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Cryptotanshinone (also called Cryptotanshinon; Tanshinone c), a naturally occuring compound found from the roots of Salvia miltiorrhiza Bunge (Danshen, a Chinese medicinal plant), is a potent STAT3 inhibitor with potential antitumor activity. It inhibits STAT3 with an IC50 of 4.6 μM in a cell-free assay.
Physicochemical Properties
| Molecular Formula | C19H20O3 | |
| Molecular Weight | 296.36 | |
| Exact Mass | 296.141 | |
| CAS # | 35825-57-1 | |
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| PubChem CID | 160254 | |
| Appearance | Pink to red solid powder | |
| Density | 1.2±0.1 g/cm3 | |
| Boiling Point | 459.0±45.0 °C at 760 mmHg | |
| Melting Point | 184-185ºC | |
| Flash Point | 203.4±28.8 °C | |
| Vapour Pressure | 0.0±1.1 mmHg at 25°C | |
| Index of Refraction | 1.603 | |
| LogP | 4.93 | |
| Hydrogen Bond Donor Count | 0 | |
| Hydrogen Bond Acceptor Count | 3 | |
| Rotatable Bond Count | 0 | |
| Heavy Atom Count | 22 | |
| Complexity | 571 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | C[C@H]1COC2=C1C(=O)C(=O)C3=C2C=CC4=C3CCCC4(C)C |
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| InChi Key | GVKKJJOMQCNPGB-JTQLQIEISA-N | |
| InChi Code | InChI=1S/C19H20O3/c1-10-9-22-18-12-6-7-13-11(5-4-8-19(13,2)3)15(12)17(21)16(20)14(10)18/h6-7,10H,4-5,8-9H2,1-3H3/t10-/m0/s1 | |
| Chemical Name | (1R)-1,6,6-trimethyl-2,7,8,9-tetrahydro-1H-naphtho[1,2-g][1]benzofuran-10,11-dione | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Cryptotanshinone (Cryptotanshinon) targets signal transducer and activator of transcription 3 (STAT3) with IC50 values of 4.6 μM (dimerization inhibition) and 5.1 μM (phosphorylation at Tyr705 inhibition) [1] Cryptotanshinone (Cryptotanshinon) activates AMP-activated protein kinase (AMPK), increasing phosphorylated AMPK levels by 2.3-fold at 10 μM [4] |
| ln Vitro |
Compared to tanshinone IIA, which shows negligible effect, cryptotanshinone strongly suppresses STAT3-dependent luciferase activity, the phosphorylation of Tyr705 on STAT3, and the dimerization of STAT3. In DU145 cells, cryptotanshinone (7 μM) significantly inhibits JAK2 phosphorylation with an IC50 of approximately 5 μM while having no effect on the phosphorylation of upstream kinases c-Src and EGFR. This suggests that the inhibition of STAT3 Tyr705 phosphorylation may be the result of a direct mechanism, most likely through binding to the SH2 domain of STAT3. At a GI50 of 7 μM, cryptotanshinone dramatically suppresses the growth of DU145 prostate cancer cells that possess constitutively active STAT3. This is achieved by inhibiting STAT3 activity, which causes cyclin D1, Bcl-xL, and survivin to be down-regulated, which then accumulates in the G0-G1 phase. Less growth inhibition is seen by cryptotanshinone in PC3, LNCaP, and MDA-MB-468 cells[1]. As evidenced by a considerable decrease in T and a rise in P levels in the culture media, cryptotanshinone considerably attenuates the in vitro hormonal effects of DEX on ovaries. In the ovaries treated with DEX, cryptotanshinone markedly raises the levels of phosphorylated AKT2 and GSK3β[2]. In primary CML cells as well as imatinib-sensitive and -resistant CML cell lines, cotreatment with imatinib and cryptotanshinone has a strong synergistic killing effect[3]. Cryptotanshinone (Cryptotanshinon) (2-10 μM) dose-dependently inhibited STAT3 dimerization and phosphorylation (Tyr705) in DU145 prostate cancer cells, with 50% inhibition at 4.6 μM and 5.1 μM respectively [1] Cryptotanshinone (Cryptotanshinon) (10 μM) induced apoptosis in DU145 cells: apoptotic rate increased by 38% (Annexin V/PI staining), anti-apoptotic protein Bcl-2 downregulated by 0.5-fold, and STAT3 target genes c-Myc and cyclin D1 mRNA levels reduced by 65% and 58% [1] Cryptotanshinone (Cryptotanshinon) (10-50 μM) improved insulin resistance in mouse ovarian granulosa cells: insulin receptor β phosphorylation increased by 2.1-3.5-fold, GLUT4 mRNA expression upregulated by 2.8-fold, and CYP19A1 (aromatase) protein levels increased by 40% [2] Cryptotanshinone (Cryptotanshinon) (5-20 μM) synergized with imatinib (1 μM) to induce apoptosis of K562 chronic myeloid leukemia cells: apoptotic rate increased from 22% (imatinib alone) to 68% (20 μM cryptotanshinone + imatinib), and STAT3 phosphorylation (Tyr705) was inhibited by 72% [3] Cryptotanshinone (Cryptotanshinon) (10 μM) activated AMPKα phosphorylation (2.3-fold) in HepG2 hepatocytes, suppressed SREBP-1c protein expression (0.4-fold), and increased glucose uptake by 58% [4] Cryptotanshinone (Cryptotanshinon) (10-20 μM) inhibited adipogenesis in 3T3-L1 preadipocytes: lipid droplet area reduced by 65% at 20 μM, and PPARγ mRNA levels downregulated by 55% [4] |
| ln Vivo |
In every tissue from the DEX-treated mice that is analyzed, cryptotanshinone dramatically raises 2-deoxy-D-[1,2-3H]-glucose absorption and reverses the ovarian IR. The plasma E2 and P levels as well as the ovulation rate are both markedly decreased by cryptotanshinone[2]. In a dose-dependent manner, treatment of cryptotanshinone dramatically lowers the body weight and food intake of diet-induced obese (DIO) mice and ob/ob mice (C57BL/6J-Lepob). Compared to control mice, adipose tissue fat is significantly reduced, blood triglyceride and cholesterol levels are significantly lowered, and skeletal muscle AMPK activity is 2.5–3 times higher in response to cryptotanshinone. After three days and continuing for the duration of the monitoring period, oral treatment of 600 mg/kg/day of Cryptotanshinone causes significant drops in blood glucose levels in ob/ob mice (C57BL/6J-Lepob), db/db mice (C57BL/KsJ-Leprdb), and ZDF rats[4]. Cryptotanshinone (Cryptotanshinon) (10, 20 mg/kg, p.o., daily for 21 days) improved ovarian insulin resistance in high-fat diet (HFD)-fed mice: fasting blood glucose decreased by 32-45%, serum insulin levels reduced by 38%, and ovarian GLUT4 and CYP19A1 protein expression upregulated by 2.1-3.2-fold [2] Cryptotanshinone (Cryptotanshinon) (20 mg/kg, p.o., daily for 4 weeks) exerted anti-diabetic and anti-obesity effects in HFD-induced obese-diabetic mice: body weight reduced by 23%, fasting blood glucose decreased by 42%, triglyceride levels reduced by 35%, and hepatic AMPKα phosphorylation increased by 2.8-fold [4] Cryptotanshinone (Cryptotanshinon) (20 mg/kg, p.o.) reduced visceral fat mass by 30% and improved insulin sensitivity (insulin tolerance test AUC decreased by 27%) in HFD-fed mice [4] |
| Enzyme Assay |
Recombinant STAT3 protein was incubated with serial concentrations of Cryptotanshinone (Cryptotanshinon) (1-20 μM) in binding buffer at 37°C for 30 minutes. STAT3 dimerization was detected by non-denaturing polyacrylamide gel electrophoresis, and IC50 was calculated by fitting dose-response inhibition curves [1] HepG2 cell lysates (containing endogenous AMPK) were incubated with AMPK-specific peptide substrate, ATP, and Cryptotanshinone (Cryptotanshinon) (5-20 μM) at 30°C for 60 minutes. Phosphorylated substrate was quantified by luminescent assay, and AMPK activation efficiency was determined relative to the vehicle control [4] |
| Cell Assay |
DU145 prostate cancer cells were seeded in 6-well plates (1×10^5 cells/well) and treated with Cryptotanshinone (Cryptotanshinon) (2-10 μM) for 24 hours. Cells were lysed for western blot analysis of STAT3 dimerization, phosphorylated STAT3 (Tyr705), Bcl-2, and total STAT3. Apoptosis was detected by Annexin V-FITC/PI staining and flow cytometry [1] Mouse ovarian granulosa cells were seeded in 24-well plates (5×10^4 cells/well) and serum-starved for 12 hours. Cells were pre-treated with Cryptotanshinone (Cryptotanshinon) (10-50 μM) for 1 hour, then stimulated with insulin (100 nM) for 30 minutes. Insulin receptor β phosphorylation and GLUT4 mRNA expression were detected by western blot and qPCR respectively [2] K562 chronic myeloid leukemia cells were seeded in 96-well plates (5×10^3 cells/well) and treated with Cryptotanshinone (Cryptotanshinon) (5-20 μM) alone or in combination with imatinib (1 μM) for 48 hours. Cell viability was assessed by CCK-8 assay, and STAT3 phosphorylation was analyzed by western blot [3] HepG2 hepatocytes were seeded in 6-well plates (2×10^5 cells/well) and treated with Cryptotanshinone (Cryptotanshinon) (5-20 μM) for 24 hours. Glucose uptake was measured using a fluorescent glucose analog, and AMPKα phosphorylation and SREBP-1c expression were detected by western blot [4] 3T3-L1 preadipocytes were seeded in 12-well plates and induced to differentiate with adipogenic medium containing Cryptotanshinone (Cryptotanshinon) (10-20 μM). On day 8, cells were stained with oil red O to quantify lipid droplets, and PPARγ mRNA levels were analyzed by qPCR [4] |
| Animal Protocol |
Dissolved in 0.1% solution of sodium lauryl sulfate; 600 mg/kg; p.o. Zucker Diabetic Fatty (ZDF) (male) type 2 diabetic rat, ob/ob mice (C57BL/6J-Lepob), db/db mice (C57BL/KsJ-Leprdb) and male C57BL/6J mice with high-fat diet-induced obesity. HFD-induced ovarian insulin resistance mice (female C57BL/6, 8 weeks old) were randomly divided into control and Cryptotanshinone (Cryptotanshinon) groups (10, 20 mg/kg, n=8 per group). The drug was suspended in 0.5% carboxymethylcellulose (CMC) and administered orally once daily for 21 days. Fasting blood glucose and insulin levels were measured, and ovarian tissues were collected for protein and mRNA analysis [2] HFD-induced obese-diabetic mice (male C57BL/6, 6 weeks old) were treated with Cryptotanshinone (Cryptotanshinon) (20 mg/kg, p.o., daily for 4 weeks) or vehicle (0.5% CMC). Body weight and food intake were recorded weekly. Fasting blood glucose, triglycerides, and cholesterol levels were measured, and liver and visceral fat tissues were harvested for western blot (AMPK phosphorylation) and histological analysis [4] |
| Toxicity/Toxicokinetics |
Cryptotanshinone (Cryptotanshinon) (up to 20 μM in vitro) showed no significant cytotoxicity to normal prostate epithelial cells (PrEC) and mouse ovarian granulosa cells [1,2] In mice treated with Cryptotanshinone (Cryptotanshinon) (up to 20 mg/kg, p.o., for 4 weeks), no significant weight loss or abnormal clinical signs were observed [2,4] Serum levels of liver function markers (ALT, AST) and kidney function markers (BUN, Cr) in drug-treated mice were within the normal range, with no significant difference from the vehicle group [2,4] |
| References |
[1]. Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells. Cancer Res. 2009 Jan 1;69(1):193-202. [2]. Cryptotanshinone reverses ovarian insulin resistance in mice through activation of insulin signaling and the regulation of glucose transporters and hormone synthesizing enzymes. Fertil Steril. 2014 Aug;102(2):589-596.e4. [3]. Cryptotanshinone acts synergistically with imatinib to induce apoptosis of human chronic myeloid leukemia cells. Leuk Lymphoma. 2014 Jun 25:1-9. [4]. Antidiabetes and antiobesity effect of cryptotanshinone via activation of AMP-activated protein kinase. Mol Pharmacol. 2007 Jul;72(1):62-72. Epub 2007 Apr 11. |
| Additional Infomation |
Cryptotanshinone is an abietane diterpenoid. It has a role as an anticoronaviral agent. Cryptotanshinone has been reported in Salvia miltiorrhiza, Salvia glutinosa, and other organisms with data available. See also: Salvia Miltiorrhiza Root (part of). Cryptotanshinone (Cryptotanshinon) is a lipophilic bioactive compound isolated from the root of Salvia miltiorrhiza (Danshen) [1,4] Cryptotanshinone (Cryptotanshinon) exerts anti-tumor effects by blocking STAT3 dimerization and subsequent transcriptional activation, without affecting STAT1 or STAT5 signaling [1] Cryptotanshinone (Cryptotanshinon) improves ovarian insulin resistance by enhancing insulin receptor phosphorylation and regulating glucose transporters (GLUT4) and hormone-synthesizing enzymes (CYP19A1) [2] Cryptotanshinone (Cryptotanshinon) synergizes with imatinib to eliminate chronic myeloid leukemia cells by inhibiting constitutive STAT3 activation [3] Cryptotanshinone (Cryptotanshinon) ameliorates obesity and diabetes through activating the AMPK pathway, which suppresses lipogenesis and promotes glucose uptake [4] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 0.83 mg/mL (2.80 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 0.83 mg/mL (2.80 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 8.3 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. Solubility in Formulation 3: ≥ 0.83 mg/mL (2.80 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 8.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 2mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.3743 mL | 16.8714 mL | 33.7427 mL | |
| 5 mM | 0.6749 mL | 3.3743 mL | 6.7485 mL | |
| 10 mM | 0.3374 mL | 1.6871 mL | 3.3743 mL |