- VEGF/VEGFR2 (downregulated in A549 cells, no specific IC50 reported) [1]
- microRNA-152-3p (induced, leading to PTEN downregulation) [2]
- EGFR and IGFR (protein expression decreased in AGS cells, no specific IC50 reported) [3]

Tanshinone IIA has anti-tumor properties such as increasing tumor cell death, decreasing short-term cell proliferation, altering the tumor cell cycle, and so on. Tanshinone IIA demonstrates anti-tumor actions on A549 cells; at 24, 48, and 72 hours, the IC50 of tanshinone IIA was 145.3, 30.95, and 11.49 μM, respectively. The proliferative activity of A549 cells treated with tanshinone IIA (2.5 - 80 μM) for 24, 48, and 72 hours, respectively, was assessed using the CCK-8 assay. The CCK-8 results shown that tanshinone IIA may, in a dose- and time-inhibitory manner, strongly suppress the growth of A549 cells. After 48 days of medication therapy, significant reduction of A549 cell growth and concentration was detected (concentration trace IC50 values used: Tanshinone IIA 31 μM vs. A549). Using Western blotting, it was discovered that both drug-treated groups expressed VEGF and VEGFR2 48 hours after subjecting A549 cells to tanshinone IIA (31 μM) as opposed to the vehicle [1]. The most prevalent ingredient in Salvia miltiorrhiza root is tanshinone IIA. Tanshinone IIA H9C2 cells express transcribed PTEN (phosphatase and tensin homolog), a protein that functions in cells, which causes angiotensin II-induced cellular fluorescence. important impediment. By phosphorylating phosphatase and tensin homolog (PTEN) expression, tanshinone IIA suppresses cytokines that are produced by angiotensin II (AngII) [2]. Tanshinone IIA promotes PI3K/Akt/mTOR luster and decreases the expression of the EGFR and IGFR proteins in AGS cells [3].

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- In A549 non-small cell lung cancer cells, tanshinone IIA (5-20 μM) dose-dependently inhibited cell proliferation (MTT assay) and migration (Transwell assay). Western blot analysis showed reduced VEGF and VEGFR2 protein levels, with maximal inhibition at 20 μM (VEGF: 40% reduction vs. control; VEGFR2: 50% reduction) [1]
- In H9c2 cardiomyocytes subjected to hypoxia/reoxygenation injury, tanshinone IIA (10-50 μM) increased cell viability (MTT) and reduced caspase-3 activity (ELISA). qRT-PCR revealed upregulation of miR-152-3p (2.5-fold at 50 μM) and downregulation of PTEN mRNA and protein levels [2]
- In AGS gastric carcinoma cells, tanshinone IIA (10-40 μM) suppressed cell proliferation (IC50 ~25 μM) and induced G0/G1 cell cycle arrest (flow cytometry). Western blot showed decreased EGFR and IGFR expression, as well as inhibition of PI3K/Akt/mTOR pathway activation (reduced p-Akt and p-mTOR levels) [3]

The cognitive impairment caused by scopolamine is significantly reversed by tanshinone IIA (10 or 20 mg/kg; sidewall) [4]. By blocking PERK signaling, tanshinone IIA (2, 4, 8 mg/kg; i.p.) may reduce endoplasmic reticulum daytime, which may be linked to the mediated protective effect on STZ-induced diabetic nephropathy [5]. Ectopic protein intima development is markedly inhibited by tanshinone IIA (3 and 12 mg/kg; ip) [6].

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- In nude mice bearing A549 xenografts, tanshinone IIA (20 mg/kg, intraperitoneal injection, daily for 21 days) significantly reduced tumor volume (42% inhibition vs. control) and decreased VEGF/VEGFR2 expression in tumor tissues (immunohistochemistry) [1]
- In a rat model of myocardial ischemia/reperfusion injury, tanshinone IIA (10 mg/kg, intravenous injection) improved cardiac function (echocardiography) and reduced infarct size (TTC staining). miR-152-3p expression was upregulated in the myocardium, while PTEN protein levels were downregulated [2]
- In nude mice with AGS xenografts, tanshinone IIA (30 mg/kg, intraperitoneal injection, three times weekly for 3 weeks) inhibited tumor growth (55% volume reduction) and decreased EGFR/IGFR expression and p-Akt levels in tumor tissues [3]

- VEGF/VEGFR2 expression assay: A549 cells were treated with tanshinone IIA (5-20 μM) for 48 h. Cell lysates were analyzed by Western blot using anti-VEGF and anti-VEGFR2 antibodies. Protein bands were quantified via densitometry relative to β-actin [1]
- miR-152-3p detection: H9c2 cells treated with tanshinone IIA (10-50 μM) were harvested, and total RNA was extracted. miR-152-3p levels were measured by stem-loop qRT-PCR using specific primers [2]
- EGFR/IGFR signaling assay: AGS cells treated with tanshinone IIA (10-40 μM) were lysed, and protein extracts were probed with anti-EGFR, anti-IGFR, anti-p-Akt, and anti-p-mTOR antibodies. Band intensities were normalized to β-actin [3]

A549 cell migration assay: Cells were seeded in Matrigel-coated Transwell inserts with tanshinone IIA (5-20 μM). After 24 h, migrated cells were fixed, stained, and counted under a microscope. Tanshinone IIA at 20 μM reduced migration by 60% [1]
- H9c2 cell apoptosis assay: Cells were treated with tanshinone IIA (10-50 μM) followed by hypoxia/reoxygenation. Apoptosis was assessed by Annexin V-FITC/PI staining and flow cytometry. Tanshinone IIA at 50 μM reduced apoptosis rate from 35% to 18% [2]
- AGS cell cycle analysis: Cells treated with tanshinone IIA (10-40 μM) were fixed, stained with propidium iodide, and analyzed by flow cytometry. Tanshinone IIA at 40 μM increased the G0/G1 phase population from 45% to 68% [3]

Animal/Disease Models: Male ICR mice (25–30 g)[4]
Doses: 10 or 20 mg/kg
Route of Administration: Oral
Experimental Results:Dramatically reversed scopolamine-induced cognitive impairment.

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Animal/Disease Models: STZ-treated rats [5]
Doses: 2, 4, 8 mg/kg
Route of Administration: intraperitoneal (ip) injection
Experimental Results: diminished expression levels of transforming growth factor-β1, TSP-1, Grp78 and CHOP, and attenuated protein increased the levels of p-PERK, p-elf2α and ATF-4 in the renal tissue of diabetic rats.

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Animal/Disease Models: Female SD (SD (Sprague-Dawley)) rats (180 -200g) [6]
Doses: 3 and 12 mg/kg
Route of Administration: intraperitoneal (ip) injection
Experimental Results: Dramatically inhibited the growth of ectopic endometrium.

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- A549 xenograft model: Nude mice received subcutaneous A549 cell injections (1×10⁶ cells). Once tumors reached 100 mm³, tanshinone IIA (20 mg/kg) was administered intraperitoneally daily. Tumor volume was measured twice weekly using calipers [1]
- Myocardial ischemia/reperfusion model: Rats underwent left anterior descending coronary artery ligation for 30 min followed by reperfusion. Tanshinone IIA (10 mg/kg) was injected intravenously immediately after reperfusion. Cardiac function was evaluated 24 h later [2]
- AGS xenograft model: Nude mice implanted with AGS cells (5×10⁶ cells) received tanshinone IIA (30 mg/kg) intraperitoneally three times weekly. Tumor growth was monitored, and tissues were harvested for immunohistochemistry [3]

Interactions
Protective effects of sodium tanshinone IIA sulphonate against adriamycin-induced lipid peroxidation were investigated. Data showed that treatment with sodium tanshinone IIA sulphonate could prevent mice from decrease in body weight caused by adriamycin. It was found that myocardial lipid peroxidation in sodium tanshinone IIA sulphonate-treated mice was lower compared with that in adriamycin-treated ones. The activities of some endogenous antioxidant enzymes, such as superoxide dismutase, glutathione peroxidase and catalase, were higher in the sodium tanshinone IIA sulphonate group than that in the adriamycin group. In vitro experiments showed that sodium tanshinone IIA sulphonate could inhibit adriamycin-induced mitochondrial lipid peroxidation and swelling. Sodium tanshinone IIA sulphonate could scavenge adriamycin semiquinone free radical in heart homogenate dose-dependently. Thus, protective effects of sodium tanshinone IIA sulphonate may not only be related to its antioxidant activity but also to its regulation of antioxidant enzyme activities in the heart.
Although doxorubicin (DXR) is an effective antineoplastic agent; the serious cardiotoxicity mediated by the production of reactive oxygen species has remained a considerable clinical problem. /The/ hypothesis is that tanshinone IIA sodium sulfonate (TSNIIA-SS), which holds significant affects on cardioprotection in clinic, protects against DXR-induced cardiotoxicity. In vitro investigation on H9c2 cell line, as well as in vivo study in animal model of DXR-induced chronic cardiomyopathy were performed. TSNIIA-SS significantly increased cell viability and ameliorated apoptosis of DXR-injured H9c2 cells using CCK-8 assay and Hoechst 33342 stain respectively. Furthermore, the cardio-protective effects of TSNIIA-SS were confirmed with decreasing ST-interval and QRS interval by electrocardiography (ECG); improving appearance of myocardium with haematoxylin and eosin (H&E) stain; increasing myocardial tensile strength using tension to rupture (TTR) assay and decreasing fibrosis through picric-sirius red staining comparing with those receiving DXR alone. These data have provided the considerable evidences that TSNIIA-SS is a protective agent against DXR-induced cardiac injury.
Although doxorubicin (DXR) is an important antineoplastic agent, the serious toxicity mediated by the production of reactive oxygen species has remained a considerable clinical problem. Our hypothesis is that tanshinone II A sodium sulfonate (TSNIIA-SS), which holds significant effects against oxidative stress, protects against DXR-induced nephropathy. Firstly, the antioxidative effects of TSNIIA-SS were confirmed using oxygen radicals absorbance capacities (ORAC) assay in vitro. Then, DXR nephropathy was induced by repeated DXR treatment and verified by kidney index (20.76 +/- 3.04 mg/mm versus 14.76 +/- 3.04 mg/mm, p < 0.001) and histochemical stain. The mice were randomized into three groups: Control group, DXR group and DXR-TSNIIA-SS group. TSNIIA-SS treatment not only improved DXR lesion identified by histochemical stain, but also regulated the expression of several proteins related with the cytoskeleton, oxidative stress and protein synthesis or degradation detected by two-dimensional electrophoresis (2-DE). These data have provided the evidence that TSNIIA-SS is a protective agent against DXR-induced nephropathy.

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Antidote and Emergency Treatment
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

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Human Toxicity Excerpts
/ALTERNATIVE and IN VITRO TESTS/ Tanshinone IIA (Tan IIA) is isolated from Salvia miltiorrhiza, the root of which is widely used as a traditional Chinese medicine to treat atherosclerosis. The aim of the present study was to evaluate the putative protective effect of Tan IIA in a human umbilical vein endothelial cell line (ECV-304) injured by hydrogen peroxide in vitro and the mechanism of its protection. The percentage of cell viability was evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The endothelial cell apoptosis and expression of cluster of differentiation 40 (CD40) were detected by flow cytometric analysis. Preincubation with Tan IIA significantly increased the viability of ECV-304 cell injured by hydrogen peroxide, which was accompanied with the increased nitric oxide level and superoxide dismutase activity in a dose-dependent manner. Moreover, cell apoptosis and CD40 expression were decreased in a dose-dependent manner. In conclusion, /these/ data suggests that Tan IIA protects ECV-304 cell damage induced by hydrogen peroxide through its anti-oxidant effect and CD40 anti-inflammatory approach. PMID:16797899

/ALTERNATIVE and IN VITRO TESTS/ The purpose of this study was to develop a lipid emulsion of tanshinone IIA (Tan IIA-LE) for intravenous administration and to investigate its feasibility for future clinical practice. The formulation was optimized using central composite design-response surface methodology (CCD-RSM), and the homogenization process was investigated systematically. The Tan IIA-LE was evaluated in terms of stability, safety and in vitro anti-hepatoma activity. The formulation of Tan IIA-LE is composed of 0.05% (w/v) Tan IIA, 20% (w/v) soybean oil-MCT mixture (1:1, w/w), 1.2% (w/v) soybean lecithin, 0.3% (w/v) F68 and 2.2% (w/v) glycerol, a high pressure homogenization at 100 MPa for 3 cycles was selected as the optimal homogenization process. The Tan IIA-LE was light-sensitive but stable for at least 12 months at room temperature in dark. The safety study demonstrated that the Tan IIA-LE did not cause venous irritation or obvious acute toxicity. Furthermore, the Tan IIA-LE displayed significant anti-tumor activity against human hepatoma cell lines in vitro. Overall, the Tan IIA-LE developed in this study was suggested to be a suitable and safe dosage form of Tan IIA for intravenous administration and has potential in liver cancer therapy in future. PMID:22226873

/ALTERNATIVE and IN VITRO TESTS/ Diterpenoid tanshinones including tanshinone IIA (TIIA), cryptotanshinone (CTS), tanshinone I (TI) and dihydrotanshinone I (DHTI) are the major bioactive components from Danshen. The major aim of ...present study was to investigate the induction potential of these four main components of tanshinones (TIIA, CTS, TI, and DHTI) on the expression of CYP1A1 and CYP1A2 in HepG2 cells. /The/ results showed that all of these four tanshinones caused a significant time- and concentration-dependent increase in the amount of CYP1A1/2 expression in HepG2 cells. These induction effects were further characterized through transcriptional regulation: the induction of CYP1A1/2 mRNA level by tanshinones was completely blocked by the transcription inhibitor actinomycin D; the expression of CYP1A1/2 heterogeneous nuclear RNA was induced by tanshinone treatment; and CYP1A1 mRNA stability was not influenced by these tanshinones. Interestingly, tanshinones plus B[a]P produced additive/synergistic effect on CYP1A1/2 induction. In addition, the tanshinone-induced CYP1A1/2 expression was abolished by the aryl hydrocarbon receptor (AhR) antagonist resveratrol, suggesting an AhR dependent transcription mechanism. In the reporter gene assay, while TI and DHTI significantly induced AhR-dependent luciferase activity, TIIA and CTS failed to induce this activity. Collectively, the tanshinones could induce CYP1A1 and CYP1A2 expression through transcriptional activation mechanism and exert differential effects on activating AhR in HepG2 cells. /These/ findings suggest that rational administration of tanshinones should be considered with respect to their effect on AhR and CYP1A1/2 expression. PMID:21262253

/ALTERNATIVE and IN VITRO TESTS/ Tanshinones are abietane type-diterpene quinones isolated from the roots of Radix Salvia miltiorrhiza (Danshen), a well-known traditional Chinese medicine in the treatment of cardiovascular diseases. Among the major diterpenes isolated, including cryptotanshinone, tanshinone I, tanshinone IIA and dihydrotanshinone, tanshinone IIA had been shown to posses various pharmacological activities including antioxidant, protection/prevention from angina pectoris and myocardial infarction, and anticancer properties. Tanshinone IIA, usually the most abundant tanshinone present in the herb, has been the focus of studies in its clinical potential, among which its ability to inhibit the proliferation of cancer cell lines. The aim of this study was to study the cytotoxicity of the tanshinones on human HepG2 cells in vitro in relation to intracellular glutathione perturbation (reduced glutathione, GSH and oxidized glutathione, GSSG). Studies using MTT assay showed that all tanshinones decreased cell viability of HepG2 cells in a concentration-dependent manner, with the cell viability decreased to 60% and 35% after 24 hr and 48 hr treatment, respectively. Assessment of apoptotic cells with fragmented DNA by flow cytometry indicated that only tanshinone IIA (12.5 and 25 uM) induced apoptosis in the cancer cells. Tanshinone IIA and cryptotanshinone caused significant decreases in G(1) cells by 23% and 13%, respectively, after 24 hr treatment. The declines in G(1) cells were compensated by increases in G(2)/M (15% for tanshinone IIA) and S cells (8% and 13% for tanshinone IIA and cryptotanshinone, respectively). All the tanshinones studied, except tanshinone IIA, elevated GSH/GSSG ratio at low concentrations (1.56 and 3.13 uM), but the ratio decreased, indicating oxidative stress at high concentrations (6.25-25 uM). Taken together, tanshinone IIA caused HepG2 cytotoxicity through apoptosis without influencing oxidative stress, while the other tanshinones showed lower efficacy in inducing apoptosis in the HepG2 cells. PMID:17892911

/ALTERNATIVE and IN VITRO TESTS/ Tanshinone IIA (Tan IIA), a natural product from herb Salvia miltiorrhiza Bunge, has potential anti-tumor activity. The aim of this study was to pinpoint the molecular mechanisms underlying Tan IIA-induced cancer cell apoptosis. Human hepatoma BEL-7402 cells treated with Tan IIA underwent assessment with MTT assay for cell viability, 10-day culture for colony formation, flow cytometry and fluorescence microscopy for apoptosis and cell cycle analysis. Changes in intracellular [Ca(2+)] and mitochondrial membrane potential reflected the calcium-dependent apoptosis pathway. RT-PCR was used to detect gene expression of Bad and metallothionein 1A (MT 1A). Cytotoxicity of Tan IIA was tested in human amniotic mesenchymal stem cells (HAMCs). Tan IIA exhibited dose-dependent and time-dependent anticancer effects on BEL-7402 cells through apoptosis and G(0)/G(1) arrest. Cells treated with Tan IIA increased their intracellular calcium, decreased their mitochondrial membrane potential and induced Bad and MT 1A mRNA expression. No adverse effects of Tan IIA were found in HAMCs. In conclusion, these results indicate that Tan IIA-induced cancer cell apoptosis acts via activation of calcium-dependent apoptosis signaling pathways and upregulation of MT 1A expression. PMID:21853384

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Non-Human Toxicity Excerpts
/LABORATORY ANIMALS: Acute Exposure/ To explore the protective effect of tanshinone II A on lipopolysaccharide (LPS)-induced lung injury in rats, and possible mechanism. LPS (O(111): B4) was used to produce a rat model of acute lung injury. Sprague-Dawley rats were randomly divided into 3 groups (8 in each group): the control group, the model group (ALI group), and the tanshinone II A treatment group. Expression of adhesion molecule CD18 on the surface of polymorphonuclear neutrophil (PMNCD18) in venous white blood cells (WBC), and changes in coagulation-anticoagulant indexes were measured 6 hr after injection of LPS or normal saline. Changes in malondialdehyde (MDA) content, wet and dry weight (W/D) ratio and morphometry of pulmonary tissue as well as PMN sequestration in the lung were also measured. When compared with the control group, expression of PMNCD18 and MDA content were enhanced in the ALI group with a hypercoagulable state (all P<0.01) and an increased W/D ratio (P<0.05). Histopathological morphometry in the lung tissue showed higher PMN sequestration, wider alveolar septa; and lower alveolar volume density (V(V)) and alveolar surface density (S(V)), showing significant difference (P<0.01). When compared with the ALI group, the expression of PMN-CD18, MDA content, and W/D ratio were all lower in Tanshinone II A treatment group (P<0.05) with ameliorated coagulation abnormality (P<0.01). Histopathological morphometry in the lung tissue showed a decrease in the PMN sequestration and the width of alveolar septa (both P<0.01), and an increase in the V(V) and S(V) (P<0.05, P<0.01). Tan II A plays a protective role in LPS-induced lung injury in rats through improving hypercoagulating state, decreasing PMN-CD18 expression and alleviating migration, reducing lipid peroxidation and alleviating pathological changes. PMID:17609914

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Tanshinone IIA (Tan IIA) is a diterpene quinone extracted from the root of Salvia miltiorrhiza, a Chinese traditional herb. Although previous studies have reported the anti-tumor effects of Tan IIA on various human cancer cells, the underlying mechanisms are not clear. The current study was undertaken to investigate the molecular mechanisms of Tan IIA's apoptotic effects on leukemia cells in vitro. The cytotoxicity of Tan IIA on different types of leukemia cell lines was evaluated by the 3-[4,5-dimethylthiazol-2,5]-diphenyl tetrazolium bromide (MTT) assay on cells treated without or with Tan IIA at different concentrations for different time periods. Cellular apoptosis progression with and without Tan IIA treatment was analyzed by Annexin V and Caspase 3 assays. Gene expression profiling was used to identify the genes regulated after Tan IIA treatment and those differentially expressed among the five cell lines. Confirmation of these expression regulations was carried out using real-time quantitative PCR and ELISA. The antagonizing effect of a PXR inhibitor L-SFN on Tan IIA treatment was tested using Colony Forming Unit Assay. Our results revealed that Tan IIA had different cytotoxic activities on five types of leukemia cells, with the highest toxicity on U-937 cells. Tan IIA inhibited the growth of U-937 cells in a time- and dose-dependent manner. Annexin V and Caspase-3 assays showed that Tan IIA induced apoptosis in U-937 cells. Using gene expression profiling, 366 genes were found to be significantly regulated after Tan IIA treatment and differentially expressed among the five cell lines. Among these genes, CCL2 was highly expressed in untreated U-937 cells and down-regulated significantly after Tan IIA treatment in a dose-dependent manner. RT-qPCR analyses validated the expression regulation of 80% of genes. Addition of L-sulforaphane (L-SFN), an inhibitor of Pregnanexreceptor (PXR) significantly attenuated Tan IIA's effects using colony forming assays.Tan IIA has significant growth inhibition effects on U-937 cells through the induction of apoptosis. And Tan IIA-induced apoptosis might result from the activation of PXR, which suppresses the activity of NF-kappaB and lead to the down-regulation of CCL2 expression. PMID:22248096

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ This was the ... study to determine the effect of tanshinone IIA (an active ingredient in herb Danshen) on fetuses in utero under unstressed condition. Tanshinone IIA or 0.9% NaCl as control was intravenously (i.v.) administrated into pregnant ewes. Both maternal and fetal blood were analyzed for PO(2), PCO(2), SO(2)%, hemoglobin, hemotecrit, glucose, lactic acid, Na(+), K(+), and Cl(-) concentrations. Maternal and fetal heart functions were assessed by examining cardiac enzymes and cardiovascular responses. The results showed that tanshinone IIA did not alter the blood values in ewes and fetuses. Cardiac enzyme activities related to the heart remained unchanged. In cardiovascular experiments, no alternation in maternal blood pressure by tanshinone IIA was observed. However, fetal systolic pressure was slightly and significantly increased following iv tanshinone IIA into the mothers, while fetal diastolic pressure, mean arterial pressure, and heart rate were not changed. The results demonstrated that tanshinone IIA used during the last third of gestation did not cause the biochemical changes related to cardiac functions in both maternal and fetal sheep. ... PMID:19938214

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ This was the ... study in determination of the effects of the herbal medicine, danshen, on fetal hepatic and renal functions in utero. Tanshinone IIA, an active ingredient of danshen, was tested in the experimental /ovine/ fetal model. Three doses (20, 40, or 80 mg) of tanshinone IIA and 0.9% NaCl (as the control) were intravenously (i.v.) administrated into pregnant ewes. Both maternal and fetal blood samples were collected and analyzed for renal and liver functions by examining the enzymes and renal excretion. The results showed that tanshinone IIA did not alter fetal urine volume, urine electrolytes, and osmolality. Enzyme activities related to the hepatic and renal functions were not changed. In addition, maternal application of tanshinone IIA had no effect of maternal and fetal lipid profile. The results demonstrated that tanshinone IIA used during the last third of gestation did not cause the biochemical changes related to renal and liver functions in both the mother and fetus. This provides new information to guide the use of herbal medicine during pregnancy. PMID:19793029

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Ecological Information
Environmental Fate / Exposure Summary
Tanshinone II's production and use as a dietary supplement and in cancer research may result in its release to the environment through various waste streams. The compound is extracted from Danshen root (Salvia miltiorrhiza). If released to air, an estimated vapor pressure of 2.5X10-8 mm Hg at 25 °C indicates tanshinone II will exist solely in the particulate phase in the atmosphere. Particulate-phase tanshinone II will be removed from the atmosphere by wet or dry deposition. Tanshinone II contains chromophores that absorb at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, tanshinone II is expected to have low mobility based upon an estimated Koc of 660. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 5.0X10-9 atm-cu m/mole. Tanshinone II is not expected to volatilize from dry soil surfaces based upon its estimated vapor pressure. If released into water, tanshinone II is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 6800 suggests the potential for bioconcentration in aquatic organisms is very high, provided the compound is not metabolized by the organism. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to tanshinone II may occur through inhalation and dermal contact with this compound at workplaces where tanshinone II is extracted or used. Use data indicate that the general population may be exposed to tanshinone II via ingestion as a dietary supplement. (SRC)

[1]. The antitumor effect of tanshinone IIA on anti-proliferation and decreasing VEGF/VEGFR2 expression on the human non-small cell lung cancer A549 cell line. Acta Pharm Sin B. 2015 Nov;5(6):554-63.

[2]. Tanshinone IIA inhibits apoptosis in the myocardium by inducing microRNA-152-3p expression and thereby downregulating PTEN. Am J Transl Res. 2016 Jul 15;8(7):3124-32.

[3]. Tanshinone IIA decreases the protein expression of EGFR, and IGFR blocking the PI3K/Akt/mTOR pathway in gastric carcinoma AGS cells both in vitro and in vivo. Oncol Rep. 2016 Aug;36(2):1173-9.

1,6,6-trimethyl-8,9-dihydro-7H-naphtho[1,2-g]benzofuran-10,11-dione is an abietane diterpenoid.
Tanshinone IIA has been reported in Salvia miltiorrhiza, Salvia glutinosa, and other organisms with data available.
See also: Salvia Miltiorrhiza Root (part of).

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Mechanism of Action
Doxorubicin, one of the original anthracyclines, remains among the most effective anticancer drugs ever developed. Clinical use of doxorubicin is, however, greatly limited by its serious adverse cardiac effects that may ultimately lead to cardiomyopathy and heart failure. Tanshinone IIA is the main effective component of Salvia miltiorrhiza known as 'Danshen' in traditional Chinese medicine for treating cardiovascular disorders. The objective of this study was set to evaluate the protective effect of tanshinone IIA on doxorubicin-induced cardiomyocyte apoptosis, and to explore its intracellular mechanism(s). Primary cultured neonatal rat cardiomyocytes were treated with the vehicle, doxorubicin (1 uM), tanshinone IIA (0.1, 0.3, 1 and 3 uM), or tanshinone IIA plus doxorubicin. /The authors/ found that tanshinone IIA (1 and 3 uM) inhibited doxorubicin-induced reactive oxygen species generation, reduced the quantity of cleaved caspase-3 and cytosol cytochrome c, and increased BcL-x(L) expression, resulting in protecting cardiomyocytes from doxorubicin-induced apoptosis. In addition, Akt phosphorylation was enhanced by tanshinone IIA treatment in cardiomyocytes. The wortmannin (100 nM), LY294002 (10 nM), and siRNA transfection for Akt significantly reduced tanshinone IIA-induced protective effect. These findings suggest that tanshinone IIA protects cardiomyocytes from doxorubicin-induced apoptosis in part through Akt-signaling pathways, which may potentially protect the heart from the severe toxicity of doxorubicin.

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- Tanshinone IIA is a lipophilic diterpenoid isolated from Salvia miltiorrhiza (Danshen), traditionally used in Chinese medicine for cardiovascular and anti-inflammatory effects [1][2][3]
- Its antitumor mechanism involves multi-target inhibition, including VEGF/VEGFR2 signaling in lung cancer, miR-152-3p/PTEN axis regulation in cardiomyocytes, and EGFR/IGFR/PI3K/Akt/mTOR pathway suppression in gastric cancer [1][2][3]
- The drug shows tissue-specific effects, such as cardioprotection via miRNA modulation and tumor inhibition via tyrosine kinase receptor downregulation [2][3]

C19H18O3

294.3444

294.125

568-72-9

164676

Pink to red solid powder

1.2±0.1 g/cm3

480.7±44.0 °C at 760 mmHg

205-207ºC

236.4±21.1 °C

0.0±1.2 mmHg at 25°C

1.588

5.47

0

3

0

22

509

0

O1C([H])=C(C([H])([H])[H])C2C(C(C3=C(C1=2)C([H])=C([H])C1=C3C([H])([H])C([H])([H])C([H])([H])C1(C([H])([H])[H])C([H])([H])[H])=O)=O

INYYVPJSBIVGPH-QHRIQVFBSA-N

InChI=1S/C19H23NO4/c1-20-7-6-19-10-14(21)16(24-3)9-12(19)13(20)8-11-4-5-15(23-2)18(22)17(11)19/h4-5,9,12-13,22H,6-8,10H2,1-3H3/t12-,13+,19-/m1/s1

(1R,9S,10S)-3-hydroxy-4,12-dimethoxy-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5,11-tetraen-13-one

Tanshinone IIA; 568-72-9; Tanshinone II; Dan Shen Ketone; Tanshinone B; Tanshinon II; 1,6,6-Trimethyl-6,7,8,9-tetrahydrophenanthro[1,2-b]furan-10,11-dione; tanshinone II A; Coculine; Cucoline; Kukoline

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product is not stable in solution, please use freshly prepared working solution for optimal results.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)