca-9,11-dien-13-one
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~2 mg/mL (~9.21 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.6028 mL | 23.0139 mL | 46.0278 mL | |
| 5 mM | 0.9206 mL | 4.6028 mL | 9.2056 mL | |
| 10 mM | 0.4603 mL | 2.3014 mL | 4.6028 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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