Multiple pro-apoptotic targets of abietane diterpenoids from Salvia species.

FITOTE-03066; No of Pages 15 Fitoterapia xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Fitoterapia journal homepage: www.elsevier.com/locate/fitote

Review

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Multiple pro-apoptotic targets of abietane diterpenoids from Salvia species

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M. Akaberi a, S. Mehri b, M. Iranshahi a,⁎ a b

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Biotechnology Research Center and School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

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Article history: Received 22 September 2014 Accepted in revised form 6 November 2014 Available online xxxx

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Keywords: Tanshinone IIA Salvinorin A Carnosol Cell signaling NF-κB

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The genus Salvia contains a large number of biologically active diterpenoids with various skeletons including abietanes, labdanes, clerodanes, pimaranes and icetexanes. Diterpenes of Salvia species showed various biological activities, particularly cytotoxic and anti-proliferative properties. In recent years many studies have been focused on the molecular mechanisms of these diterpenes in cancer cells. It should be noted, however, that anticancer studies on diterpenoids from Salvia species were dominated by tanshinones (a class of abietanes) over the past decades. A large number of targets of diterpenes have been identified in cancer cells including NF-κB, STAT3, Bcl-xL, β-catenin, cytochrome C and caspases. These studies give us deeper insights into the mechanisms of actions and cell signaling pathways of anticancer diterpenoids from Salvia species. This paper reviews protein targets of diterpenoids from Salvia species and highlights the gaps in our knowledge deserving future research. © 2014 Published by Elsevier B.V.

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Introduction . . . . . . . . AMPK . . . . . . . . . . . AR and ER receptors . . . . Aurora A . . . . . . . . . Caspases. . . . . . . . . . Cytochrome c . . . . . . . ER (endoplasmic reticulum) . HIF-1 . . . . . . . . . . . IL-8 . . . . . . . . . . . . JNK . . . . . . . . . . . . MAPKs . . . . . . . . . . Metallothionein 1A . . . . . Microtubules. . . . . . . . MMPs . . . . . . . . . . . NQO1 . . . . . . . . . . . STAT3 . . . . . . . . . . . Survivin . . . . . . . . . . Telomerase . . . . . . . . VCAM-1 and ICAM-1 . . . .

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⁎ Corresponding author. Tel.: +98 511 8823255; fax: +98 511 8823251. E-mail address: [email protected] (M. Iranshahi).

http://dx.doi.org/10.1016/j.ﬁtote.2014.11.008 0367-326X/© 2014 Published by Elsevier B.V.

Please cite this article as: Akaberi M, et al, Multiple pro-apoptotic targets of abietane diterpenoids from Salvia species, Fitoterapia (2014), http://dx.doi.org/10.1016/j.ﬁtote.2014.11.008

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20. Wnt/β-catenin . . . . . . . . . . . . . . 21. Concluding remarks and future perspectives . Acknowledgments . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . .

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It was reported that carnosol (Fig. 2) had growth inhibitory effects against human prostate cancer PC3 cells in vitro. Results suggested that carnosol targeted multiple signaling pathways including 5′-AMP-activated protein kinase (AMPK) pathway. AMPK is a serine/threonine protein kinase, which plays a role in cellular energy homeostasis. AMPK is composed of a catalytic α, and regulatory β and γ subunits. AMPK is activated when conditions deplete cellular ATP and elevate AMP levels, such as glucose deprivation, hypoxia, ischemia and heat shock which have been associated with an increased AMP/ATP ratio. The activated AMPK phosphorylates a range of enzymes incorporating in energy depending events. Activated Akt phosphorylates TSC2 (tuberous sclerosis 2) at phosphorylation sites Ser-939 and Thr-1462 that leads to the inhibition of TSC2 thereby activating the mTOR (serine/threonine kinase) pathway. Carnosol led to a significant dose-dependent decrease in the activated forms of Akt at phosphorylation sites Thr-308 and Ser-473 as well as the inhibition of PI3K (p85) and PI3K. It activated α-unit of AMPK, then the activated AMPK-α inhibited the phosphorylation of

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The genus Salvia belongs to the family Lamiaceae, a large family of about 220 genera and 4000 species, distributed throughout most of the world. This genus encompasses 900 species worldwide [1–3]. Some of them, such as Salvia miltiorrhiza, Salvia divinorum and Salvia officinalis have a large number of therapeutical applications in folklore and modern medicine [2]. S. miltiorrhiza (Danshen) is one of the most popular herbal medicines for the treatment of cardiovascular diseases in Asian countries, particularly in China [4]. It is also used for the treatment of various types of hepatitis, dysmenorrhea and cerebrovascular diseases [5]. On the other hand, S. divinorum is a hallucinogenic plant and its active compound, salvinorin A, has been found to be responsible for psychotropic property [6,7]. S. officinalis, as one of the most widespread species, has been used for the treatment of various diseases such as eczemas and tuberculosis since ancient times. The aforementioned species together with other species such as Salvia yunnanensis, Salvia canariensis, Salvia parryi, Salvia microphylla, Salvia cavaleriei and Salvia aegyptiaca showed several pharmacological effects and various therapeutical uses inspiring medicinal chemists, pharmacognosists and pharmacologists to find active constituents and their mechanisms of action. In the past decades, an extensive amount of chemical and pharmacological works has been conducted on Salvia species. Phytochemical analyses of these plants resulted in the identification of sesquiterpenoids, diterpenoids, sesterterpenoids, triterpenoids, steroids, phenolics, etc [8]. Among the mentioned classes of natural products, diterpenoids (or diterpenes) are the largest group. Recently, Wu et al. published a comprehensive review on the constituents of Salvia species and their biological activities in the journal Chemical Reviews [8]. According to this review, diterpenes comprise 545 of the 791 Salvia constituents [8]. Diterpenes isolated from Salvia species is further divided into some subgroups including abietane diterpenes, labdane diterpenes, clerodane diterpenes, pimarane diterpenes, and icetexane diterpenes (Fig. 1). Cancer is one of the most causes of deaths worldwide. The causes of this disease are diverse, complex, and only partially understood. Majority (almost 80%) of anti-cancer drugs being used in modern medicine are either natural products or derivatives of natural products such as paclitaxel, taxotere, vincristine, vinblastine, camptothecin, irinotecan, topotecan, and teniposide [9]. Attempts to find new anti-cancer drugs, particularly from natural sources, still remain a topic of interest. Researchers are interested in finding anti-cancer drugs with specific cytotoxicity against cancerous cells in order to avoid deleterious effects on normal cells. In the current paper, proteins, genes, enzymes and ligands affected by Salvia diterpenes, are discussed. Some of these cellular targets may be related with one another; however, we tried to show these correlations for a better view.

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Salvia diterpenes exhibited an array of interesting biological properties, which has inspired pharmacologists and molecular biologists to find out their molecular targets. A large number of papers have been published regarding cellular targets of Salvia diterpenes, particularly in cancer cells. However, no comprehensive review on their molecular mechanisms and cellular targets of Salvia diterpenes has been published so far. This review deals with molecular mechanisms and cellular targets of these compounds in cancer cells and their potential for the treatment of cancer. This review gives a deeper insight to oncologists and drug discovery researchers about cellular targets of Salvia diterpenes, while highlights the gaps in our knowledge deserving future research.

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Fig. 1. Diterpenoid skeletons isolated from Salvia species.


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Fig. 2. The most famous anti-cancer abietane diterpenoids from Salvia species that their cellular targets, at least in part, have been identified.

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Studies show that there is a relationship between estrogen or androgen activities, and prostate cancer. As the age increases, estrogen content and the risk of prostate cancer elevate. Molecular modeling suggests that carnosol acted as an antagonist to androgen receptors (AR) and estrogen receptors (ER) and fitted within the ligand-binding domain of both AR and ER-α,

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mTOR at Ser-2448 leading to cell growth inhibition at G2 cell cycle [10]. A recent study showed that cryptotanshinone could also activate AMPK signaling pathway and induce cell cycle arrest at the G1 phase [11]. As mentioned above, the activated AMPK consequently activates tumor suppressors including LKB1 (liver kinase B1), TSC2 and p53, and suppresses mTOR.

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disrupted androgen and estrogen activity in prostate cancer. In comparison to other drugs including tamoxifen, toremifene, and fulvestrant that are commonly used as anti-androgens and antiestrogens, carnosol had no agonist effect for both of these receptors at doses up to 100 μmol/L. Further investigation showed that carnosol decreased mRNA and protein expression of AR and ER-α. It was revealed that carnosol physically interacted with the ligand binding domain (LBD) of both AR and ER-α. It had a minimal effect on the growth of normal PrECs (prostate epithelial cells) [12]. Defeng et al. indicated that cryptotanshinone suppressed androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells. AR is a ligandactivated transcription factor mediating the biological responses to androgens. When the ligand binds to the AR, the ligand–receptor complex translocates to the nucleus, and then


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Aurora A is a member of a novel oncogenic family of mitotic serine/threonine kinases. Studies suggest that Aurora A plays an important role in centrosome maturation [23], spindle formation [24] and G2-M transition [25]. In 2012, Yanli et al., showed that tanshinone I had been an efficacious and safe agent for the inhibition of lung cancer cell growth and proposed that Aurora A had been a molecular target for this activity in vivo. Their findings showed that tanshinones including cryptotanshinone,

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Caspases, or cysteine-aspartic proteases or cysteinedependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis (programmed cell death), necrosis, and inflammation [28]. The caspases can be activated through either the intrinsic (mitochondrial mediated) or extrinsic (death receptor mediated) apoptotic pathways. The intrinsic apoptotic pathway is characterized by permeabilization of the mitochondria and release of cytochrome c into the cytoplasm. Cytochrome c then forms a multi-protein complex known as the ‘apoptosome’ and initiates activation of the caspase cascade through caspase-9. The extrinsic apoptotic pathway is activated by death receptors on the plasma membrane such as tumor necrosis factor receptor 1 (TNFR1) and Fas/CD95 (Fig. 3). As ligands bind to these receptors, the death inducing signaling complex (DISC) is formed leading to the initiation of the caspase cascade through caspase-8 [29–31]. In 1999, Sung et al. examined cellular effects of tanshinone IIA (Fig. 2) on HL-60 human promyelocytic leukemic cells and K562 human erythroleukemic cells. They showed that caspase3 activity was significantly increased during tanshinone IIA treatment in both HL-60 and K-562 cells, whereas caspase-1 activity was not changed. They suggested that tanshinone IIA could induce HL-60 and K-562 cellular apoptosis through selective members of caspase family [32]. In the same year, Yoon et al. showed that tanshinone IIA induced apoptosis in HL-60 human premyelocytic leukemia cell line through the specific proteolytic cleavage of poly (ADP-ribose) polymerase (PARP), a nuclear enzyme which is involved in DNA repair process, and the activation of caspase-3 [33]. In 2008, Lee's study demonstrated that tanshinones including tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone possessed inhibitory effects on HepG-2 cell growth in vitro. It was proposed that this cytotoxicity might be a consequence of changing GSH/GSSG ratio which is often used as an indicator of oxidative stress. As the content of ROS increased in the cell, GSH oxidized to GSSG. When GSH supply diminished, excessive amounts of ROS were accumulated and cell was exposed to oxidative stress [34]. Among these compounds, dihydrotanshinone and tanshinone I showed much correlation between cytotoxic activity and oxidative stress. But the mechanism of the cytotoxic activity of cryptotanshinone and tanshinone IIA was probably different that might be related to their different chemical structures. Cytometric assessment and western blot analysis showed that tanshinone IIA arrested cells at G2/M and S phases. However,

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tanshinone IIA and tanshinone I significantly down-regulated Aurora A expression level in vitro, and tanshinone I also downregulated Aurora A protein levels in vivo. Knock down of Aurora A significantly reduced tanshinone I-induced cell cycle arrest and apoptosis, showing Aurora A as a possible mediator of tanshinone I-induced inhibition in these cells. In addition, tanshinone I attenuated Aurora A by suppressing acetylation of the histone H3 accompanied by Aurora A [26]. In addition, tanshinone I-induced inhibition cell growth in DU145, MCF-7, MDA-MB-231 and H1299 cell lines is associated with down-regulation of aurora A [26,27]. Tanshinone I can arrest cell cycle progression at G2/M phases through downregulation of Aurora A expression [26].

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binds to specific androgen response elements on the chromosome. Since the structure of cryptotanshinone is similar to dihydrotestosterone (DHT), it can effectively bind to AR and inhibits the DHT-induced AR transactivation and prostate cancer cell growth. Results showed that cryptotanshinone only affected AR-positive prostate cancer cells. Cryptotanshinone inhibited AR to suppress androgen/AR-mediated cell growth and prostate specific antigen (PSA) expression through blocking AR N–C dimerization and the AR-coregulator complex formation [13]. Tanshinone IIA also suppressed the expression of AR and PSA at G1 cell cycle arrest in LNCaP prostate cancer cells [14]. In a recent study, Wang et al. showed that tanshinone IIA downregulated the expression of AR and ER in WPMY-1 and RWPE-1 cells. In addition, they indicated that the expression of cyclin B1 and cyclin D1 was down-regulated in WPMY-1 and RWPE-1 cells, respectively [15]. In general, tanshinones including tanshinone I, tanshinone IIA and cryptotanshinone suppressed cell growth and ARdependent transcription in AR-responsive prostate cancer cells. Tanshinone IIA and cryptotanshinone suppress AR downstream target PSA expression at concentrations below 2.5 μM, but did not affect cellular AR level. Concentrations higher than 5 μM cause additional actions on nuclear translocation and 26S proteasomal-dependent degradation of AR [16]. Cryptotanshinone and its sodium salt derivative inhibited AR-dependent transcription without affecting AR protein level at low concentrations (b2 μM). These compounds exert their effect through disruption of AR N–C terminal interaction, coregulator recruitment and DNA binding [13,17,18]. The inhibitory activity of tanshinones [tanshinone IIA, cryptotanshinone and PTS33 (a sodium salt derivative of cryptotanshinone with increased water-solubility)] relies on a full-length AR, because a truncated AR without LBD could not be regulated by them [13,17,18]. Tanshinones might suppress AR signaling through regulating androgen synthesis or metabolites. Cryptotanshinone decreased plasma 17α-hydroxy progesterone in male offspring with high circulatory androgen stimulated by prenatal androgenization [19]. Another study indicated that cryptotanshinone decreased plasma androgen level in female offspring receiving prenatal androgenization and reversed the increased plasma testosterone level induced by protein kinase B (Akt2) deletion in mice. The effect was related to the reduction of the androgen synthesis enzyme CYP17 [19–21]. In total, cryptotanshinone can diminish the plasma level of androgens via down-regulating the expression of the enzymes for androgen synthesis. In addition, tanshinone IIA activated androgen metabolism enzyme CYP3A-mediated 6β-hydroxylation of testosterone in human liver microsomes indicating tanshinone IIA could regulate androgen metabolism [22].

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cryptotanshinone with a similar structure to that of tanshinone IIA, didn't cause apoptosis and significant cell cycle arrest, although strongly inhibited the cell growth. Western blotting of cell proteins showed that tanshinone IIA induced apoptosis through activation of caspase-3 [34]. Growth inhibition and apoptosis inducing activities of tanshinone I on three kinds of monocytic leukemia cells (U937, THP-1 and SHI 1) were investigated by Liu et al. Results revealed that tanshinone I could inhibit the growth of these three types of leukemia cells and cause apoptosis. Tanshinone I caused cleavage of the caspase-3 zymogen protein and PARP, a known substrate of caspase-3 [35]. Investigations on human erythroleukemic K562 cells show that tanshinone A can arrest K562 cells in the G0/G1 phase and induce apoptosis, decrease the mitochondrial transmembrane potential and increase the activity of caspase-3 [36]. Tanshinone IIA induces apoptosis both in the endogenous and exogenous pathways in Acute Promyelocytic Leukemia cell

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Fig. 3. A schematic view of molecular targets of abietane diterpenoids from Salvia species in cancer cells. Red numbers, inhibit/inactivate; Green numbers, activate. 1, tanshinone I; 2, tanshinone IIA; 3, cryptotanshinone; 4, dihydrotanshinone; 5, carnosol; 6, carnosic acid. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

line. In the intrinsic pathway, tanshinone IIA increases the activation of caspase-3, while in the extrinsic apoptotic pathway, caspase-8 is activated [37]. Many other literatures have shown the activation of caspase-3 in the apoptosis induced by tanshinones [38,39]. After treatment of tanshinone IIA, caspase dependent apoptosis is observed in the osteosarcoma MG-63 cell line (including caspase-3, caspase-8, and caspase-9) [40], BT-20 human breast cancer cell line (including caspase-12, caspase-3) [41], 786-O human renal cell carcinoma cells (caspase-3) [42], A549 non-small cell lung cancer cells [43], human oral cancer KB cell line [44], gastric carcinoma AGS (caspases 3, 9 and 12) [45] and human bladder cancer cells [46]. Tanshinone IIA can also inhibit tumor growth in a J5 xenograft animal model via increasing caspase-3 expression [47]. Chen et al. have shown that tanshinone IIA increases caspase-9 cleavage in gastric cancer cell lines in an intrinsic apoptotic pathway [48]. Tanshinone IIA treatment also led to


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Endoplasmic reticulum (ER) stress-mediated cytotoxicity was reported in tanshinone IIA-treated breast cancer BT-20 cells [41]. The findings of a recent study on LNCaP cells suggested that tanshinone IIA treatment caused G0/G1 cell cycle arrest and its cytotoxicity was mediated at least partly by ER stress induction [58]. Dihydrotanshinone also induced apoptosis in DU 145 prostate cancer cells through inducing classical endoplasmic reticulum (ER) stress resulted in the up-regulation of ER stress markers including GRP78 (G-protein coupled receptor 78) and GADD153 (growth arrest and DNA damageinducible protein 153), eIF2α, JNK and XBP1 mRNA splicers. Dihydrotanshinone treatment caused a significant accumulation of polyubiquitinated proteins and HIF-1α. These findings indicated that dihydrotanshinone was a proteasome inhibitor inducing ER stress or enhanced apoptosis caused by the classic ER stress-dependent pathway [59].

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HIF-1 or hypoxia-inducible factor-1 is an important target in the development of anticancer drugs [60]. The hypoxia inducible factor 1 (HIF-1) is a heterodimeric transcription factor that is an important regulator of the growing tumor's response to hypoxia. HIF-1 activity in tumors depends on the availability of the HIF-1A subunit, the levels of which increase under hypoxic conditions and through the activation of oncogenes and/or inactivation of tumor suppressor genes. HIF-1 activates genes that allow the cancer cell to survive and grow in the hostile hypoxic tumor environment. Increased tumor HIF-1A has been correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis, leading to the current interest in HIF-1A as a cancer drug target [61]. Cells that become hypoxic convert to a glycolytic metabolism, become resistant to apoptosis (programmed cell death), and are more likely to migrate to less hypoxic areas of the body (metastasis). Hypoxic cells also produce pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), which stimulate new blood vessel formation from existing vasculature, increasing tumor oxygenation and, ultimately, tumor growth. For this reason, hypoxic tumors are the most proangiogenic and aggressive of tumors [62]. In fact, hypoxia-mediated increase in HIF-1α plays an important role in both the establishment and progression of many common cancer cells via the HIF-1-dependent activation of genes that allow them to survive and metastasize in the hostile hypoxic tumor environment. Moreover, increased HIF-1 activity arises through the activation of oncogenes and/or inactivation of tumor suppressor genes [60]. Cryptotanshinone and dihydrotanshinone I, isolated from S. miltiorrhiza, potently inhibits hypoxia-induced luciferase

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The cytochrome complex, belonging to the cytochrome c family of proteins, is a small heme protein found loosely associated with the inner membrane of the mitochondria. Unlike other cytochromes, cytochrome c is a highly soluble protein, and is an essential component of the electron transport chain, where it carries one electron. It is capable of undergoing oxidation and reduction, but does not bind to oxygen [55]. Cytochrome c is also an intermediate in apoptosis, a controlled form of cell death used to kill cells in the process of development or in response to infection or DNA damage. Cytochrome c binds to cardiolipin in the inner mitochondrial membrane, thus anchoring its presence and keeping it from releasing out of the mitochondria and initiating apoptosis. While the initial attraction between cardiolipin and cytochrome c is electrostatic due to the extreme positive charge on cytochrome c, the final interaction is hydrophobic, where a hydrophobic tail from cardiolipin inserts itself into the hydrophobic portion of cytochrome c. During the early phase of apoptosis, mitochondrial ROS production is stimulated, and cardiolipin is oxidized by a peroxidase function of the cardiolipin–cytochrome c complex. The hemoprotein is then detached from the mitochondrial inner membrane and can be extruded into the soluble cytoplasm through pores in the outer membrane. The sustained elevation in calcium levels precedes cyt c release from the mitochondria. The release of small amounts of cyt c leads to an interaction with the IP3 receptor (IP3R) on the endoplasmic reticulum (ER), causing ER calcium release. The overall increase in calcium triggers a massive release of cyt c, which then acts in the positive feedback loop to maintain ER calcium release through the IP3Rs. This explains how the ER calcium release can reach cytotoxic levels. This release of cytochrome c in turn activates caspase 9, a cysteine protease. Caspase 9 can then go on to activate caspase 3 and caspase 7, which are responsible for destroying the cell from within. Tanshinone IIA causes the enhancement of cytochrome c release in a variety of cancer cells. For instance, tanshinone IIA activates the release of cyt c into the cytoplasm in gastric cancer cell lines [48], in MR2 cells [37], in LNCaP and PC3 cells [49], and in NQO1(+) A549 cells [56]. Dihydrotanshinone I-induced cell cycle arrest and apoptosis are also associated with an increase in cytochrome c release in breast adenocarcinoma [53].

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Tanshinone I induces apoptosis of T-HSC/Cl-6 cells which involves caspase activation through cyt c release and loss of mitochondrial membrane potential [57]. Acetyl tanshinone IIA (Fig. 2) also induces apoptosis via cytochrome c release in various cancer cell lines including SKBR-3, MCF-7, MDA-MB453, HL-60, HeLa and SiHa cells [54].

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the activation cleavage of pro-caspases-9 and -3, but not to procaspase-8 in LNCaP and PC-3 cells [49]. In addition, caspase-12 is increased in HepJ5 cells treated by tanshinone IIA [50]. The inhibition of the proliferation of human small cell lung cancer H146, colon cancer and leukemia THP-1 cells induced by tanshinone IIA is also associated with the activation of caspase3 [51,52]. In addition, dihydrotanshinone induces apoptosis via the activation of caspase-9, caspase-3, and caspase-7 in adenocarcinoma cells [53]. Acetyl tanshinone IIA (Fig. 2) also induces apoptosis via the activation of caspase 3 in various cell lines including SK-BR-3, MCF-7, MDA-MB453, HL-60, HeLa and SiHa cells [54].

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411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441


481

Migration, invasion and MMP inhibitory activity induced by tanshinone I in macrophage conditional medium-stimulated CL1-5 lung cancer cells in vitro and the inhibition of tumorigenesis and metastasis of CL1-5 lung cancer xenografts in severe combined immunodeficient (SCID) mice, are associated with the reduction of interleukin-8 (IL-8), which is an angiogenesis factor promoting angiogenesis and metastasis [68]. It was shown that, tanshinone I, cryptotanshinone and dihydrotanshinone also inhibited IL-12 production in lipopolysaccharide (LPS)-activated mouse macrophages in a concentration-dependent manner. It was suggested that inhibition of IL-12 occurred at transcriptional level through inhibiting transcriptional factor NF-κB to bind to the IL-12 promoter [69]. In addition, recent findings revealed that tanshinone IIA increased anti-inflammatory cytokine IL-10, and reduced proinflammatory cytokines IL-2 and IL-4 [70].

482

10. JNK

483

JNK (c-Jun NH2-terminal kinase) is a key regulator of many cellular events including apoptosis. In the absence of NF-κB activation, prolonged JNK activation contributes to TNF-induced apoptosis. JNK is also essential for UV-induced apoptosis. But recent studies revealed that JNK suppressed apoptosis in IL-3dependent hematopoietic cells via phosphorylation of the proapoptotic Bcl-2 family protein BAD. Thus, JNK has pro- or antiapoptotic functions, depending on cell type, nature of the death stimulus, duration of its activation and the activity of other signaling pathways [71]. Among diterpenoids from Salvia species, dihydrotanshinone [72] and cryptotanshinone [73,74] inactivate JNK, while DYZ-2-90 (Fig. 2), a modified compound from Neo-tanshinlactone, induces apoptosis via the activation of JNK [54].

468 469 470 471 472 473 474 475 476 477 478 479 480

484 485 486 487 488 489 490 491 492 493 494 495 496

12. Metallothionein 1A

520

Metallothionein (MT) has been extensively investigated as a molecular marker of various types of cancer. MTs are cysteine-rich low-molecular-mass intracellular proteins occurring in a wide variety of eukaryotes and constituting the major fraction of intracellular protein thiols [83]. MTs are involved in many physiological and pathophysiological processes such as intracellular storage, transport and metabolism of metal ions, whereas they regulate essential trace metal homeostasis and play a protective role in heavy metal detoxification reactions [84,85]. The synthesis of MT was shown to be increased during oxidative stress [17,18] to protect the cells against cytotoxicity [86,87], radiation and DNA damage [88–90]. Tanshinone IIA exerts antitumor activity, at least in part, via the activation of calcium-dependent apoptosis signaling pathways and the up-regulation of MT1A expression in human hepatoma cells and human nasopharyngeal carcinoma CNE cells [91,92].

521 522

13. Microtubules

538

Tanshinone IIA is the only SD that has been investigated for its interaction with microtubules. It has been demonstrated that tanshinone IIA induces apoptosis in HeLa cells through mitotic arrest by disrupting the mitotic spindle [93]. It seems that apoptosis occurs through mitochondria-dependent pathway. Mitotic cells are selectively killed over interphase by tanshinone IIA. Microtubule induced agents (MIAs) and tanshinone IIA both cause apoptosis, however, there are some differences and some similarities between the apoptotic effects of these compounds. Both of them induce apoptosis through mitotic arrest that is mediated by mitochondria-dependent pathways, as obvious from cytochrome c release, caspase-3 activation, and degradation of Mcl-1. Tanshinone IIA induced-apoptosis is partly mediated by JNK. In comparison to MIAs such as taxol and

539

E

466 467

C

461 462

E

459 460

R

457 458

R

455 456

O

453 454

N C

451 452

U

449 450

498 499

F

465

447 448

Mitogen-activated protein kinase (MAPK) pathways play essential roles in the regulation of cellular responses, including cell survival, apoptosis, proliferation, and differentiation [75,76]. The three major subfamilies of MAPK are extracellular signalregulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 MAPK. Cryptotanshinone sensitizes DU145 prostate cancer cells Fas (APO-1/CD95)-mediated apoptosis through Bcl-2 and MAPK regulation [77]. Fas/APO-1/CD95 is a potential anticancer factor and induces apoptosis in tumor cells but some cancer cells such as prostate cancer cells show resistance to this route of apoptosis [78–81]. Investigations show that the resistance is due to the expression of the apoptosis inhibitory protein, Bcl-2, in the response to Fas in DU145 prostate cancer cells. Some natural products including cryptotanshinone can suppress Bcl-2 expression and increase Fas sensitivity in this cell line. Furthermore, it has been shown that JNK and p38 MAPK which cause upstream of Bcl-2 expression, can be blocked by cryptotanshinone [77]. Dihydrotanshinone can also induce caspase-dependent apoptosis in HepG2 cells through the activation of ROS-mediated p38 MAPK [82].

R O O

9. IL-8

446

497

P

464

444 445

11. MAPKs

D

463

expression on AGS (human Caucasian gastric adenocarcinoma) cells and Hep3B cells (human hepatocarcinoma cell line). In addition, dihydrotanshinone and tanshinone IIA dosedependently suppressed the HIF-1alpha accumulation [63,64]. In addition, Liang et al. showed that dihydrotanshinone caused a significant accumulation of HIF-1 in DU145 cells via an endoplasmic reticular (ER) stress pathway [59]. But in another study, it was shown that dihydrotanshinone I inhibited HIF-1α expression at low concentrations [63]. In 2012, Lee et al. investigated the roles of AEG-1 (astrocyte elevated gene 1) and HIF-1α in cryptotanshinone-induced antitumor activity in hypoxic PC-3 cells [65]. They suggested that cryptotanshinone exerted its antitumor activity via the inhibition of HIF-1α, AEG1, and VEGF as a potent chemotherapeutic agent. Tanshinone IIA is also reported to inhibit HIF-1α in a series of cancer cells [66]. In a recent work, Fu et al. showed that tanshinone IIA down-regulated the expression of HIF1α and TWIST, and consequently, returned E-cadherin and vimentin (hypoxia reduced E-cadherin and increased vimentin protein levels) to normal levels in MCF-7 and HCC1973 cells [67].

T

442 443

7


500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519

523 524 525 526 527 528 529 530 531 532 533 534 535 536 537

540 541 542 543 544 545 546 547 548 549 550 551 552

573

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily [95]. Collectively, they are capable of degrading all kinds of extracellular matrix proteins. They are known to be involved in the cleavage of cell surface receptors, the release of apoptotic ligands (such as the Fas ligand), and chemokine/cytokine in/activation. MMPs are also thought to play a major role on cell behaviors such as cell proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, apoptosis, and host defense [96]. Among diterpenoids from Salvia species, carnosol and tanshinone IIA could affect these enzymes according to the literature. Carnosol decreased MMP-9 mRNA and protein expression and modulated the activities of its upstream regulators including Akt, p38, JNK and Erk1/2 [97]. Tanshinone IIA mediates MMP collapse in Acute Promyelocytic Leukemia cell line in a time- and dosedependent manner, releasing multiple death-promoting molecules including cyt-c, apoptosis-inducing factor, endonuclease G and Smac/DIABLO (the mitochondrial protein that potentiates some forms of apoptosis). Released cyt c together with ATP bind to Apaf-1 (apoptotic protease activating factor 1) in the cytosol leads to the activation of pro-caspases-3 and 9 into an apoptosome and causes apoptosis [37]. Tanshinone IIA is shown to reduce antiapoptotic MMP-2, and MMP-9 levels [98]. Tanshinone IIA decreases MMP in human small cell lung cancer H146 cells [51]. It decreases proangiogenesis MMP-2 secretion and increases anti-angiogenesis TIMP-2 secretion [99]. Additionally, tanshinone IIA reduces MMP-2 and MMP-9 and increases tissue inhibitors of metalloproteinase TIMP-1 and TIMP-2 in HT29 and SW480 colon cancer cells in a concentration- and time-dependent manner [100]. Tanshinone IIA inhibits migration, invasion and in vivo metastasis rate in human HepG2 and SMMC-7721 liver cancer cells through decreasing both the expression and activity of MMP-2 and MMP-9 [101]. It also inhibits MMP expression and activity in other cancer cells such as osteosarcoma and stomach tumor [40,102].

579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611

613 614

16. STAT3

639

STAT3 is activated in the response to various cytokines and growth factors and is usually expressed in a range of malignant tumors. The overexpression and constitutive activation of STAT3 promote tumorigenesis by transcriptionally up-regulating its down-stream targets including cyclin D1, survivin and VEGF, which are involved in proliferation, apoptosis and angiogenesis. Cryptotanshinone inhibits STAT3 Tyr705 phosphorylation in DU145 prostate cancer cells resulting in the down-regulation of target proteins such as cyclin D1, survivin, and Bcl-xL. Studies showed that cryptotanshinone suppressed STAT3 dimerization, nuclear translocation and DNA binding. Investigations indicated that cryptotanshinone as compared with tanshinone IIA had more inhibitory activity in the same concentration on STAT3 [108–110]. In a recent study, cryptotanshinone was also able to decrease in phosphorylation and dimerization of STAT3 and the expression levels of Mcl-1 in human mucoepidermoid carcinoma cell lines. Unlike previous studies, Bcl-xL expression was not changed [111]. However, studies showed that tanshinone IIA could significantly reduce STAT3 and its downstream targets [109]. It was shown that tanshinone IIA inhibited JAK2/STAT5 signaling, while cryptotanshinone targets the JAK2/STAT3 [112].

640

17. Survivin

662

Survivin is an inhibitor of apoptosis. The survivin protein inhibits caspase activation, thereby leading to negative regulation of apoptosis or programmed cell death. This has been shown by the disruption of survivin induction pathways leading to the increase of apoptosis and the decrease of

663 664

D

T

578

C

576 577

E

574 575

R

568 569

R

566 567

O

564 565

C

562 563

N

560 561

U

558 559

NAD(P)H:quinone oxidoreductase (NQO1) is an emerging and promising therapeutic target in cancer therapy. It is a cytosolic flavoenzyme that catalyzes the obligatory twoelectron reduction of a variety of quinone substrates, using both NADH and NADPH as electron donors [103]. In some human tumors such as non-small cell lung cancer, this enzyme is elevated [104]. On the other hand, it was found that NQO1 catalyzed quinone reduction followed by immediate glucuronidation is the predominant metabolic pathway of tanshinones [105,106]. A highly unstable catechol intermediate is the product of the reductive reaction of tanshinone IIA by NQO1 that auto-oxidizes back to the parent tanshinone and constitutes a futile redox cycle producing oxidative stress [105]. In 2012, Fang et al., showed that tanshinone IIA was a promising NQO1 specific target agent, which induced apoptotic cell death of non-small cell lung cancer (A549) cells via a unique NQO1-initiated and ROS-mediated activation of a p53independent, but caspase-dependent mitochondrial apoptotic pathway [107]. In all tested aspects including cytotoxicity, apoptosis, ROS production, and DNA damage, tanshinone IIA showed an NQO1-dependent effect. When NQO1 was silenced by specific inhibitors, these events were not observed in A549 cells. It can be concluded that tanshinone IIA is predominately metabolized by NQO1 and UGTs [107]. Thus it can be proposed that it is able to induce a p53 independent mitochondrial apoptotic pathway initiated by NQO1 and mediated by ROS.

F

14. MMPs

557

612

O

572

555 556

15. NQO1

P

570 571

vincristine, tanshinone doesn't interfere with microtubule structure in the interphase cells, and so it has fewer side effects. It is supposed that tanshinone IIA instead of interfering with the microtubule, interacts with particular microtubule-associated proteins which are needed for maintaining the structure of the mitotic spindle [93]. Cytotoxic activity of tanshinone IIA has been investigated against human cervical cancer cells. G2/M arrest is initiated after a 24 h exposure to the drug. It also causes DNA fragmentation and degradation of PARP and induces some changes to the levels of cytoskeleton proteins as well as stress associated proteins. Docking models show that tanshinone IIA can bind to the βsubunit of the microtubule proteins and regulates the expressions of proteins involved in apoptotic processes, spindle assembly, and p53 activation including vimentin, maspin, αand β-tubulin, and GRP75. Thus, tanshinone IIA strongly inhibits the growth of Hela cells through interfering in the process of microtubule assembly, leading to G2/M phase arrest and sequent apoptosis [94].

E

553 554


R O

8


615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 Q7 632 633 634 635 636 637 638

641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661

665 666 667

691 692

Telomerase is up-regulated in the majority of cancer cells and is essential for their survival. Telomerase has been an important therapeutic target for developing novel anti-cancer drugs. Several studies showed that tanshinone IIA-induced apoptosis and differentiation in human HL-60 and K562 leukemia cells were associated with the inhibition of both the expression and activity of human telomerase reverse transcriptase [66,115,116]. Soares et al. have shown that ortho-quinone tanshinones directly inhibited telomerase via an oxidative mechanism mediated by hydrogen peroxide [117].

693

19. VCAM-1 and ICAM-1

694 695

Cell adhesion molecules (CAMs) are involved in a variety of normal physiological processes such as cell–cell and cell– matrix interactions, cell migration, cell cycle, signaling, and morphogenesis during development and tissue regeneration [118]. They also are involved in a range of pathological conditions such as cancer, inflammation, pathogenic infections, and autoimmune disease [118]. Vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) are cytokine-inducible Ig gene superfamily members that bind leukocyte integrins. VCAM-1 and ICAM-1 have different functions in tumor metastasis. Some highly metastatic human melanoma cells have high affinity conformation at the cell surface and adhere to and migrate on VCAM-1, rather than on ICAM-1. According to these findings, it is important to discover therapeutic agents which have specific suppression effects on adhesion molecules, such as VCAM-1. Nizamutdinova et al., found that tanshinone I inhibited ICAM-1 and VCAM-1 expressions, which mediated cancer cell metastasis [119]. Recently this group showed that tanshinone IIA inhibited TNF-α-mediated induction of VCAM-1 through modulation of PI3/Akt, PKC and Jak/STAT-3 pathway as well as IRF-1 and GATA-6 binding activity, but in this case the inhibition of ICAM-1 was not observed [120]. Tanshinone I completely inhibited the expression of ICAM-1 and VCAM-1 in TNF-α-stimulated HUVECs, as well as the adhesion of MDAMB-231 cells to HUVECs and the migration of MDA-MB-231 cells through extracellular matrix [119]. The effect of tanshinone VI was also investigated on ICAM-1 and VCAM-1 in TNF-alpha-stimulated endothelial cells [121]. Tanshinone VI could inhibit the up-regulation of ICAM-1 and VCAM-1 induced by TNF-alpha dose-dependently. It was

698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724

C

696 697

E

689 690

R

687 688

R

685 686

O

683 684

N C

677 678

U

675 676

20. Wnt/β-catenin

729

Wnt signaling induces a specific transcriptional program, which controls several developmental processes. In the absence of Wnt, β-catenin is continuously degraded. Axin and adenomatous polyposis coli (APC) tumor suppressor causes the phosphorylation of β-catenin by glycogen synthase kinase 3 (GSK3) which earmarks it for proteasomal degradation. If this process fails in the colonic epithelium, β-catenin is stabilized due to inactivating mutations of APC, so tumorigenesis initiates. The enzymatic activators of β-catenin are not well established to be inhibited, but some small molecules can reduce its activity or stability by targeting one of its regulators including BCL9 and Pygo proteins. BCL9 and Pygo proteins are new targets for cancer therapy. Carnosic acid can selectively disrupt the binding of β-catenin to BCL9 in vitro without affecting its binding to transcription factor. Biophysical analysis shows that labile α-helix structure at the terminus of β-catenin armadillo repeat domain (ARD) is required for the carnosic acid response. In fact, carnosic acid targets oncogenic β-catenin in colorectal cancer cells via the disruption of BCL9 and β-catenin [122].

730 731

748

21. Concluding remarks and future perspectives

749

To date, different classes of diterpenoids have been identified from the genus Salvia including abietane, clerodane, icetexane, labdane and pimarane. Among the mentioned classes abietane diterpenes, particularly the subclass tanshinones, showed the most promising anti-proliferative and apoptogenic activities. Many cellular proteins/enzymes/genes have been targeted by diterpenes from Salvia species (Table 1). Among these compounds, tanshinone IIA has been more widely studied for its mechanisms of actions. Up to now, more than 40 cellular targets have been identified for tanshinone IIA (Table 1). It should be noted, however, that some of these cellular targets are located in a single signaling pathway, and obviously, affect one another. For example, when tanshinone IIA could suppress STAT3, Bcl-xL would consequently be suppressed, and cytochrome c and caspase 9 would be activated as well. This point should be considered in any interpretation of the cellular targets and underlying mechanisms of Salvia diterpenoids. Although it seems that tanshinones including tanshinone I, IIA, cryptotanshinone and dihydrotanshinone inhibit/ activate similar protein or gene targets, it was proved that they might target different cellular signaling pathways. For instance, tanshinone IIA inhibits JAK2/STAT5 signaling, while cryptotanshinone targets JAK2/STAT3. Moreover, tanshinone IIA enhances the expression of both SHP-1 (Src homology region 2 domain-containing phosphatase-1) and SHP-2, whereas cryptotanshinone enhances the expression of only SHP-1 [112]. Diterpenes of Salvia spp. have been evaluated for anti-cancer properties mostly in in vitro models. To date, all clinical trials have only been restricted to Chinese formulations including Fufang Danshen (tablets from S. miltiorrhiza). It is time for researchers to move toward testing purified components in

750

F

681 682

673 674

R O O

18. Telomerase

672

725 726

P

680

670 671

suggested that the antitumor properties of tanshinone VI might be attributed to the inhibition of cell adhesion, at least in part, due to the down-regulation of cell adhesion molecules [121].

T

679

tumor growth. The protein survivin is expressed highly in most human tumors and fetal tissue, but it is completely absent in terminally differentiated cells [113]. Tanshinones including tanshinone I, tanshinone IIA and cryptotanshinone induced apoptosis is associated with downregulation of survivin gene expression and protein levels. Tanshinone IIA-induced apoptosis is associated with the down-regulation of survivin in leukemia THP-1 cells [52]. Cryptotanshinone-induced cell cycle arrest is also associated with the down-regulation of survivin [114]. Tanshinone I significantly down-regulates survivin in three types of monocytic leukemia cells (U937, THP-1 and SHI 1) [35].

D

668 669

9

E



727 728

732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747

751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 Q8 771 772 773 774 775 776 777 778 779 780 781

10 t1:1 t1:2


Table 1 A tabulated overview of the targets of diterpenes from Salvia spp. in cancer cells. The targets of this table have not been addressed in the text.

t1:3

Target

Compound

Studying Model

t1:4 t1:5

AP-1 (the activator protein 1)

Carnosol

Human mammary epithelial cells

References

Blockage the increased binding of AP-1 to the COX-2 promoter Tanshinone IIA Human liver and lung tumors Suppression the AP-1-mediated transcription of aldo-keto reductase 1B10 (AKR1B10) AR (androgen receptor) PTS33 LNCaP and CWR22Rv1 The inhibition of AR protein expression Bax/Bcl-2 Tanshinone I Myeloid leukemia cells Up-regulation of Bax expression Down-regulation the level of the antiEstrogen receptor-positive (MCF-7) and estrogen receptor-negative (MDA-MB-231) apoptotic protein, Bcl-2, and up-regulation the level of the pro-apoptotic protein, Bax breast cancer cells Tanshinone IIA Human gastric adenocarcinoma cell line Increase the ratio of Bax/Bcl-2 SGC-7901 and gastric carcinoma AGS Small cell lung cancer H146 cells Increase the Bax/Bcl-2 ratio Leukemia THP-1 cell Down-regulation of the anti-apoptotic protein Bcl-2 and up-regulation of the proapoptotic protein Bax BT-20 human breast cancer cell Increase the protein expression of Bax but decrease Bcl-xL expression Cryptotanshinone Human multiple myeloma U266 cells and Decrease the expression of Bcl-2 HL-60 Taxodione, ferruginol and HL-60 The enhancement of the expression of Bax 6-hydroxysalvinolone Tanshinone A K562 The suppression of Bcl-2 Bcl-xL protein Dihydrotanshinone Breast adenocarcinoma Decrease the anti-apoptotic protein Bcl-xL level Cryptotanshinone DU145 prostate cancer cells Decrease the expression of Bcl-xL Tanshinone IIA Gastric carcinoma AGS Decrease the expression of Bcl-xL Binding immunoglobulin Tanshinone IIA Gastric carcinoma AGS Decrease the expression of BiP protein (BiP) Ca2+ Tanshinone IIA Human small cell lung cancer H146 cells Increase the production of Ca2+ in cells Calreticulin Tanshinone IIA Hep-J5 cells Increase the protein expression of calreticulin C/EBPβ Tanshinone IIA Acute Promyelocytic Leukemia cells Up-regulation the expression of the target c-Fos Tanshinone IIA HL-60 cell The elevation of c-Fos Chks Cryptotanshinone Melanoma cancer cell lines, B16 and Increase the expression of Chks B16BL6 CD9 Tanshinone IIA PGCL3 cells Increase CD9 CD11b Tanshinone IIA Leukemia NB4 cells Increase CD11b ATRA-resistant leukemia cells CD31 Tanshione IIA J5 xenograft animal model Down-regulate the expression CD31 CD33 Tanshinone IIA Leukemia NB4 cells Down-regulate the expression of CD33 ATRA-resistant leukemia cells Decrease the expression of CD33 CD42a and CD63 Tanshinone IIA PGCL3 cells Decrease the expression of CD42a and CD63 Cdc25c and Cdc2 Tanshinone IIA human HCC J5 cells Decrease the expression of Cdc25c and Cdc2 Cdc25 Miltirone A549 and HCT116 The inhibition of Cdc25 activity C/EBP-homologous Tanshinone IIA Gastric carcinoma AGS Up-regulate the expression of CHOP protein (CHOP) c-jun N-terminal kinase Cryptotanshinone Human prostate DU145 carcinoma cells Blockage the Fas-induced JNK activation (JNK) c-myc Tanshinone IIA HL-60 cells Decrease the expression of c-myc Tanshinone A K562 The suppression of c-myc Cyclin A1, cyclin B1 and Cryptotanshinone Melanoma B16 cells Down-regulation the expression of cyclin Cdk1/Cdc2 A1, cyclin B1 and Cdk1/Cdc2 Tanshinones I and IIA Three human lung adenocarcinoma cell Inhibition the growth of lung cancer cells via lines, A549, CL1-0, and CL1-5 suppressing the expression of VEGF, cyclin A, and cyclin B proteins Cyclins A, D1, D2, Cdks 2 Carnosol Human prostate cancer PC3 cells Inhibition the cyclins D1, D2, and E along and 6 with cdks 2 and 6 Cyclin B and cyclin C2 Tanshinone IIA Human hepatocellular carcinoma (HCC) Down-regulation the expression of cyclin B and cyclin C2 cells, EC-1 and ECa-109 esophageal carcinoma cell lines Cyclin D1 Cryptotanshinone Chronic myeloid leukemia k562 cells Inhibition the expression of cyclin D1 Tanshinones Cultured rat vascular smooth muscle cells Inhibition the expression of cyclin D1 Cyclin D1, CDK2 and CDK4 Tanshinone IIA LNCaP cells Down-regulation the cyclin D1, CDK2 and CDK4 Cyclin D1, cyclin D3, Dihydrotanshinone Human breast cancer cell lines MCF-7 Inhibition the expression of cyclin D1, cyclin cyclin E, and CDK4 and MDA-MB-231 D3, cyclin E, and CDK4 Cyclin D, CDK4 and Tanshinone I Breast cancer cells Decrease the expression of cyclin D, CDK4 cyclin B and cyclin B a E6AP and E2F1 Tanshinone IIA CaSki (human cervical cancer) Downregulation of HPV E6 and E7 genes, and inactivation of tumor suppressor proteins of p53 and pRb

t1:26 t1:27 t1:28

t1:29 t1:30 t1:31

t1:32 t1:33 t1:34 t1:35 t1:36 t1:37 t1:38

D

E

T

C

E

R

R

t1:20 t1:21 t1:22 t1:23 t1:24 t1:25

O

t1:18 t1:19

C

t1:16 t1:17

N

t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15

U

t1:8

P

R O

O

F

t1:6 t1:7

Result

[123] [124] [17] [39] [38]

[45,125] [51] [52]

[41] [126,127] [128] [54] [53] [108] [45] [45] [51] [50] [129] [130] [131] [132] [133] [37] [47] [133] [37] [132] [50] [134] [45] [77] [130] [54] [131] [135]

[10] [50,136]

[112,137] [53] [14] [53] [138] [139]



11

Table 1 (continued) Compound

Studying Model

Result

References

Eukaryotic initiation factor 4E ER (estrogen receptor) ERCC1 (DNA excision repair protein) GADD153

Cryptotanshinone

K562/ADM cells

Inhibition the activity of eIF4E

[140]

Neo-tanshinlactone Tanshinone IIA

MCF-7 and ZR-75-1 Cisplatin-resistant ovarian cancer cells

The overexpression of ER was inhibited Decrease the mRNA expression of ERCC1

[54] [141]

Tanshinone IIA

Glucose regulation protein 78 (GRP78) HER-2 IFN-γ

Dihydrotanshinone

t1:49 t1:50

Mammalian target of rapamycin (mTOR)

Cryptotanshinone

MCF-7 and ZR-75-1 Keyhole limpet hemocyanin (KLH)primed mouse lymph node cells Cancer cells

t1:51 t1:52

Tanshinone IIA Carnosol

Gastric carcinoma AGS Human prostate cancer PC3

t1:53

Mcl-1 mTOR/HSP70S6k/4E-BPI pathway NF-κB

Tanshinone IIA

t1:54

NF-κB P65

Tanshinone IIA

Human HepG2 and SMMC-7721 liver cancer cells Human colon carcinoma cells Human breast cancer stem cells

The up-regulation of the protein expression of GADD153 Up-regulation of glucose regulation protein 78 (GRP78/Bip) The overexpression of HER-2 was inhibited Inhibition of IFN-gamma production in a dose-dependent manner Inhibition of the signaling pathway of the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation Decrease the expression of Mcl-1 Inhibition of the phosphorylation of mTOR at Ser-2448 leading to cancer inhibition Blockage the activation of NF-kappa B

[50]

t1:45 t1:46 t1:47 t1:48

Human hepatocellular carcinoma (HCC) cells Human prostate DU145 carcinoma cells

[100] [142]

t1:55

PARP [poly (ADP-ribose) polymerase]

Tanshinone IIA Cryptotanshinone Dihydrotanshinone

LNCaP, PC3 and KB cells HL-60 HCT-116 P53- and HCT-116 P53+

Taxodione, Ferruginol and 6-hydroxysalvinolone Tanshinone IIA Tanshinone IIA

HL-60

The suppression of NF-κB P65 signal Decrease the expression levels of NF-κB P65 in nucleus The cleavage of PARP The cleavage of PARP The cleavage of PARP and the induction of p53-independent apoptosis The cleavage of PARP

Tanshinone IIA Dihydrotanshinone Tanshinone IIA

BT-20 cells Breast adenocarcinoma cells ER-positive and ER-negative breast cancer cells HepG2 hepatoma

p53

Tanshinone I Tanshinone I

t1:61

p53, p21 and p27

Tanshinone IIA

O

Tanshinone IIA t1:62

p53 and p21

t1:63

ROS

t1:64 t1:65

Retinoblastoma (Rb) protein STAT4

t1:66 t1:67 t1:68

Translationally-controlled tumor protein (TCTP) TNF-α

t1:69 t1:70

Urokinase plasminogen activator (uPA)

U

N C

Cryptotanshinone

R O O

P

D

R

p53 and p21

Human colon cancer Colo 205 cells Human gastric adenocarcinoma cell line SGC-7901 LNCaP prostate cancer cells, EC-1 and ECa-109 esophageal carcinoma cell lines 786-O human renal cell carcinoma cells

R

t1:60

E

Cryptotanshinone

E

t1:59

BT-20 cells U-937 cell

T

t1:58

Phospho-JNK P×R (pregnane × receptor) p38

C

t1:56 t1:57

Neo-tanshinlactone Tanshinone IIA

F

Target t1:39 t1:40 t1:41 t1:42 t1:43 t1:44

Melanoma cell lines

Tanshinone IIA Tanshinone IIA Cryptotanshinone

Human small cell lung cancer H146 cells A549 cells Cancer cells

Cryptotanshinone

MCF-7 in an in vivo model

Tanshinone IIA

Gastric carcinoma AGS

Tanshinone IIA

Colon cancer cells

Tanshinone IIA

Human colon carcinoma cells

[59] [54] [69] [137]

[45] [10] [101]

[49,143] [127] [144] [128]

Increase the protein expression of phospho-JNK [41] The activation of P × R [145] Increase phospho-p38 protein expression Increase the expression of p38 Increase the expression of p53

[41] [53] [146]

Activation AMPK signaling pathway, including LKB1, p53, TSC2, thereby leading to suppression of mTORC1 Increase the expression of p53, p21 Up-regulation the expression of the target

[147]

[148] [125]

Activation the p53/p21/p27 signaling pathway

[14,136]

The activation of p53 and up-regulation of its target genes, including p21 Increase the expression of p53 in both B16 and B16BL6, but increase p21 expression in B16BL6 cells Increase the production of ROS Increase the production of ROS Inhibition of retinoblastoma (Rb) protein phosphorylation Up-regulating of JAK2 and STAT4 phosphorylation, and consequently, inducing cytotoxic CD4+ T cells to secrete perforin Decrease the expression of TCTP

[42]

Up-regulation of the protein expression of TNF-alpha Inhibition in vitro and in vivo invasion and metastasis of CRC cells by reducing the levels of urokinase plasminogen activator (uPA) and matrix metalloproteinases 2 (MMP-2) and MMP-9, and by increasing the levels of tissue inhibitor of matrix metalloproteinase protein TIMP-1 and TIMP-2

[131]

[51] [149] [137] [67]

[45] [150] [100]

(continued on next page)


12


Table 1 (continued)

Tanshinone I

Studying Model

Result

References

Human gastric cancer cell line SGC7901 Gastric cancer SGC-7901 cell Subcutaneous colorectal cancer xenografts in mice Hepatocellular carcinoma cell line SMMC-7721 HUVECs and MDA-MB-231 breast cancer cells

The inhibition of VEGF

[151] [152] [153]

VEGF

Tanshinone I and Tanshinone IIA

Three human lung adenocarcinoma cell lines, A549, CL1-0, and CL1-5

t1:74

X-box-binding protein 1 (XBP1)

Dihydrotanshinone

Human prostate DU145 carcinoma cells

t1:75

a

Associated proteins of human papilloma virus E6 and E7 genes.

796 797

The authors would like to thank Dr. Javad Asili for his scientific supports.

798

References

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animal models, pre-clinical investigations, and even, clinical trials. Although the pure diterpenes have not been clinically evaluated for cancer treatment yet, however, they reached to phase II and III clinical trials for other diseases. For instance, a phase II/III clinical trial (NCT01637675) is investigating tanshinone IIA sulfonate's effects in pulmonary hypertension [155]. One phase II trial (NCT01452477) is studying tanshinone's (total tanshinones from the roots of S. miltiorrhiza) therapeutic effects in polycystic ovary syndrome. It seems that other Salvia diterpenes can likewise translate into clinical trial if they show safety/efficacy in in vivo studies [156].

783 784

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[119] Inhibition the TNF-alpha-induced production of vascular endothelial growth factor (VEGF) and VEGF-mediated tube formation Inhibition the growth of lung cancer cells via [135] suppressing the expression of VEGF, cyclin A, and cyclin B proteins Increase X-box-binding protein 1 (XBP1) [59] mRNA splicing forms

R O

t1:73

[154]

F

Compound

VEGF (vascular endothelial Tanshinone IIA growth factor)

O

Target t1:71 t1:72


826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880


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U

881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 Q9 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960

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961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 Q10 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040

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New Dimeric and seco-Abietane Diterpenoids from Salvia wardii.

Erratum to: New Dimeric and seco-Abietane Diterpenoids from Salvia wardii.

Abietane and nor-abitane diterpenoids from the roots of Salvia rhytidea.

Labdane diterpenoids from Salvia reuterana.

Diterpenoids from the Roots of Salvia yunnanensis.

Synthetic derivatives of aromatic abietane diterpenoids and their biological activities.

In vitro antiprotozoal activity of abietane diterpenoids isolated from Plectranthus barbatus Andr.

New Abietane and Kaurane Type Diterpenoids from the Stems of Tripterygium regelii.

A new rearranged tricyclic abietane diterpenoid from Salvia chloroleuca Rech. f. & Allen.

Isolation and bioactivity of diterpenoids from the roots of Salvia grandifolia.

Two diterpenoids and a cyclopenta[c]pyridine derivative from roots of Salvia digitaloids.

Nor-diterpenoids from the Rare Chloranthaceae Plant Chloranthus sessilifolius and Their Antineuroinflammatory Activities.

Effect of abietane- type pigments from Salvia miltiorrhiza on post-hypoxic recovery of cardiac contractile force in rats.

Nitrogen-Containing Diterpenoids, Sesquiterpenoids, and Nor-Diterpenoids from Cespitularia taeniata.

Diterpenoids from Isodon sculponeatus.

An application of HPLC for identification of abietane-type pigments from Salvia miltiorrhiza and their effects on post-hypoxic cardiac contractile force in rats.

Discovery of novel diterpenoids from Sinularia arborea.

Antifilarial activity of diterpenoids from Taxodium distichum.

Icetexane diterpenoids from Perovskia atriplicifolia.

New Diterpenoids from Clerodendranthus spicatus.

Botryane, noreudesmane and abietane terpenoids from the ascomycete Hypoxylon rickii.

Flies as pollinators of melittophilous Salvia species (Lamiaceae).

Cytotoxic, antioxidant and antimicrobial activities and phenolic contents of eleven salvia species from iran.

A comparative analysis of essential oils from several wild species of Salvia.