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| Targets |
Cyclin D1 (protein expression reduced) [2]
Transcriptional regulation of multiple cell cycle-related genes (see In Vitro section) [2] |
|---|---|
| ln Vitro |
In MCF-7 human breast adenocarcinoma cells, Auraptene (10 µM) pretreatment significantly inhibited IGF-1 (10 ng/mL) stimulated S phase entry. After 24 hours of IGF-1 treatment, the percentage of cells in S phase was reduced from 57.2% (IGF-1 alone) to 9.5% (IGF-1 + Auraptene), with a corresponding increase in G1 phase cells from 42.6% to 87.4%. This effect was not observed at the 8-hour time point. [2]
In MCF-7 cells, Auraptene (10 µM) pretreatment significantly modulated the transcription of multiple cell cycle-related genes in the presence of IGF-1 (10 ng/mL), as measured by qRT-PCR array. At 8 hours post-IGF-1 treatment, 9 genes were significantly changed compared to IGF-1 alone: E2F1 (-7.88 fold), CDC45L (-6.51 fold), E2F2 (-9.81 fold), MCM3 (-6.08 fold), MCM6 (-3.71 fold), and UHRF1 (-17.01 fold) were downregulated; while CDKN2B (5.83 fold), DDIT3 (9.36 fold), and JUN (3.65 fold) were upregulated. [2] In MCF-7 cells, at 24 hours post-IGF-1 treatment, Auraptene (10 µM) pretreatment significantly modulated 14 cell cycle-related genes compared to IGF-1 alone. Downregulated genes included CDC45L (-20.71 fold), CDC2 (-38.29 fold), CCNA2 (-20.25 fold), KIF20B (-32.48 fold), CHEK1 (-9.01 fold), CDKN2C (-8.98 fold), CHEK2 (-10.83 fold), E2F1 (-10.44 fold), CCNB2 (-6.81 fold), and UHRF1 (-45.85 fold). Upregulated genes included DDIT3 (53.22 fold), CDKN2B (6.14 fold), GADD45A (10.16 fold), and DUSP1 (7.51 fold). E2F1, CDC45L, UHRF1, DDIT3, and CDKN2B were modulated at both time points. [2] No significant change in cyclin D1 mRNA level was observed in MCF-7 cells treated with IGF-1 and Auraptene, suggesting its effect on cyclin D1 protein is post-transcriptional. [2] Previous studies showed that in MCF-7 cells, 10 µM Auraptene reduced cyclin D1 protein expression by about 40% after treatment with IGF-1. [2] 0 |
| ln Vivo |
Dietary administration of Auraptene at 500 ppm significantly delayed tumor latency in the N-methylnitrosourea (MNU)-induced mammary carcinogenesis model in female Sprague-Dawley rats. [2]
HPLC analysis detected Auraptene in the low µM concentration range in mammary tissues of rats fed a diet containing either 200 or 500 ppm Auraptene. [2] Mammary tumors from rats treated with Auraptene at 500 ppm showed a significant reduction in cyclin D1 protein expression compared to tumors from the MNU-only group. [2] Dietary administration of Auraptene at 500 ppm decreased mammary carcinoma incidence and delayed median time to tumor in MNU-treated rats. [2] |
| Cell Assay |
For cell cycle analysis, MCF-7 cells (1 x 10⁶) were plated in 10 cm dishes. After 24 hours of serum starvation, cells were pretreated with 10 µM Auraptene (in 0.01% DMSO) or vehicle for 2 hours. Cells were then stimulated with 10 ng/mL IGF-1. At 8 and 24 hours post-IGF-1 stimulation, cells were harvested, washed with cold PBS, and fixed in 70% cold ethanol overnight. Fixed cells were washed, stained with propidium iodide solution mix (containing Triton-X 100, RNase, and propidium iodide in PBS), and incubated for 30 minutes at room temperature. Cell cycle distribution was analyzed by flow cytometry. The experiment was repeated 3 times. [2]
For gene expression analysis, MCF-7 cells (1 x 10⁵) were plated in 6 cm dishes and subjected to the same serum starvation, Auraptene (10 µM) pretreatment, and IGF-1 (10 ng/mL) stimulation protocol as described for cell cycle analysis. At 8 and 24 hours after IGF-1 treatment, RNA was isolated. Isolated RNA was treated with DNase to remove genomic contamination, and its quality was assessed. cDNA was synthesized from 1 µg of RNA and used for qPCR array analysis (Human Cell Cycle Tox and Cancer 96 StellARray qPCR array) to assess the expression of cell cycle-related genes. The experiment was conducted in triplicate at both time points. [2] |
| Animal Protocol |
For the mammary carcinogenesis study, female Sprague-Dawley rats were administered Auraptene at 500 ppm in the diet. The effect on tumor latency and incidence was assessed in the N-methylnitrosourea (MNU)-induced model. [2]
To measure tissue drug levels, rats were fed a diet containing Auraptene at either 200 or 500 ppm. Mammary tissue was collected and analyzed by HPLC to detect the concentration of Auraptene. [2] For the mammary carcinogenesis study, female Sprague-Dawley rats were administered Auraptene at 500 ppm in the diet. The effect on tumor latency and incidence was assessed in the N-methylnitrosourea (MNU)-induced model. [2] To measure tissue drug levels, rats were fed a diet containing Auraptene at either 200 or 500 ppm. Mammary tissue was collected and analyzed by HPLC to detect the concentration of Auraptene. [2] |
| ADME/Pharmacokinetics |
HPLC analysis of mammary tissues from rats fed a diet containing Auraptene at 200 or 500 ppm detected the compound in the low micromolar (µM) concentration range. [2]
The major metabolites of Auraptene are umbelliferone and 7-ethoxycoumarin, which also possess chemopreventive effects. [2] |
| Toxicity/Toxicokinetics |
Auraptene was well tolerated in the rat mammary carcinogenesis model. No observable changes in gross behavior and no significant weight loss were noted in rats treated with MNU plus auraptene compared to those treated with MNU alone. [3]
The 500 ppm dose in this study corresponds to an approximate daily intake of 40 mg/kg body weight for the rats, which is noted to be well below the safety limit. [3] |
| References |
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| Additional Infomation |
Auraptene belongs to the coumarin class of compounds, and its structure is similar to that of umbelliferone, except that the hydrogen on the phenolic hydroxyl group is replaced by a geranyl group. Auraptene has been isolated from various edible fruits and vegetables and possesses a variety of therapeutic effects. It can function as a plant metabolite, antitumor agent, apoptosis inducer, dopaminergic agonist, neuroprotective agent, antihypertensive agent, γ-secretase regulator, wound healing agent, EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor, PPARα agonist, gastrointestinal drug, matrix metalloproteinase inhibitor, antioxidant, and hepatoprotective agent. It belongs to the coumarin class of compounds and is also a monoterpene compound. Functionally, it is related to umbelliferone. Auraptene has been reported in Sinacalia tangutica, Polygala paniculata, and other organisms with available data.
Auraptene is a citrus coumarin being investigated for its chemopreventive effects in various cancer models, including skin, colon, prostate, and breast. Its mechanisms of action include anti-inflammatory, antiproliferative, and pro-apoptotic effects. [2] Many genes modulated by Auraptene in this study, such as CDKN2B, E2F family members, UHRF1, DUSP1, CCNB2, CHEK1, and CDKN2C, are known to be deregulated in various cancers. [2] Several of the genes modulated by Auraptene, such as CDC2 (CDK1) and CCNA2, are targets of existing or investigational anticancer therapies like Flavopiridol and UCN-01. [2] Previous studies have shown that Auraptene changes the protein levels of COX-2, iNOS, and pro-MMP-7 without changing their transcript levels, suggesting action on translational machinery. [2] |
| Molecular Formula |
C19H22O3
|
|---|---|
| Molecular Weight |
298.38
|
| Exact Mass |
298.156
|
| CAS # |
495-02-3
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| PubChem CID |
1550607
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
455.5±45.0 °C at 760 mmHg
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| Melting Point |
66 °C
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| Flash Point |
195.4±23.3 °C
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| Vapour Pressure |
0.0±1.1 mmHg at 25°C
|
| Index of Refraction |
1.549
|
| LogP |
5.69
|
| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
22
|
| Complexity |
469
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
O(C1C([H])=C([H])C2C([H])=C([H])C(=O)OC=2C=1[H])C([H])([H])/C(/[H])=C(\C([H])([H])[H])/C([H])([H])C([H])([H])/C(/[H])=C(\C([H])([H])[H])/C([H])([H])[H]
|
| InChi Key |
RSDDHGSKLOSQFK-RVDMUPIBSA-N
|
| InChi Code |
InChI=1S/C19H22O3/c1-14(2)5-4-6-15(3)11-12-21-17-9-7-16-8-10-19(20)22-18(16)13-17/h5,7-11,13H,4,6,12H2,1-3H3/b15-11+
|
| Chemical Name |
7-[(2E)-3,7-dimethylocta-2,6-dienoxy]chromen-2-one
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| Synonyms |
7-GeranyloxycoumarinAuraptenAuraptene
|
| 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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~167.57 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.97 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (6.97 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (6.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.3514 mL | 16.7572 mL | 33.5143 mL | |
| 5 mM | 0.6703 mL | 3.3514 mL | 6.7029 mL | |
| 10 mM | 0.3351 mL | 1.6757 mL | 3.3514 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04744922 | COMPLETED | Dietary Supplement: Extracts of citrus peels standardized in AUR and NAR (phytocomplex). |
Subjective Cognitive Decline | IRCCS Centro San Giovanni di Dio Fatebenefratelli | 2021-04-07 | Not Applicable |
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