Tanshinone IIA

The roots of Salvia miltiorrhiza

Tanshinone IIA (Tan IIA) is one of the main fat-soluble compositions in the root of red-rooted salvia. Tanshinone IIA may suppress angiogenesis by targeting the protein kinase domains of VEGF/VEGFR2.

In Vitro:The anti-tumor effect of Tanshinone IIA includes inhibiting tumor cell proliferation, disturbing tumor cell cycle, promoting tumor cell apoptosis, and inhibiting tumor cell invasion and transfer. Tanshinone IIA has anti-proliferative effects on A549 cells: the IC50 of Tanshinone IIA after 24, 48 and 72 h are 145.3, 30.95 and 11.49 μM, respectively. The CCK-8 assay is used to evaluate the proliferative activity of A549 cells treated with Tanshinone IIA (2.5-80 μM) for 24, 48 and 72 h, respectively. The CCK-8 results show that Tanshinone IIA can significantly inhibit A549 cell proliferation in a dose- and time-dependent manner. Obvious apoptosis and cell growth inhibition of A549 cells are observed after drug treatment for 48 h (concentrations used are approximately IC50 values: Tanshinone IIA 31 μM on A549). Western blotting finds that 48 h exposures to Tanshinone IIA (31 μM) in A549 cells, downregulates expression of VEGF and VEGFR2 protein in both drug treatment groups vs. vehicle[1]. Tanshinone IIA, one of the most abundant constituents of the root of Salvia miltiorrhiza, protects rat myocardium-derived H9C2 cells against apoptosis. Treatment of H9C2 cells with Tanshinone IIA inhibits angiotensin II-induced apoptosis by downregulating the expression of PTEN (phosphatase and tensin homolog), a tumor suppressor that plays a critical role in apoptosis. Tanshinone IIA inhibits angiotensin II (AngII)-induced apoptosis by downregulating the expression of phosphatase and tensin homolog (PTEN)[2]. Tanshinone IIA decreases the protein expression of EGFR, and IGFR blocking the PI3K/Akt/mTOR pathway in gastric carcinoma AGS cells[3].

References:
[1]. Xie J, et al. 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]. Zhang Z, et al. 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]. Su CC, et al. 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.

Tanshinone IIA protects cardiac myocytes against oxidative stress-triggered damage and apoptosis.[Pubmed:17537428]

Eur J Pharmacol. 2007 Jul 30;568(1-3):213-21.

Tanshinone IIA (tan), a derivative of phenanthrenequinone, is one of the key components of Salvia miltiorrhiza Bunge. Previous reports showed that tan inhibited the apoptosis of cultured PC12 cells induced by serum withdrawal or ethanol. However, whether tan has a cardioprotective effect against apoptosis remains unknown. In this study, we investigated the effects of tan on cardiac myocyte apoptosis induced both by in vitro incubation of neonatal rat ventricular myocytes with H(2)O(2) and by in vivo occlusion followed by reperfusion of the left anterior descending coronary artery in adult rats. In vitro, as revealed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay, treatment with tan prior to H(2)O(2) exposure significantly increased cell viability. Tan also markedly inhibited H(2)O(2)-induced cardiomyocyte apoptosis, as detected by ladder-pattern fragmentation of genomic DNA, chromatin condensation, and hypodioloid DNA content. In vivo, tan significantly inhibited ischemia/reperfusion-induced cardiomyocyte apoptosis by attenuating morphological changes and reducing the percentage of terminal transferase dUTP nick end-labeling (TUNEL)-positive myocytes and caspase-3 cleavage. These effects of tan were associated with an increased ratio of Bcl-2 to Bax protein in cardiomyocytes, an elevation of serum superoxide dismutase (SOD) activity and a decrease in serum malondialdehyde (MDA) level. Taken together, these data for the first time provide convincing evidence that tan protects cardiac myocytes against oxidative stress-induced apoptosis. The in vivo protection is mediated by increased scavenging of oxygen free radicals, prevention of lipid peroxidation and upregulation of the Bcl-2/Bax ratio.

Tanshinone IIA Inhibits Proliferation and Induces Apoptosis Through the Downregulation of Survivin in Keloid Fibroblasts.[Pubmed:26101974]

Ann Plast Surg. 2016 Feb;76(2):180-6.

Keloids are considered benign dermal fibroproliferative tumors. Keloid fibroblasts (KFs) persistently proliferate and fail to undergo apoptosis, and no treatment is completely effective against these lesions. Tanshinone IIA induces apoptosis and inhibits the proliferation of various tumor cell types. In this study, we investigated the effect of Tanshinone IIA on the regulation of proliferation, cell cycle, and apoptosis in KFs, and investigated potential mechanisms involved in the effects. First, KFs and normal skin fibroblasts (NSFs) were treated with various concentrations of Tanshinone IIA. Cell counting kit-8 (CCK-8) was used to assess the proliferative activity of KFs and NSFs, and flow cytometry was used to investigate the cell cycle and apoptosis in KFs. We found that the proliferation of all Tanshinone IIA-treated KFs was significantly decreased after treatment for 72 hours (P < 0.001). Also, NSFs treated with Tanshinone IIA did not exhibit noticeable effects compared with KFs. In addition, the percentages of G0/G1 cells in all Tanshinone IIA-treated KFs were significantly increased after treatment for 72 hours (P < 0.001). And the percentages of cells undergoing early apoptosis in all Tanshinone IIA-treated KFs were significantly increased after treatment for 120 hours (P < 0.001). Furthermore, the apoptosis antibody array kit and Western blot analysis revealed that Tanshinone IIA decreased survivin expression in KFs (P < 0.001). In conclusion, Tanshinone IIA downregulates survivin and deactivates KFs, thus suggesting that Tanshinone IIA could serve as a potential clinical keloid treatment.

Anabolic effect of the traditional Chinese medicine compound tanshinone IIA on myotube hypertrophy is mediated by estrogen receptor.[Pubmed:26018796]

Planta Med. 2015 May;81(7):578-85.

Skeletal muscle loss during menopause is associated with a higher risk of developing diabetes type II and the general development of the metabolic syndrome. Therefore, strategies combining nutritional and training interventions to prevent muscle loss are necessary. Danshen Si Wu is a traditional Chinese medicine used for menopausal complains. One of the main compounds of Danshen Si Wu is Tanshinone IIA. Physiological effects of Tanshinone IIA have been described as being mediated via the estrogen receptor. Therefore, it was the aim of this study to determine its tissue specific ERalpha- and ERbeta-mediated estrogenic activity, to investigate its antiestrogenic properties, and, particularly, to study estrogen receptor-mediated biological responses to Tanshinone IIA on skeletal muscle cells. The purity of Tanshinone IIA was analyzed by LC-DAD-MS/MS analysis. ERalpha/ERbeta-mediated activity was dose-dependently analyzed in HEK 239 cells transfected with ERalpha or ERbeta expression vectors and respective reporter genes. Androgenic, antiandrogenic, and antiestrogenic properties of Tanshinone IIA were analyzed in a yeast reporter gene assay. The effects of Tanshinone IIA on proliferation and cell cycle distribution were investigated in ERalpha positive T47D breast cancer cells. The ability of Tanshinone IIA to stimulate estrogen receptor-mediated myotube hypertrophy was studied in C2C12 myoblastoma cells. Our data show that Tanshinone IIA is quite potent at stimulating ERalpha and ERbeta reporter genes with comparable efficacy. Tanshinone IIA displayed antiestrogenic and also antiandrogenic properties in a yeast reporter gene assay. It inhibited the growth of T47D breast cancer cells by suppressing proliferation and arresting the cells in G0/G1. Tanshinone IIA also stimulated the hypertrophy of C2C12 myotubes via an estrogen receptor-mediated mechanism. Summarizing our results, Tanshinone IIA can be characterized as an estrogen receptor partial agonist with antiandrogenic properties. It seems to inhibit ERalpha-mediated cell proliferation but induces ERbeta-related biological responses like hypertrophy of myotubes. These findings are interesting with respect to the treatment of a variety of complains of postmenopausal females, including muscle wasting.

Tanshinone IIA prevents the loss of nigrostriatal dopaminergic neurons by inhibiting NADPH oxidase and iNOS in the MPTP model of Parkinson's disease.[Pubmed:25491263]

J Neurol Sci. 2015 Jan 15;348(1-2):142-52.

Tanshinone IIA is one of the major constituents of Salvia miltiorrhiza Bunge known as Danshen. Recent reports have shown that Tanshinone IIA has neuroprotective effects against cerebral ischemia/reperfusion injury and traumatic injury of the spinal cord in rats. However, whether Tanshinone IIA has any neuroprotective effect in Parkinson's disease remains unknown. In this study, we evaluated whether Tanshinone IIA promotes the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. MPTP induced degeneration of nigrostriatal DA neurons and microglial activation as visualized by tyrosine hydroxylase and CD11b immunoreactivity. The results of Western blot and immunohistochemistry showed upregulation of NADPH oxidase and iNOS in the MPTP-treated substantia nigra pars compacta. Treatment with Tanshinone IIA prevented degeneration of nigrostriatal DA neurons and increased the level of striatal dopamine content. This neuroprotection afforded by Tanshinone IIA was associated with the suppression of microglial activation and reduced expression of NADPH oxidase and iNOS. The present findings show that Tanshinone IIA may possess anti-inflammatory and anti-oxidative properties and may have therapeutic value in the treatment of Parkinson's disease.

Tanshinone IIA protects against methylglyoxal-induced injury in human brain microvascular endothelial cells.[Pubmed:25932127]

Int J Clin Exp Med. 2015 Feb 15;8(2):1985-92. eCollection 2015.

Tanshinone IIA is one of the major diterpenes from Salvia miltiorrhiza Bunge and has been shown to possess a protective effect on the endothelial cells. The present study aimed to investigate whether Tanshinone IIA could protect against methylglyoxal (MGO)-induced injury in human brain microvascular endothelial cells (HBMEC). Using cultured HBMEC, cell viability was measured by MTT assay and trypan blue dye exclusion test. Cellular oxidative stress was measured by production of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS) and H2O2. AnnexinV/PI staining and western blot were performed to determine cell apoptosis and protein expression. We found that MGO treatment caused a concentration and time-dependent decrease in cell viability, which was inhibited by pretreatment with Tanshinone IIA. Exposure to MGO promoted the accumulation of AGEs, and production of ROS, TBARS and H2O2 in the cultured HBMEC, which were inhibited by Tanshinone IIA pretreatment. Addition of Tanshinone IIA significantly reduced MGO-induced cell apoptosis as shown by flow cytometry. On the molecular level, Tanshinone IIA administration altered the expression of apoptosis-related proteins such as p53, Bax, Bcl-2 and cyto C. In addition, MGO treatment remarkably increased the phosphorylation of MAPK family including p38, JNK and ERK. By contrast, addition of Tanshinone IIA inhibited the activation of MAPK family members. These data indicated that Tanshinone IIA could protect against MGO-induced cell injury through inhibiting MAPK activation in HBMEC.

Effect of Tanshinone IIA intrathecal injections on pain and spinal inflammation in mice with bone tumors.[Pubmed:25867360]

Genet Mol Res. 2015 Mar 20;14(1):2133-8.

The study aimed to investigate the effect of intrathecal injections of Tanshinone IIA on thermal hyperalgesia in a mouse model of bone cancer-pain. Spinal IL-1beta, IL-6, TNF-alpha expression levels were analyzed. C3H/HeNCrlVr male mice were assigned to groups that either received dose-dependent injections of Tanshinone IIA, or the DMSO + Sham, Tanshinone IIA + Sham, DMSO + Tumor, and Control groups. Paw withdrawal thermal latency (PWTL) was measured with a radiant heat stimulus and mRNA expression levels were determined using real-time PCR. Fourteen days post-injection, PWTL in the DMSO + Tumor group was lower than that in the controls (P < 0.05). Twenty-one days post-injection, compared with the Control group, there was no significant difference in PWTL and IL-1beta, IL-6, and TNF-alpha expression levels between the Tanshinone IIA + Sham and DMSO + Sham groups (P > 0.05). PWTL in the DMSO + Tumor group was significantly lower than the Control group (P < 0.05), while the expression levels of IL-1beta, IL-6, and TNF-alpha were significantly higher than controls. Compared with the DMSO + Tumor group, PWTLs were higher in the Tanshinone IIA - 20-mug and 40-mug groups, while expression levels of IL-1beta, IL-6, and TNF-alpha were significantly lower (P < 0.05). These measures were not significantly different between the Tanshinone IIA 10 mug and the DMSO + Tumor groups (P > 0.05). In conclusion, Tanshinone IIA may inhibit the release of inflammatory cytokines, such as, IL-1 beta, IL-6 alpha, TNF-alpha.

Tanshinone IIA inhibits leukemia THP-1 cell growth by induction of apoptosis.[Pubmed:19288011]

Oncol Rep. 2009 Apr;21(4):1075-81.

Tanshinone IIA, a diterpene quinone extracted from the traditional herbal medicine, Salvia miltiorrhiza Bunge, has been reported to have anti-tumor effects on a large variety of cancer cells. The present study was undertaken to investigate the in vitro antiproliferation and apoptosis inducing effects of Tanshinone IIA on leukemia THP-1 cell lines and its mechanisms of action. MTT assay was used to detect the cell growth inhibitory rate; cell apoptotic rate and the mitochondrial membrane potential (Deltapsim) were investigated by flow cytometry (FCM), apoptotic morphology was observed by Hoechst 33258 staining and DNA fragmentation analysis. The expression of caspase-3 and different apoptosis modulators were analyzed by Western blotting. The results revealed that Tanshinone IIA inhibited the growth of THP-1 cells and caused significant apoptosis, the suppression was both in time- and dose-dependent manner. After treatment by Tanshinone IIA for 48 h, the percentage of disruption of Deltapsim gradually increased in a dose-dependent manner along with marked changes of cell apoptosis. Western blotting showed cleavage of the caspase-3 zymogen protein (32-kDa) with the appearance of its 20-kDa subunit and a dose-dependent cleavage of PARP, with the appearance of 89-kDa fragment; The expression of Bcl-2 and survivin was down-regulated remarkably while Bax expression was up-regulated concurrently after the cells were treated with Tanshinone IIA for 48 h. We therefore conclude that Tanshinone IIA has significant growth inhibition effects on THP-1 cells by induction of apoptosis, and that Tanshinone IIA-induced apoptosis on THP-1 cells is mainly related to the disruption of Deltapsim and activation of caspase-3 as well as down-regulation of anti-apoptotic protein Bcl-2, survivin and up-regulation of pro-apoptotic protein Bax. The results indicate that Tanshinone IIA may serve as a potential anti-leukemia reagent.

Tanshinone IIA protects PC12 cells from beta-amyloid(25-35)-induced apoptosis via PI3K/Akt signaling pathway.[Pubmed:22314911]

Mol Biol Rep. 2012 Jun;39(6):6495-503.

For the aging populations of any nation, Dementia is becoming a primary problem and Alzheimer's dementia (AD) is the most common type. However, until now, there is no effective treatment for AD. Tanshinone IIA (Tan IIA) has been reported for neuroprotective potential to against amyloid beta peptides (Abeta)-induced cytotoxicity in the rat pheochromocytoma cell line PC-12, which is widely used as AD research model, but the mechanism still remains unclear. To investigate the effect of Tan IIA and the possible molecular mechanism in the apoptosis of PC12 cells, we induced apoptosis in PC12 cells with beta-amyloid(25-35), and treated cells with Tan IIA. After 24 h treatment, we found that Tan IIA increased the cell viability and reduced the number of apoptotic cells induced by Abeta(25-35). However, neuroprotection of Tan IIA was abolished by PI3K inhibitor LY294002. Meanwhile, Treatment with lithium chloride, a phosphorylation inhibitor of GSK3beta, which is a downstream target of PI3K/Akt, can block Abeta(25-35)-induced cell apoptosis in a Tan IIA-like manner. Our findings suggest that Tan IIA is an effective neuroprotective agent and a viable candidate in AD therapy and PI3K/Akt activation and GSK3beta phosphorylation are involved in the neuroprotection of Tan IIA.

Anticancer effects of tanshinone I in human non-small cell lung cancer.[Pubmed:19001436]

Mol Cancer Ther. 2008 Nov;7(11):3527-38.

Tanshinones are the major bioactive compounds of Salvia miltiorrhiza Bunge (Danshen) roots, which are used in many therapeutic remedies in Chinese traditional medicine. We investigated the anticancer effects of tanshinones on the highly invasive human lung adenocarcinoma cell line, CL1-5. Tanshinone I significantly inhibited migration, invasion, and gelatinase activity in macrophage-conditioned medium-stimulated CL1-5 cells in vitro and also reduced the tumorigenesis and metastasis in CL1-5-bearing severe combined immunodeficient mice. Unlike Tanshinone IIA, which induces cell apoptosis, tanshinone I did not have direct cytotoxicity. Real-time quantitative PCR, luciferase reporter assay, and electrophoretic mobility shift assay revealed that tanshinone I reduces the transcriptional activity of interleukin-8, the angiogenic factor involved in cancer metastasis, by attenuating the DNA-binding activity of activator protein-1 and nuclear factor-kappaB in conditioned medium-stimulated CL1-5 cells. Microarray and pathway analysis of tumor-related genes identified the differentially expressed genes responding to tanshinone I, which may be associated with the Ras-mitogen-activated protein kinase and Rac1 signaling pathways. These results suggest that tanshinone I exhibits anticancer effects both in vitro and in vivo and that these effects are mediated at least partly through the interleukin-8, Ras-mitogen-activated protein kinase, and Rac1 signaling pathways. Although tanshinone I has a remarkable anticancer action, its potential anticoagulant effect should be noted and evaluated.

Growth inhibition and induction of apoptosis and differentiation of tanshinone IIA in human glioma cells.[Pubmed:16955220]

J Neurooncol. 2007 Mar;82(1):11-21.

Tanshinone IIA is a derivative of phenanthrene-quinone isolated from Danshen, a widely used Chinese herbal medicine. It has antioxidant properties, cytotoxic activities against multiple human cancer cells, inducing apoptosis and differentiation of some human cancer cells. The purpose of this study is to confirm its anticancer activity on human glioma cells, and to elucidate mechanism of its activity. Human glioma cells were tested in vitro for cytotoxicity, colony formation inhibition, BrdU incorporation after treatment with Tanshinone IIA. Its effect of apoptosis induction was detected through EB/AO staining, cell cycle analysis and the expressions of ADPRTL1 and CYP1A1 genes, the differentiation induction effect was investigated through morphology, mRNA and protein expressions of GFAP and nestin genes by RT-PCR and immunocytochemistry. Tanshinone IIA demonstrated a dose- and time-dependent inhibitory effect on cell growth, IC(50) was 100 ng/ml, and it significantly inhibited colony formation and BrdU incorporation of human glioma cells. After treatment with 25-100 ng/ml of Tanshinone IIA, the apoptotic cells increased significantly (P < 0.01), the cells in G(0)/G(1) phase increased (P < 0.01), and decreased in S phase, ADPRTL1 and CYP1A1 mRNA expression increased 1-2 folds. The cells treated with 100 ng/ml Tanshinone IIA demonstrated astrocytes or neuron-like morphology, GFAP mRNA and protein expressions increased, nestin mRNA and protein expressions decreased significantly. The findings in this study suggested that Tanshinone IIA exhibited strong effects on growth inhibition and induction of apoptosis and differentiation in human glioma cells. It might serve as a novel promising differentiation-inducing and/or therapeutic agent for human gliomas, and need to be investigated further.

Tanshinone IIA (Tan IIA) is one of the main fat-soluble compositions in the root of red-rooted salvia. Tanshinone IIA may suppress angiogenesis by targeting the protein kinase domains of VEGF/VEGFR2.

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