Salvia Miltiorrhiza, or Dan Shen, is a Chinese herb, first mentioned in the second century as a superior herb with bitter cool properties used to support healthy blood circulation. Blood flow is life itself and is a core factor of our physical health. Poor blood circulation results in improper functioning of internal organs; therefore, it is at the root of many serious health issues.*
Tanshins contained in Salvia Miltiorrhiza, derives its name from tanshinones, a group of bioactive compounds isolated from Salvia miltiorrhiza (Dan shen). Dan Shen is a well-researched plant, also called ‘red ginseng’. The research verifies the use the ancients gave for this herb.*
Supports healthy vascular integrity*
Helps promote normal cell cycle*
Encourages healthy cellular metabolism*
Tanshins and Chemo therapy
Tanshinones, just like berberine down-regulate CYP3A4. This enzyme detoxifies (breaks down) chemo agents. This means these products make chemo more effective as well as reduce side effects of the chemo. It increases drug efficacy and gives patients better results.*
In the course of screening of angiogenesis inhibitor from natural products, cryptotanshinone from Salvia miltiorrhiza (Dan shen) was isolated as a potent small molecule inhibitor of angiogenesis. Cryptotanshinone inhibits bFGF-induced angiogenesis of BAECs at ten micromolar ranges in vitro without cytotoxicity. These results demonstrate that cryptotanshinone is a new anti-angiogenic agent and double bond at C-15 position of the dihydro-furan ring plays a crucial role in the activity (Hur et al, 2005).*
Cryptotanshinone (CPT), a natural compound, is a potential anti-cancer agent. Chen et al., (2010) have shown that CPT inhibited cancer cell proliferation by arresting cells in G(1)-G(0) phase of the cell-cycle. This is associated with the inhibition of cyclin D1 expression and retinoblastoma (Rb) protein phosphorylation.*
Furthermore, they found that CPT inhibited the signaling pathway of the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation. This is evidenced by the findings that CPT inhibited type I insulin-like growth factor I- or 10% fetal bovine serum-stimulated phosphorylation of mTOR, p70 S6 kinase 1, and eukaryotic initiation factor 4E binding protein 1 in a concentration- and time-dependent manner. Expression of constitutively active mTOR conferred resistance to CPT inhibition of cyclin D1 expression and Rb phosphorylation, as well as cell growth. The results suggest that CPT is a novel anti-proliferative agent.*
Cryptotanshinone (20 or 40mg/kg) was orally administered 12 and 1h prior to GalN (700mg/kg)/LPS (10µg/kg) injection. The increased mortality and TNF-α levels by GalN/LPS were declined by cryptotanshinone pre-treatment. In addition, cryptotanshinone attenuated GalN/LPS-induced apoptosis, characterized by the blockade of caspase-3, -8, and -9 activation, as well as the release of cytochrome c from the mitochondria. Furthermore, cryptotanshinone significantly inhibited the activation of NF-κB and suppressed the production of pro-inflammatory cytokines.*
These findings suggest that the hepato-protective effect of cryptotanshinone is likely to be associated with its anti-apoptotic activity and the down-regulation of MAPKs and NF-κB associated at least in part with suppressing TAK1 phosphorylation (Jin et al., 2013).*
Cryptotanshinone & COX-2
Cyclooxygenase-2 (COX-2) is a key enzyme that catalyzes the biosynthesis of prostaglandins from arachidonic acid and plays a critical role in some pathologies including inflammation, neurodegenerative diseases and cancer. Cryptotanshinone is a major constituent of tanshinones, which are extracted from the medicinal herb Salvia miltiorrhiza Bunge, and has well-documented antioxidative and anti-inflammatory effects. This study confirmed the remarkable anti-inflammatory effect of cryptotanshinone in the carrageenan-induced rat paw edema model. Since the action of cryptotanshinone on COX-2 has not been previously described, the study further examined the effect of cryptotanshinone on cyclooxygenase activity in the exogenous arachidonic acid-stimulated insect sf-9 cells, which highly express human COX-2 or human COX-1.*
The study also examined the effect on cyclooxygenases expression in human U937 promonocytes stimulated by lipopolysaccharide (LPS) plus phorbolmyristate acetate (PMA). Cryptotanshinone reduced prostaglandin E2 synthesis and reactive oxygen species generation catalyzed by COX-2, without influencing COX-1 activity in cloned sf-9 cells. In PMA plus LPS-stimulated U937 cells, cryptotanshinone had negligible effects on the expression of COX-1 and COX-2, at either a mRNA or protein level. These results demonstrate that the anti-inflammatory effect of cryptotanshinone is directed against enzymatic activity of COX-2, not against the transcription or translation of the enzyme (Dao-Zhong Jin et al, 2006).*
Because signal transducer and activator of transcription 3 (STAT3) is constitutively activated in most human solid tumors and is involved in the proliferation, angiogenesis, immune evasion, and antiapoptosis of cancer cells, researchers have focused on STAT3 as a target for cancer therapy.*
Shin et al., (2009) screened for natural compounds that inhibit the activity of STAT3 using a dual-luciferase assay. Cryptotanshinone was identified as a potent STAT3 inhibitor. Cryptotanshinone rapidly inhibited STAT3 Tyr705 phosphorylation in DU145 prostate cancer cells and the growth of the cells through 96 hours of the treatment. Inhibition of STAT3 Tyr705 phosphorylation in DU145 cells decreased the expression of STAT3 downstream target proteins such as cyclin D1, survivin, and Bcl-xL.
Cryptotanshinone from Salvia miltiorrhiza BUNGE has an inhibitory effect on TNF-α-induced matrix metalloproteinase-9 production and HASMC migration via down-regulated NF-κB and AP-1(Shin et al, 2009).*
Searching for efficacious and safe agents for the chemoprevention and therapy of prostate cancer has become the top priority of research. The objective of this study was to determine the effects of a group of tanshinones from a Chinese herb Salvia Miltiorrhiza; cryptotanshinone (CT), tanshinone IIA (T2A) and tanshinone I (T1) on prostate cancer. The in vitro studies showed that these tanshinones inhibited the growth of human prostate cancer cell lines in a dose-dependent manner via cell cycle arrest and apoptosis induction. Tanshinones significantly downregulated the Aurora A expression, suggesting Aurora A may be a functional target of tanshinones (Gong et al, 2011).*
Cryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells.
The androgen receptor (AR) is the major therapeutic target for the treatment of prostate cancer (PCa). Anti-androgens to reduce or prevent androgens binding to AR are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy is only effective for a short period of time. Shu et al., (2012) found a natural product/Chinese herbal medicine cryptotanshinone (CTS), with a structure similar to dihydrotestosterone (DHT), can effectively inhibit the DHT-induced AR transactivation and prostate cancer cell growth. The results indicated that 0.5 μM CTS effectively suppresses the growth of AR-positive PCa cells, but has little effect on AR negative PC-3 cells and non-malignant prostate epithelial cells. Furthermore, the data indicated that CTS could modulate AR transactivation and suppress the DHT-mediated AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration resistant CWR22rv1 cells. Importantly, CTS selectively inhibits AR without repressing the activities of other nuclear receptors, including ERα, GR, and PR. The mechanistic studies indicate that CTS functions as an AR inhibitor to suppress androgen/AR-mediated cell growth and PSA expression by blocking AR dimerization and the AR-coregulator complex formation. Furthermore, Shu et al., (2012) showed that CTS effectively inhibits CWR22Rv1 cell growth and expressions of AR target genes in the xenograft animal model. The mechanisms of CTS may explain how CTS inhibits the growth of PCa cells and therefore help to establish new therapeutic concepts for the treatment of PCa.*
Effects of TANSHINS on Cytochrome P450 Isoforms.
The cytochrome P450 enzymes are found primarily in the liver. TANSHINS (CTS) significantly increased the activity of CYP1A2 in a dose-dependent manner. In CTS groups at the dosages of 20 ~ 540 mg/kg, the activity of CYP1A2 was 60 % ~ 430 % higher, CYP1A2 protein expression level was 130 % ~ 320 % higher, and CYP1A2 mRNA expression level was 10 % ~ 150 % higher than that of the negative control group. CTS had no effect on other kinds of CYP isoforms. CTS can induce hepatic microsome CYP1A2 expression significantly, which indicates potential drug-drug interaction might occur when CTS is co-administrated with those drugs metabolized by CYP1A2 such as Capecitabine / Capecitabine (Xeloda), Lapatinib / Lapatinib (Tykerb) (Ying, Ying, Huichang and Min, 2009).*
Coexisted components of Salvia miltiorrhiza enhance intestinal absorption of cryptotanshinone
Cryptotanshinone, derived from the roots of Salvia miltiorrhiza Bge and Salvia przewalskii Maxim, is the major active component and possesses significant antibacterial, antidermatophytic, antioxidant, anti-inflammatory and anticancer activities. The intestinal absorptive characteristics of cryptotanshinone was investigated, as well as the absorptive behavior influenced by co-administration of the diterpenoid tanshinones and danxingfang using an in vitro everted rat gut sac model. The results showed a good linear correlation between cryptotanshinone of absorption and the incubation time from 10 to 70min. The concentration dependence showed that a non-linear correlation existed between the cryptotanshinone absorption and the concentration at 100μg/ml. Coexisting diterpenoid tanshinones and danxingfang could significantly enhance the absorption of cryptotanshinone. Coexisting diterpenoid tanshinones and danxingfang, which influenced cryptotanshinone's absorption, manifested as similar to that of the P-glycoprotein inhibitor. The underlying mechanism of the improvement of oral bioavailability was proposed that coexisting diterpenoid tanshinones and danxingfang could decrease the efflux transport of cryptotanshinone by P-glycoprotein (Haixue et al, 2012).*
Apoptosis Induced by Tanshinone IIA and Cryptotanshinone
Though tanshinone IIA and cryptotanshinone possess a variety of biological effects such as anti-inflammatory, antioxidative, antimetabolic, and anticancer effects, the precise molecular targets or pathways responsible for anticancer activities of tanshinone IIA and cryptotanshinone in chronic myeloid leukemia (CML) still remain unclear.*
The effect of tanshinone IIA and cryptotanshinone on the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling during apoptotic process was investigated. It was found that both tanshinone IIA and cryptotanshinone induced apoptosis occurred through the activation of caspase-9/3 and Sub-G1 accumulation in K562 cells. However, they were also found to have the distinct JAK/STAT pathway, in which tanshinone IIA inhibits JAK2/STAT5 signaling, whereas cryptotanshinone targets the JAK2/STAT3.*
In addition, tanshinone IIA enhanced the expression of both SHP-1 and -2, while cryptotanshinone regulated the expression of only SHP-1. Both tanshinone IIA and cryptotanshinone attenuated the expression of bcl-xL, survivin, and cyclin D1. Furthermore, tanshinone IIA augmented synergy with imatinib, a CML chemotherapeutic drug, better than cryptotanshinone in K562 cells.*
Overall, our findings suggest that the anticancer activity of tanshinone IIA and cryptotanshinone is mediated by the distinct the JAK/STAT3/5 and SHP1/2 signaling, and tanshinone IIA has the potential for combination therapy with imatinib in K562 CML cells (Jung et al., 2013).*
Anti-atherosclerotic effect of tanshinone IIA
Tanshinone IIA is one of the major diterpenes in Salvia miltiorrhiza. The inhibitory effect of Tanshinone IIA on atherosclerosis has been reported, but the underlying mechanism is not fully understood. The anti-atherosclerosis effect of Tanshinone IIA on the adhesion of monocytes to vascular endothelial cells and related mechanism was studied. Results showed that Tanshinone IIA, at the concentrations without cytotoxic effect, dose-dependently inhibited the adhesion of THP-1 monocytes to the TNF-α-stimulated human vascular endothelial cells. The expressions of cell adhesion molecules including VCAM-1, ICAM-1 and E-selectin were induced by TNF-α in HUVECs at both the mRNA and protein levels. The mRNA and protein expressions of VCAM-1 and ICAM-1, but not E-selectin, were both significantly suppressed by Tanshinone IIA in a dose dependent manner. In addition, the TNF-α-induced mRNA expression of fractalkine/CX3CL1 and the level of soluble fractalkine were both reduced by Tanshinone IIA.*
Chang et al., (2013) found that Tanshinone IIA significantly inhibited TNF-α-induced nuclear translocation of NF-κB which was resulted from the inhibitory effect of Tanshinone IIA on the TNF-α-activated phosphorylation of IKKα, IKKβ, IκB and NF-κB. As one of the major components of Salvia miltiorrhiza, Tanshinone IIA alone exerted more potent effect on inhibiting the adhesion of monocytes to vascular endothelial cells when compared with Salvia miltiorrhiza.*
All together, these results demonstrated a novel underlying mechanism for the anti-inflammatory effect of Tanshinone IIA by modulating TNF-α-induced expression of VCAM-1, ICAM-1 and fractalkine through inhibition of TNF-α-induced activation of IKK/NF-κB signaling pathway in human vascular endothelial cells (Chang et al, 2013).*
Synergistic antitumor effects of tanshinone II A in combination with Cryptotanshinone Restores Sensitivity via apoptosis in the prostate cancer cells. Treatment with the combination of Chinese herbs and cytotoxic chemotherapies showed a higher survival rate in clinical trials. In this report, the results demonstrated that the tanshinone II A, a key component of Salvia miltiorrhiza bunge, when it is combined with the cytotoxic drug cisplatin showed synergistic antitumor effects on human prostate cancer PC3 cells and LNCaP cells in vitro.*
Anti-proliferative effects were detected with MTT assay. Cell cycle distribution and apoptosis were detected by flow cytometer. Protein expression was detected by Western blotting. The intracellular concentration of cisplatin was detected by high performance liquid chromatography. The results demonstrated that tanshinone II A significantly enhanced the anti-proliferative effects of cisplatin on human prostate cancer PC3 cells and LNCaP cells with the increase of the intracellular concentration of cisplatin.*
These effects were correlated with cell cycle arrested at S phase and cell apoptosis. The apoptosis might be achieved through death receptor pathway and mitochondrial pathway. Furthermore, the Bcl-2 family members were also involved in this apoptotic process. Collectively, these results indicated that the combination of tanshinone II A and cisplatin had a better treatment effect in vitro not only on androgen-dependent LNCaP cells but also on androgen-independent PC3 cells (Hou et al, 2013).*
Anticancer activity, breast cancer
Human ER positive breast cancer cells (MCF-7) and ER negative cells (MDA-MB-231) were tested in vitro for cytotoxicity of tanshinone II A with MTT method. The effect of tanshinone II A on DNA synthesis and apoptosis of both human breast cancer cells were evaluated with Brdu incorporation and flow cytometry. Immunohistochemistry were applied to test the P53, CerBb-2 and Bcl-2 protein expression of both cells.*
After Tanshinone II A treatment, a dose- and time-dependent decreased proliferation in both MCF-7 and MDA-MB-231 cells were observed (P < 0.05) with a IC50 0.25 microg/mL. A decreased BrdU incorporation and an increased apoptosis in both cells were also observed (P < 0.05 and P < 0.01 respectively). Immunohistochemistry test demonstrated that tanshinone A upregulate P53 expression in both cells and also weakly upregulate the CerBb-2 expression in MCF-7 (P < 0.05), whereas no influence on CerBb-2 expression of MDA-MB-231 and on Bcl-2 expression of both cells were demonstrated (P > 0.05).*
This study suggested that tanshione II A could inhibit the proliferation, induce apoptosis of ER-positive breast cancer cell MCF-7 and ER-negative breast cancer cell in vitro. The mechanism may be associated with the inhibition of DNA synthesis, induction of apoptosis, but may not with the expression level of gene p53, cer Bb-2 and bcl-2 (Zhang and Lu, 2009).*
Breast cancer, in vivo
Established the animal model of nude mices bearing human breast cell (both ER positive MCF-7 and ER negative MDA-MB-231) were used. Each group was divided into 3 subgroups, respectively by intraperitoneal injection of Tan II A at a dose of 30 mg/kg 4 times/week, by gavage of Tamoxifen at a dose of 1 mg/kg 7 times/ week and by solvent control for 4 weeks. All animals were tested for anti-cancer activity including the weights and the volumes of the tumor, apoptosis index by flow cytometry and expression of p53, bcl-2, cerbB-2 by immunohistochemistry method after the treatment.*
In MCF-7 group, there were a 33.64% tumor mass volume reduction and a 32.24% tumor mass weight reduction after Tan II A treatment; in MDA-MB-231 group, a 38.34% tumor mass volume reduction and a 39.82% tumor mass weight reduction were observed in Tan II A subgroups; the differences between Tan II A and Tamoxifen or solvent control were statistically significant in both groups (P < 0.05); increase of apoptosic fiction by flow cytometry examination in Tan II A subgroups in both MCF-7 (48.31% +/- 5.84%) and MDA-MB-231(50.25% +/- 5.03%) groups were observed, there were both significant differences between Tan II A and the other subgroups (P < 0.05). Statistically significant decrease of p53 and bcl-2 expression were observed in Tan lI A between solvent control subgroup in both MCF-7 and MDA-MB-231 groups (P < 0.05) while cerbB-2 had no significant difference with control group (P > 0.05).*
Hence, Tan lI A was found to inhibit both breast cancer cell MCF-7 and MDA-MB-231 growth in vivo, which had better anti-cancer effect than Tamoxifen. The mechanism may be associated with the induction of apoptosis, down regulation of the expression level of gene bcl-2 and p53, but may not with the expression level of cerbB-2 (Zhang et al, 2010).*
Tanshinone IIA and non-small cell lung cancer
The binding mode of tanshinone IIA within the crystal structure of the VEGFR2 protein was evaluated with molecular docking analysis by use of the CDOCKER algorithm in Discovery Studio 2.1. The CCK-8 results showed that tanshinone IIA can significantly inhibit A549 cell proliferation in a dose- and time-dependent manner. The expression of VEGF and VEGFR2 was decreased in Western blot. Finally, molecular docking analysis revealed that tanshinone IIA could be stably docked into the kinase domain of VEGFR2 protein with its unique modes to form H-bonds with Cys917 and π-π stacking interactions with Val848. In conclusion, tanshinone IIA may suppress A549 proliferation, induce apoptosis and cell cycle arrest at the S phase. This drug may suppress angiogenesis by targeting the protein kinase domains of VEGF/VEGFR2 (Xie et al., 2015).*
Tanshinone IIA (Tan-2A; 20 and 60 mg/kg/day) significantly decreased the tumor size of MDA-MB-231 xenograft mice after 90 days compared the control group. NF-κBp65 and caspase 3 protein expression had also been reduced by Tan-2A treatment in the tumors. Additionally, MDA-MB-231 cells treated with Tan-IIA for 48 hours decreased the protein expression of Erb-B2 (Su et al., 2012).*
Danshen more potently inhibited MCF-7 cell growth than a 70% ethanolic medicinal mushroom extract denoted I'm-Yunity-Plus. Danshen also inhibited cells from G1/S phase entering G2/M phases of the cell cycle after 3 days of treatment with 7.5 μl/ml. Treatment with Danshen significantly reduced the expression of Rb, which plays a pivotal role in the control of the G1/S cell cycle checkpoint. Danshen also reduced cell cycle regulator cyclin D1 expression, p53 expression, as well as p65 and p50 subunits of NF-kappaB (Hsieh, & Wu, 2006).*
VEGF is a sub-family of growth factors, specifically the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis (the growth of blood vessels from pre-existing vasculature) (Ferrara & Gerber, 2002). VEGF is critical for vascularization of tissues, including tumors (Loureiroa & D’Amore, 2005).*
VEGF over-expression in breast cancer cells potently increased intratumoral lymphangiogenesis, resulting in significantly enhanced metastasis to regional lymph nodes and to lungs. These results establish the occurrence and biological significance of intratumoral lymphangiogenesis in breast cancer and identify VEGF as a molecular link between tumor lymphangiogenesis and metastasis (Skobe et al., 2001).*
VEGF in breast cancer is not limited to angiogenesis, and that VEGF signaling in breast carcinoma cells is important for the ability of these cells to evade apoptosis and progress towards invasive and metastatic disease. VEGF and VEGF receptor-based therapeutics, in addition to targeting angiogenesis, may also target tumor cells directly (Mercurio et al., 2005).*
Tanshinone IIA (T2A) inhibited the high expression of HIF-1α in MCF7 and MDA-MB-231 cells under normoxic conditions in a dose-dependent manner. Hypoxia markedly induced HIF-1α expression, but T2A still inhibited HIF-1α expression at concentrations of 5-20 μM in whole cell and nuclear extracts. Moreover, both cell lines were pre-treated with an mTOR inhibitor, which exacerbated the inhibitory effects of T2A on HIF-1α expression, as well as VEGF expression under both normoxic and hypoxic conditions. A MDA-MB-231 xenograft model showed that T2A (50 mg/kg) treatment could significantly (P<0.01) reduce tumor volume compared to vehicle controls. Microvessel density analysis via CD-31 (a platelet marker) demonstrated that T2A could decrease blood vessel formation in tumors, which correlated with reduced mRNA VEGF levels in real-time PCR analyses. The data shows that the mTOR/p70S6K signaling pathway was involved in T2A-induced inhibition of HIF-1α and VEGF expression, leading to the inhibition angiogenesis and tumor growth in nude mice (Li et al., 2015).*
The deposition of fibrin(ogen), along with other adhesive glycoproteins, into the extracellular matrix (ECM) serves as a scaffold to support binding of growth factors and to promote the cellular responses of adhesion, proliferation, and migration during angiogenesis and tumor cell growth. Fibrin(ogen) within the tumor stroma likely affects the progression of tumor cell growth and metastasis (Simpson-Haidaris & Rybarczyk, 2001).*
Elevated levels are often a marker of cancer progression, and tumor angiogenesis and metastatic spread of cancer. More specifically fibrin/fibrinogen deposition induces fibrinolytic activity, mainly by plasmin, resulting in extracellular matrix degradation providing fertile ground for tumor cell invasion and metastasis as well as having a direct mitogenic effect (Gerner et al., 2001; Palumbo et al., 2005).*
Fibrinogen contributes to tumor cell proliferation, progression and metastasis. Elevated preoperative plasma fibrinogen was independently associated with poor prognosis in breast cancer patients and may serve as a valuable parameter for risk assessment in breast cancer patients (Wen et al., 2015).*
Tan IIA treatment significantly increased the survival rate of rabbits with LPS-induced disseminated intravascular coagulation (DIC) (P<0.05) compared with the LPS control group. Tan IIA (1-10 mg/kg) significantly reduced the elevated APTT, PT, and levels of FDP as well as improving fibrinogen and platelets levels compared to normal and heparin controls. Tan IIA (10 mg/kg) also reversed LPS-induced liver and renal injury as indicated by ALT and Cr levels, respectively. The rabbits injected with 0.5 mg/kg of LPS had markedly increased levels of TNF-α at 1, 4, 8, and 12 hours compared to normal rabbits. This was counteracted by infusions of 1, 3, and 10 mg/kg of Tan IIA, which significantly reduced plasma levels of TNF-α at each time point compared to normal rabbits. This was comparable to heparin positive control (Wu, Lin, & Sun, 2012).*
Tanshin can improve cognitive deficits, protect neuronal cells, reduce tau hyperphosylation, prevent amyloid-β fibre formation and Alzheimer’s disease
The major components of Danshen such as salvianolic acid A, salvianolic acid B, danshensu, tanshinone I, tanshinone IIA, and cryptotanshinone exhibit the neuroprotective effects, which are attracting strong attention for the treatment of AD. The major characteristics of AD such as amyloid β plaques, neurofibrillary tangles, mitochondrial dysfunction, and autophagy dysfunction are commonly used as the important indicators for evaluating the effects of potential candidate drugs [1-4].
The rhizome of Salvia miltiorrhiza (known as ‘Danshen’ in Chinese), a famous traditional Chinese medicine, which is widely used for the treatment of hyperlipidaemia, stroke, cardiovascular and cerebrovascular diseases. Increasing evidences suggest that the bioactive components of Danshen can improve cognitive deficits in mice, protect neuronal cells, reduce tau hyperphosylation, prevent amyloid-β fibre formation and Alzheimer’s disease .
Tanshinone IIA is one kind of tanshinones extracted from Danshen, which exhibits the antioxidant and anti-inflammatory activities. The effects of tanshinone II on the Aβ-related events have been reported. Shi et al. indicated that pretreatment of tanshinone IIA (10, 20, and 40 μM) protected primary cortical neurons from Aβ25–35 induced neurotoxicity . They found that tanshinone IIA reduced Aβ-induced the cleavage of p35 into p25 and thus inhibited the Cdk5 pathway, suggesting that blocking the p35/Cdk5 pathway may contribute to the protective effects of tanshinone IIA.
Liu et al. also found that tanshinone IIA (0.1, 1, and 10 μM) reduced Aβ-induced oxidative stress and apoptosis in rat cortical neurons by inhibiting lipid peroxidation and ROS increase, stabilizing mitochondrial membrane potential, as well as reducing cytochrome c release from mitochondria . The protective effects of tanshinone IIA on SH-SY5Y cells against Aβ42-induced cytotoxicity was reported by Wang et al.  and Yang et al. .
In addition to the different working concentrations, the main difference is that Wang et al. reported the protective effects of tanshinone IIA likes tanshinone I resulted from the suppression of Aβ42 fibrils formation and the disassembly Aβ42 aggregation via directly binding to Aβ, whereas Yang et al. found that reducing Aβ42-induced endoplasmic reticulum stress contribute to the protective effects of tanshinone IIA. In animal study, Maione et al. indicated that tanshinone IIA (10 mg/kg) reduced memory decline and the increase of neuroinflammatory markers in Aβ42-injected mice .
These results show that the multiple mechanisms involve in the protective effects of tanshinone IIA against Aβ toxicity.
Tanshinone IIA was reported to reduce Aβ-induced the activation of tau-related kinase Cdk5, thereby attenuate the expression of phosphorylated tau in primary cortical neurons . Tanshinone IIA also plays as a Nrf2 inducer in various cells [11,12]. In SH-SY5Y cells, tanshinone IIA (5, 10, and 20 μg/ml) could induce the expression of NRF2 binding site-regulated genes, thereby provided the neuroprotection against neurotoxin 6-OHDA .
Zhu et al. reported that tanshinone IIA (0.2, 1, 2 and 5 μg/ml) also protects hippocampal neuronal cells HT-22 from ischemic damages such ROS increase, abnormal autophagy induction, and mitochondrial impairment via enhancing PI3K/Akt/mTOR signals . These abilities of tanshinone IIA may bring the benefit to reduce the characteristics in AD brain.
Cryptotanshinone also is one kind of tanshinones. Several studies suggest that the activities of cryptotanshinone involved in reducing the Aβ aggregation and toxicity, as well as up-regulating α-secretase. Mei et al. reported that cryptotanshinone (1, 2.5, and 5 μM) could inhibit Aβ42 spontaneous aggregation and (5 and 10 μM) dramatically reduced Aβ42-induced cell apoptosis and ROS increase in SH-SY5Y cells . In addition, cryptotanshinone (3 and 10 mg/kg) has been reported to reduce memory decline and neuroinflammation in Aβ42-injected mice , supporting the anti-Aβ ability of cryptotanshinone. The abnormal processing of APP is one of Aβ-related events in AD patients .
Met et al. reported that cryptotanshinone (15 mg/kg) strongly attenuated amyloid plaque deposition and the decease of cognitive ability in APP/PS1 transgenic mice . Interesting, their further study found that cryptotanshinone was able to enhance PI3K-mediated the expression of α-secretase which cleave APP in non-amyloidogenic pathways . This effect of cryptotanshinone on promoting APP processing toward the non-amyloidogenic generation, may provide an alternative way for reducing Aβ generation.
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Hsieh, T., & Wu, J. (2006). Differential control of growth, cell cycle progression, and gene expression in human estrogen receptor positive MCF-7 breast cancer cells by extracts derived from polysaccharopeptide I'm-Yunity and Danshen and their combination. International Journal Of Oncology, 29, 1215-