Salvia miltiorrhiza in cancer: Potential role in regulating MicroRNAs and epigenetic enzymes

Abstract

MicroRNAs are small non-coding RNAs that play important roles in gene regulation by influencing the translation and longevity of various target mRNAs and the expression of various target genes as well as by modifying histones and DNA methylation of promoter sites. Consequently, when dysregulated, microRNAs are involved in the development and progression of a variety of diseases, including cancer, by affecting cell growth, proliferation, differentiation, migration, and apoptosis. Preparations from the dried root and rhizome of Salvia miltiorrhiza Bge (Lamiaceae), also known as red sage or danshen, are widely used for treating cardiovascular diseases. Accumulating data suggest that certain bioactive constituents of this plant, particularly tanshinones, have broad antitumor effects by interfering with microRNAs and epigenetic enzymes. This paper reviews the evidence for the antineoplastic activities of S. miltiorrhiza constituents by causing or promoting cell cycle arrest, apoptosis, autophagy, epithelial-mesenchymal transition, angiogenesis, and epigenetic changes to provide an outlook on their future roles in the treatment of cancer, both alone and in combination with other modalities.

Introduction

Salvia miltiorrhiza is a common herbal beverage in Traditional Chinese Medicine (TCM). S. milthiorrhiza belongs to the Lamiaceae family, and its medicinal parts are the roots or rhizomes (Zhang et al., 2022). S. milthiorrhiza has been widely used in TCM for the treatment of cardiovascular disease (CVD) (Li et al., 2018; Ren et al., 2019). For instance, Danshen-Honghua is a commonly used herb pair for promoting blood circulation and removing blood stasis, and S. milthiorrhiza often appears in some TCM compounds used for cardiovascular and cerebrovascular diseases, such as Danhong Huayu Oral Liquid, Danhong Injection, and Xinning Tablets (Wang et al., 2019b).

S. milthiorrhiza improves microcirculation, protects the nervous system, and dilates blood vessels, and it also has antitumor properties (Tao et al., 2018). Research has shown that the compounds in S. milthiorrhiza are mainly divided into two categories as follows: fat-soluble, which mainly include diterpenoids, triterpenoids, flavonoids, nitrogenous compounds, lactones, and polysaccharides; and water-soluble, which mainly include phenolic acids (Su et al., 2015). Diterpenoids mainly include tanshinones, such as tanshinone I (tan I), tanshinone IIA (tan IIA), tanshinone IIB (tan IIB), cryptotanshinone (CPT), dihydrotanshinone I (DHT I), and isocryptotanshinone (Tian et al., 2021). The water-soluble compounds in S. milthiorrhiza are primarily salvianolic acid A (Sal A), salvianolic acid B (Sal B), salvinorin, caffeic acid, rosmarinic acid, and protocatechuic acid (Xin et al., 2020). Most of the triterpenoids are derivatives of oleanolic acid (OA) and ursolic acid (UA) (Tung et al., 2017). The flavonoids in S. milthiorrhiza are mainly luteolin (LUT) and its derivatives (Salinas-Arellano et al., 2020). The polysaccharides in S. milthiorrhiza are mainly composed of mannose, rhamnose, arabinose, glucose, and galactose (Han et al., 2019). The nitrogen-containing compounds that have been isolated from S. milthiorrhiza include neosalvianen, salvianen, and salviadione. In addition, S. milthiorrhiza also contains lactone compounds, such as Dan shen spiroketal lactone (Liang et al., 2020; Wang et al., 2020) (Figure 1). Cancer is a disease that seriously endangers human health. According to the latest data released by the World Health Organization’s International Agency for Research on Cancer (IARC), the number of new cancer cases worldwide in 2020 exceeded 19.3 million, and China ranks 68th in the world in cancer incidence rate (Sung et al., 2021). Many studies have reported that the chemical components in S. milthiorrhiza, such as tan IIA, have good antitumor activity. In addition to inhibiting the proliferation, blocking the cell cycle, inducing apoptosis, and inducing autophagic death of various types of tumor cells, tan IIA also significantly inhibits cell migration and invasion (Cao et al., 2018; Fang et al., 2020). Tan I and LUT also exert antitumor effects through mediating apoptosis and cell cycle arrest (Anson et al., 2018; Li et al., 2018a).

FIGURE 1

Antitumor activities of S. miltiorrhiza

Inhibition of proliferation

S. miltiorrhiza bioactive compounds, such as tan IIA and CPT, effectively inhibit tumor growth (Chen et al., 2014) and suppress tumor cell proliferation in vitro and in vivo (Lin et al., 2015; Zhang et al., 2019c). For example, tan IIA inhibits tumor growth in acute promyelocytic leukemia NB4 cell xenograft mice (Zhang et al., 2016c). Liu et al. (2020) reported that CPT inhibits the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway by inducing the expression of phosphatase and tensin homologue (PTEN), which represses tumor growth in 5637 cell xenograft mice. Furthermore, tanshinol represses U2-OS tumor growth in zebrafish larvae in a dose-dependent manner (Yu et al., 2022). In addition, previous studies have demonstrated that tan IIA suppresses the proliferation of different types of tumor cells in a time- and dose-dependent manner in vitro, including gastric cancer (GC; SNU-638, MKN1 and AGS cells) (Zhang et al., 2018) and non-small cell lung cancer (NSCLC; A549 and H292 cells) (Qi et al., 2022). Additionally, it has been reported that tan IIA reduces the phosphorylation of insulin-like growth factor 1 receptor (IGF-1R) and its downstream PI3K/Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways, resulting in the suppression of pheochromocytoma growth (PC12 cells) (Wang et al., 2018a). Other tanshinones also inhibit the development of tumors. For example, tan I suppresses colorectal cancer (CRC) cell proliferation by decreasing aurora A-mediated upregulation of p53 or downregulation of survivin expression to induce apoptosis in HCT116 and SW480 cells (Lu et al., 2016). In addition, CPT enhances the cytotoxicity of CD4⁺ T cells and prevents the development of H446 cells by upregulating the levels of phosphorylated JAK kinase 2 (p-JAK2) and phosphorylated signal transducer and activator of transcription 4 (p-STAT4) (Man et al., 2016). In addition, other components of S. miltiorrhiza have been reported to have antitumor properties. For example, LUT suppresses the viability of RPMI-8226 multiple myeloma cells by enhancing the expression of cleaved caspase 3 and microtubule-associated protein light chain 3 (LC3)-II/I (Chen et al., 2018). LUT also inhibits xenograft tumor growth by reducing Ki-67, p-LIMK, and p-cofilin expression (Zhang et al., 2021). Furthermore, salvianolic acid inhibits tumor cell proliferation. Sal A reduces the viability of NSCLC cells (Jin et al., 2021), and Sal B suppresses cell proliferation via regulating the Akt/mTOR pathway in DDP-resistant GC cells (Wang et al., 2021a).

The cell cycle is the foundation of cell proliferation, and blockade of the cell cycle prevents tumor development. It has been reported that tan IIA inhibits the proliferation of ovarian cancer (Zhou et al., 2020), cervical cancer (Pan et al., 2010), and GC (Chen et al., 2012) cells by arresting the cell cycle in the G2/M phase. In contrast, tan IIA arrests the cell cycle in lung cancer at the G0/G1 phase via upregulating the levels of p53 and p21 as well as downregulating the levels of cyclin D1, cyclin E1, and cyclin-dependent kinase 2 (CDK2) (Lee et al., 2016). Furthermore, tan IIA arrests the cell cycle in prostate cancer in the G0/G1 phase through increasing the expression of p21, p26, and p27 as well as decreasing the expression of cyclin D1, CDK2, and p-Rb (Chiu et al., 2013). Therefore, we propose that the different effects of tan IIA on the cell cycle may be related to cell types. Studies have indicated that other components of S. miltiorrhiza also block the cell cycle at different phases in various tumors cells. For example, LUT inhibits cell proliferation of bladder cancer and lung cancer through arresting the cell cycle in the G2/M phase and G1 phase, respectively (Iida et al., 2020; Zhang et al., 2021). LUT blocks the cell cycle in the G2/M phase through upregulating p21^Waf1/Cip1 and p27^Kip1 as well as downregulating cyclin A and D1 in bladder cancer T24 cells (Iida et al., 2020). In addition, LUT reduces the expression of cyclin D1 and cyclin D3, thereby inducing cycle arrest of lung cancer cells in the G1 phase (NCI-H1975 and NCI-H1650 cells) (Zhang et al., 2021). Moreover, OA reduces the levels of cyclin D1, CDK1, CDK2, CDK4, and CDK7 but increases the expression of p27, which in turn blocks the cell cycle of HeLa cells in the sub-G1 phase, thereby inhibiting cervical cancer cell growth (Edathara et al., 2021). Moreover, Sal B arrests the cell cycle of A549 cells in the G0/G1 phase by regulating cyclin B1 and p21, thereby repressing A549 cell proliferation (Han et al., 2022). Thus, these findings demonstrate that S. miltiorrhiza bioactive compounds suppress the proliferation of various cancers by driving cell cycle arrest, indicating the potential antitumor usage of S. miltiorrhiza bioactive compounds in the clinic.

Promotion of apoptosis

Apoptosis is an autonomous and orderly cell death process controlled by genes that occurs after cells are stimulated by physiological or pathological signals, and tumors have the ability to resist apoptosis via multiple strategies (Pistritto et al., 2016; Huang et al., 2021a). The antitumor effect of S. miltiorrhiza bioactive compounds has been linked to the induction of apoptosis in multiple studies (Sun et al., 2021). For example, tan IIA induces apoptosis of ovarian cancer A2780 cells by regulating the PI3K/Akt/c-Jun N-terminal kinase (JNK) signaling pathway, which increases the expression of caspase 3, caspase 8, and caspase 9 but decreases the expression of B cell lymphoma 2 (Bcl-2) family proteins (Bcl-w and Bcl-1L) (Zhang et al., 2019a). Tan IIA has also been shown to promote tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in glioblastoma by upregulating death receptor 5 (DR5) and blocking STAT3-mediated survivin downregulation (Zhou et al., 2021). Moreover, tan I induces leukemia cell apoptosis via inactivation of the PI3K/Akt/survivin signaling pathway, which disrupts the membrane potential, increases Bcl-2-related X (Bax) expression, and activates caspase 3 (Liu et al., 2010). Tanshinone analog 2-((Glycine methyl ester) methyl)-naphtho (TC7) induces cell apoptosis by regulating apoptosis-associated genes, such as p53, ERK1, Bax, p38, Bcl-2, caspase 8, cleaved caspase 8, and poly (ADP-ribose) polymerase 1 (PARP1), as well as the phosphorylation levels of ERK1 and p38 (Wang et al., 2019). Additionally, LUT has been reported to promote apoptosis in a variety of tumor cells, including ovarian teratomas (Liu et al., 2019) and melanomas (Yao et al., 2019), by decreasing Bcl-2 expression, increasing Bax expression, and inhibiting the PI3K/Akt signaling pathway. Moreover, Sal B induces osteosarcoma MG63 cell apoptosis by increasing the expression of cleaved caspase 3, phosphorylated-p38 mitogen-activated protein kinase (p-p38 MAPK), and phosphorylated-p53 (p-p53) (Zeng et al., 2018).

S. miltiorrhiza bioactive compounds induce apoptosis of various tumor cells through the mitochondrial pathway (Ye et al., 2017). Tan IIA regulates mitochondrial fission through the JNK/mitochondrial fission factor (MFF) axis, which in turn upregulates mitochondrial pro-apoptotic proteins (Bax and Bad), activates caspase 9, and leads to colon cancer SW837 cell apoptosis (Jieensinue et al., 2018). Reactive oxygen species (ROS) interact with membrane receptors and transcription factors/repressors to activate endogenous and exogenous apoptotic signaling pathways, thereby inducing apoptosis (Su et al., 2019). DHT provokes mitochondrial dysfunction in the early stage by decreasing mitochondrial membrane permeability (MMP) and ROS levels, leading to cell death in colon cancer cells (Wang et al., 2013). Moreover, DHT I stimulates the release of both cytochrome c and apoptosis inducing factor (AIF) in HCT116 cells, which downregulates Bcl-xl and upregulates Bax, thereby inducing apoptosis (Wang et al., 2015). Another S. miltiorrhiza component, LUT, promotes apoptosis in canine osteosarcoma cells by generating ROS, increasing loss of MMP, and reducing cytosolic Ca²⁺ concentration (Ryu et al., 2019). In addition, CPT upregulates Bax and cleaved caspase3 but downregulates the anti-apoptotic protein, Bcl-2, which reduces the level of ROS, thereby inducing apoptosis in human melanoma A375 cells (Ye et al., 2016). Furthermore, Sal B induces mitochondria-mediated apoptosis in human colon cancer cells by reducing the mitochondrial potential and increasing mitochondrial cytochrome c release (Gong et al., 2016). Collectively, inducing mitochondria-dependent apoptosis is one of the important ways for S. miltiorrhiza bioactive compounds to exert an antitumor effect.

Inhibition of migration and invasion

Metastasis and invasion are the main manifestations of tumor malignancy, and they are key factors affecting cancer prognosis (Suhail et al., 2019). Tumor cell invasion and metastasis are complicated biological processes that involve the interplay of many growth factors, cytokines, enzyme systems, matrix metalloproteinases, signaling pathways, and epithelial-mesenchymal transition (EMT) (Patriarca et al., 2020). Many studies have reported that numerous S. miltiorrhiza bioactive compounds affect tumor metastasis and invasion via regulating angiogenesis, regulating tumor cell EMT, and blocking matrix metalloproteinases from hydrolyzing the basement membrane (Zhang et al., 2012). For instance, tan IIA blocks the nuclear factor kappa-B (NF-κB) signaling pathway to inhibit the activity of MMP2 and MMP9, thereby preventing the metastasis and invasion of human hepatoma cells and hepatocellular carcinoma (HCC) cells (Shan et al., 2009; Yuxian et al., 2009; Zhang et al., 2016d).

New blood vessels in tumor tissue provide a source of nutrients for cell proliferation and are also a channel for tumor cell migration (Jiang et al., 2020). Thus, inhibiting tumor angiogenesis has become one of the current antitumor strategies (Fu et al., 2020). Rapid tumor cell proliferation generates hypoxia in local tumor tissue, which activates and upregulates hypoxia-inducible factor 1α (HIF-1α), resulting in the upregulation of the expression of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), to promote angiogenesis (Keeley et al., 2010). VEGF is a potent angiogenic factor that increases vascular permeability, enabling endothelial cell migration and inducing angiogenesis (Melincovici et al., 2018). Many components of S. miltiorrhiza have been demonstrated to suppress tumor cell invasion and metastasis via regulating HIF-1α- and VEGF- mediated signaling pathways (Macklin et al., 2017). Tan IIA, tan I, and LUT inhibit the secretion of VEGF under hypoxia by downregulating HIF-1α expression, further inhibiting the growth of new blood vessels and the metastasis and invasion of HCC cells, CRC cells, breast cancer cells, human endothelial progenitor cells, and human umbilical vein endothelial cells (Nizamutdinova et al., 2008; Li et al., 2015; Lee et al., 2017; Sui et al., 2017; Fang et al., 2018; Li et al., 2019; Xue et al., 2019; Zhou et al., 2020c).

During EMT, cells transition from an epithelial state to a mesenchymal state, enabling tumor cells to invade and metastasize (Pastushenko and Blanpain 2019). In the EMT process, epithelial proteins are up- or downregulated, and these proteins are identified as EMT markers. The occurrence of EMT is indicated by decreased E-cadherin and keratin as well increased mesenchymal markers, including vimentin, fibronectin, N-cadherin, and α-SMA (Zeisberg and Neilson 2009). Salvinorin and DHT prevent EMT in colon cancer cells and triple-negative breast cancer (TNBC) cells by increasing E-cadherin levels and decreasing N-cadherin and vimentin levels (Kashyap et al., 2021; Cao et al., 2022).

Numerous studies have shown that S. miltiorrhiza bioactive compounds reverse the levels of EMT markers through a complex pathway, including transcription factors, which inhibit the EMT process in tumor cells (Pastushenko and Blanpain 2019). TGF-β is a key factor in inducing EMT in the process of tumor cell proliferation, and elevated levels of TGF-β regulate the expression of EMT markers, which in turn induces EMT (Ali et al., 2015). It has been reported that Sal B and Sal A inhibit the EMT of renal tubular epithelial cells and endothelial cells, respectively, by inhibiting the expression of TGF-β and reversing the expression of EMT markers (Wang et al., 2010; Zhao et al., 2017). YAP/TAZ, a co-activating transcription factor, translocates into the nucleus and binds to transcription factors, such as Twist and Snail, to promote gene transcription (Noguchi et al., 2018; Ma et al., 2019). LUT inhibits the EMT in TNBC cells by inhibiting the transcription activity of YAP/TAZ as well as preventing it from entering the nucleus, further upregulating the protein levels of E-cadherin and downregulating the protein levels of fibronectin, N-cadherin, and vimentin (Cao et al., 2020).

In addition, β-catenin, a cell adhesion regulator, combines with E-cadherin protein on the cell membrane to attach it to the actin cytoskeletal protein, thereby increasing cell adhesion (Shang et al., 2017). GSK-3β is an evolutionarily conserved serine/threonine (S/T) kinase that phosphorylates and degrades cytoplasmic β-catenin, which is regulated by β-arrestin1 and the PI3K/Akt pathway (Yu et al., 2021). Studies have shown that tan IIA increases the expression of GSK-3β by inhibiting the β-arrestin1 and PI3K/Akt signaling pathways, further reducing the nuclear localization of β-catenin and blocking the EMT in CRC and HCC cells (Zhang et al., 2019; Song et al., 2020). Moreover, adhesion factors, such as CCL2, are critical in the EMT process, and the reduction of adhesion factor expression leads to reduced adhesion between transitional cells and adjacent epithelial cells, which causes epithelial cells to lose apical basal cell polarity, thereby promoting the EMT process (Jin 2020; Zou et al., 2020). Studies have shown that tan IIA suppresses the EMT in bladder cancer cells by downregulating CCL2 via blocking the STAT3 pathway (Huang et al., 2017) (Figure 2).

FIGURE 2

In conclusion, S. miltiorrhiza bioactive compounds inhibit tumor cell metastasis and invasion through different pathways, including inhibiting the activity of MMP proteins, tumor angiogenesis, and the EMT process.

Regulation of autophagy

Autophagy is a type of programmed cell death, and it is a target in cancer treatment (Rodrigues et al., 2020). Investigations have revealed that S. miltiorrhiza bioactive compounds, such as tan IIA, tan I, CPT, DHT, and LUT, induce autophagy, thereby inhibiting cancer cell proliferation (Fu et al., 2020a).

One of the critical pathways to induce autophagy is the conversion of the soluble form of microtubule-associated protein light chain 3-I (LC3-I) to lipid-soluble LC3-II, which is involved in the formation of autophagosomes, thereby inducing autophagy (Wu et al., 2015). In vitro experiments have shown that CPT and DHT induce autophagy by increasing the accumulation of LC3-II in CRC, which induces tumor cell death (Hu et al., 2015).

In addition, the coordinated action of the unc-51-like kinase 1 (ULK1) complex and Beclin 1 functions in driving autophagy (Russell et al., 2013). Beclin 1 is one of the key regulators of autophagy, which participates in the initiation of autophagosome formation, thereby promoting autophagy (Funderburk et al., 2010). For example, LUT induces autophagy in lung cancer cells, HCC cells, and skin squamous cell carcinoma cells by upregulating Beclin 1 expression, subsequently inhibiting tumor cell growth (Verschooten et al., 2012; Park et al., 2013; Potočnjak et al., 2020). Moreover, the ULK1/2 complex is activated in the early stage of autophagy and cooperates with Beclin 1 to initiate autophagosome formation and induce autophagy (Parzych and Klionsky 2014). Furthermore, tan I activates the ULK1 complex and upregulates the expression level of Beclin 1, which subsequently induces autophagy and prevents the growth of breast and liver cancer cells (Zheng et al., 2020).

Mechanistic target of rapamycin (mTOR) is a S/T kinase, which exists in two distinct complexes called mTOR complex 1 (mTORC1) and 2 (mTORC2), and mTORC1 is a key regulator of autophagy (Hua et al., 2019). The activity of mTORC1 reflects the nutritional status of the cell (Kim et al., 2011). Under nutrient-rich conditions, mTORC1 inhibits the autophagy-promoting kinase activity of the ULK1 complex by mediating specific site phosphorylation of ULK1 (Ser637 and Ser757) (Karabiyik et al., 2021). During periods of starvation and cellular stress, mTORC1 activity is inhibited and dissociates from ULK1, resulting in dephosphorylation of ULK1 (Zachari and Ganley 2017). At the same time, the ULK1 complex becomes active through autophosphorylation at Thr180, initiating autophagy (Zachari and Ganley 2017). Studies have shown that tan I inhibits the activity of mTORC1 under starvation conditions, subsequently increasing the activity of the ULK1 complex and promoting the occurrence of autophagy in breast and liver cancer cells (Zheng et al., 2020).

The mTOR pathway is regulated by multiple signaling pathways in autophagy, such as the PI3K/Akt, MAPK/MEK/ERK1/2, and AMPK pathways (Querfurth and Lee 2021). The PI3K/Akt and MAPK/MEK/ERK1/2 signaling pathways have a positive regulatory effect on mTOR, and blocking the above pathways causes autophagy, eventually leading to tumor cell death (Xu et al., 2020a). It has been reported that tan I and tan IIA induce autophagy by inhibiting the PI3K/Akt/mTOR pathway, further inhibiting the proliferation of tumor cells (including ovarian cancer cells, glioma cells, acute promyelocytic leukemia NB4 cells, acute mononuclear leukemia cells, oral squamous cell carcinoma (OSCC) cells, and melanoma cells) (Ding et al., 2017; Li et al., 2017; Qiu et al., 2018; Zhang et al., 2019c; Zhou et al., 2020b; Pan et al., 2021). In addition, tan IIA also drives autophagy through inhibiting the MEK/ERK/mTOR signaling pathway, thereby suppressing the proliferation of colon cancer cells (Qian et al., 2020).

In contrast, the AMPK pathway negatively regulates mTOR. Phosphorylated AMPK inhibits the activity of mTORC1, which indirectly increases the activity of the ULK1 complex, thereby promoting the occurrence of autophagy (Li and Chen 2019). Tan IIA activates AMPK phosphorylation to inhibit mTOR phosphorylation, thereby inducing autophagic death of leukemia cells (Yun et al., 2014). Moreover, under starvation conditions, AMPK activation directly catalyzes the phosphorylation of ULK1 to promote autophagy (Karabiyik et al., 2021). According to a previous study, tan I activates the AMPK signaling pathway to active the ULK1 complex, which subsequently induces autophagy and prevents the growth of breast and liver cancer cells (Zheng et al., 2020).

In summary, tan IIA inhibits the mTOR pathway through different mechanisms and increases the expression of autophagy-related proteins, such as LC3-II and Beclin 1, thereby inducing autophagy in tumor cells (Figure 3).

FIGURE 3

Targeting microRNAs (miRNAs)

MiRNAs are a class of non-coding small RNAs with a length of 21–25 nucleotides, and they are widely present in animal and plant cells (Mohr and Mott 2015). MiRNAs bind to the 3′-untranslated region (UTR) of messenger RNA (mRNA) to inhibit mRNA translation or induce mRNA degradation, thereby silencing gene expression at the post-transcriptional level (Lee and Dutta 2009; Wu et al., 2021). In malignant tumors, aberrant amplification, deletion, mutation, and epigenetic silencing of miRNAs have been identified to exert oncogenic or tumor-suppressive effects depending on the target (Rupaimoole and Slack 2017). As an epigenetic modification, miRNAs up- or downregulate the expression of downstream genes through targeting the promoter region of the target gene, thereby mediating the progression of indicated tumors (Ali Syeda et al., 2020). Thus, miRNAs may be used as diagnostic, prognostic, and predictive biomarkers of tumors, and targeting microRNAs may be a potential therapeutic approach for cancers (Iorio and Croce 2012). Studies have demonstrated that S. miltiorrhiza bioactive compounds mediate tumorigenesis by regulating the biological behaviors of miRNAs in cell proliferation, apoptosis, invasion, and metastasis.

Targeting miRNAs to inhibit proliferation

It has been reported that miRNAs target proliferation-related genes and proteins, such as PKM, Akt, and MEF2D, to regulate tumor cell proliferation (Xu et al., 2020). Tan IIA suppresses the proliferation of AML cells (HL-60 and THP-1), glioma cells, esophageal cancer cells (EC109), breast cancer cells, and NSCLC cells through targeting miR-497-5p/Akt3, miR-122/PKM2, miR-16-5p/TLN1, miR-125b/STAR13, and let-7a-5p/aurora kinase A (AURKA), respectively (Zhang et al., 2016; Liu et al., 2020a; Liu et al., 2020; Nie et al., 2020; You et al., 2020; Li et al., 2022). Moreover, tan I, CPT, and tan IIA share common targets, including miR-137 and let-7a-5p, which function in inhibiting the proliferation of NSCLC by regulating the expression of ULK2/IBTK and AURKA, respectively; these common targets may be a result of highly similar chemical structures (Zhang et al., 2016; Liu et al., 2020a). It has been reported that tan I and CPT show inhibitory effects in NSCLC through targeting AURKA mediated by miR-32 (Ma et al., 2015). In addition, studies have reported that CPT inhibits the proliferation of NSCLC cells through targeting miR-146a-5p/EGFR (Qi et al., 2019). Furthermore, UA downregulates miR-499a-5/secreted frizzled related protein 4 (sFRP4) and miR-149-5p/myeloid differentiation primary response 88 (MyD88), thereby inhibiting the proliferation of NSCLC cells (Chen et al., 2020; Mandal et al., 2021). Another active ingredient of salvia, OA, suppresses the proliferation of A549 and GC cells through increasing the expression of miR-122/CCNG1/MEF2D and miR-98-5p/IL-6, respectively (Zhao et al., 2015; Xu et al., 2021). Additionally, studies have shown that LUT regulates the levels of miR-203/Ras/Raf/MEK/ERK, miR-8080/AR-V7 and miR-6809-5p/flotillin 1, which in turn inhibits the proliferation of breast cancer, castration-resistant prostate cancer (CRPC), and HCC, respectively (Gao et al., 2019; Yang et al., 2019; Naiki-Ito et al., 2020).

Researchers have also indicated that abnormal miRNAs promote tumor cell proliferation by regulating the expression of cell cycle-related proteins (Mens and Ghanbari 2018). Studies have shown that UA inhibits the proliferation of BGC-823 cells by upregulating miR-133a and inhibiting Akt1 expression, thereby promoting cell cycle arrest in the G phase (Xiang et al., 2014). Zhang et al. (2016b) reported that tan IIA induces the upregulation of miR-122 expression and inhibits the expression of pyruvate kinase M2 (PKM2) in human EC109 cells, which induces human EC109 tumor cells to arrest in S phase, thereby exerting an anticancer effect (Zhang et al., 2016).

Targeting microRNAs to promote apoptosis

Specific miRNAs directly or indirectly participate in the regulation of multiple apoptotic pathways by regulating the level of downstream genes, and they can play an oncogenic or tumor suppressor role (Bejarano et al., 2021). Tan IIA targets miR-125b/gasdermin D (GSDMD) and miR-145/caspase 1, which induces apoptosis of nasopharyngeal carcinoma (NPC) cells (HK1 cells) and cervical carcinoma cells (HeLa cells), respectively (Tong et al., 2020; Wang et al., 2021c). In addition, tan IIA targets miR30b, further upregulating p53 levels, which induces apoptosis and death of HCC cells (Ren et al., 2017). Studies have found that tan I and UA target miR135a-3p/DR5 (prostate cancer), miR-21 (glioma), and let7b (malignant mesothelioma), which mediates the activation of caspase 3, thereby inducing tumor cell apoptosis and proliferation (Wang et al., 2012; Shin et al., 2014; Sohn et al., 2016). It has been reported that UA increases the level of miR-4500, which suppresses the expression of p-STAT3 and cleaved PARP, thereby inducing CRC cell apoptosis and inhibiting CRC growth (Kim et al., 2018).

Targeting microRNAs to inhibit migration and invasion

Studies have found that miRNAs play an important role in tumor invasion and metastasis by affecting indicated targets and pathways (Wang and Chen 2019). Numerous studies have demonstrated that S. miltiorrhiza bioactive compounds regulate the levels of miRNAs, thereby inhibiting metastasis and invasion of tumor cells. LUT upregulates miR-203/Ras/Raf/MEK/ERK, which upregulates E-cadherin and downregulates N-cadherin, thereby inhibiting the progression of EMT and preventing tumor cell invasion and metastasis of breast cancer (Gao et al., 2019). Furthermore, LUT upregulates miR-384 and subsequently downregulates the expression of multivitamin trophic factor (PTN), which inhibits CRC and osteosarcoma (OS) cell migration and invasion (Yao et al., 2019; Qin et al., 2022). In addition, LUT inhibits migration- and invasion-related factors, including VEGF, MMP2, and MMP9, by upregulating miR-133a-3p levels, thereby suppressing invasion and metastasis of NSCLC (Pan et al., 2022). In addition, UA targets let 7b, which inhibits the expression of p-Akt, β-catenin, and Twist, thereby repressing the EMT process (Sohn et al., 2016).

In summary, S. miltiorrhiza bioactive compounds inhibit tumor cell proliferation, migration, and invasion as well as induce apoptosis by regulating the expression of miRNAs, thereby exerting antitumor effects (Table 1).

Regulation of epigenetic enzymes

Epigenetic mechanisms refer to heritable changes in gene expression without altering the DNA sequence, and they include DNA methylation, chromatin remodeling, histone modifications, and non-coding RNAs (Kanwal et al., 2015; Huang et al., 2021b). Abnormal epigenetic alterations are often involved in tumor initiation, progression, and metastasis (Esteller 2008). S. miltiorrhiza bioactive compounds have been reported to inhibit tumorigenesis and progression by modulating indicated epigenetic mechanisms, including DNA methylation, histone acetylation, ubiquitination, and DNA topoisomerase (Tian et al., 2018; Bhattacharjee and Dashwood 2020). For example, DHT promotes Keap1-mediated degradation of nuclear factor erythroid 2-related factor 2 (Nrf2) ubiquitination, and it increases the accumulation of ROS, which in turn downregulates Bcl-2, cyclin B1, and Cdc2 levels as well as upregulates Bax levels in ovarian cancer cells in vivo and in vitro (Sun et al., 2022).

DNA methylation

In normal cells, DNA methylation occurs mainly in repetitive genomic regions and is responsible for silencing gene expression and maintaining genome stability (Sandoval et al., 2011). However, special DNA regions, such as promoters, especially CpG islands (CpGs), are often unmethylated (Bird 1986). Hypomethylation in tumor cells is mainly due to methylation deficiency in repetitive genomic regions, leading to genomic instability and activation of transposon promoters, whereas hypermethylation is the ab initio methylation of CpGs, which can lead to transcriptional silencing of growth regulatory genes (Lakshminarasimhan and Liang 2016). Cancer cells display genome-wide hypomethylation and site-specific CpG promoter hypermethylation (Rodríguez-Paredes and Esteller 2011). Abnormal increased DNA methylation leads to transcriptional repression and decreased gene expression (Pan et al., 2018). Studies have reported that S. miltiorrhiza bioactive compounds regulate the level of methylation in tumor cells and inhibit tumor development (Kim et al., 2016; Li et al., 2022). For example, tan IIA, LUT, and UA target the abnormal hypermethylation at the CpG methylation region in the Nrf2 promoter by reducing the expression of DNA methyltransferases (DNMTs), including DNMT1, DNMT3a, and DNMT3b, thereby inhibiting cell proliferation of skin and colon cancers (Wang et al., 2014; Kim et al., 2016; Zuo et al., 2018). Moreover, it has been reported that the inhibition of NRF2 promoter methylation is mediated by tan IIA via ten-eleven translocation (TET)-2 activation (Yang et al., 2020). In addition, OA decreases the promoter DNA demethylation of programmed death-ligand 1 (PD-L1) by inhibiting the expression of TET-3, which downregulates PD-L1, ultimately enhancing T cell-mediated killing of MKN-45 cells (Lu et al., 2021). Moreover, it has been reported that Sal B induces DNMT1-mediated demethylation of the PTCH1 gene, which in turn inhibits hepatic stellate cell (HSC) EMT in vivo and in vitro (Yu et al., 2015).

Histone methylation

Histone methylation is a major player in the regulation of gene expression and genetic stability, and dysfunction of histone methylation contributes to the development of various cancers (Rotili and Mai 2011). Methylation occurs primarily on lysine or arginine residues of histones H3 and H4, which is controlled by histone methyltransferases (HMTs) and histone demethylases (HDMs) (Janardhan et al., 2018). Polycomb repressive complex 2 (PRC2) is a complex that mediates gene silencing by regulating chromatin structure (Chan and Morey 2019). Enhancer of zeste homolog 2 (EZH2), a polycomb group (PcG) protein, is an enzymatic catalytic subunit of PRC2 that regulates gene expression through catalyzing primarily tri-methylation of histone H3 Lys-27 (H3K27), and it functions in the development and progression of a variety of cancers, such as breast cancer (Bachmann et al., 2006), GC (Gan et al., 2018), and NPC (Duan et al., 2020). It has been reported that tanshindiol C inhibits EZH2 activity, which in turn downregulates H3K27me3 levels, thereby inhibiting the proliferation of the Pfeiffer cell line, a type of B cell lymphoma (Woo et al., 2014). Furthermore, tan I directly binds to EZH2, which inhibits PRC2 activity, resulting in a decrease in tri-methylated modification of H3K27, and this decrease, in turn, upregulates MMP9 and ABCG2, ultimately inhibiting the proliferation of human leukemia cells in vitro and in vitro (Huang et al., 2021). Moreover, tan I reduces the expression of CCAAT-enhancer-binding protein β (C/EBPβ), which inhibits the mRNA levels of the JMJD2b histone H3K9 demethylase as well as cell cycle-related genes, further regulating the mitotic clonal expansion (MCE) process (Jung et al., 2020). Lysine specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD)-dependent amine oxidase (AO) that catalyzes the demethylation of mono- and di-methyl on H3K4 and H3K9, triggering transcriptional repression and activation, respectively (Karakaidos et al., 2019). Studies have demonstrated that CPT blocks the interaction of LSD1 and androgen receptor (AR) at the promoter of the AR target gene, prostate-specific antigen (PSA), which demethylates H3K9me1/2, thereby inhibiting the transcriptional activity of PSA and suppressing the proliferation of AR-positive prostate cancer cells (Wu et al., 2012). Moreover, tan IIA upregulates the level of H3K27me1 and H3K4m2 on the TP53 promoter by inhibiting LSD1, thereby activating the transcriptional activity of p53 (Zheng et al., 2018). It has been reported that the mRNA and protein levels of p53 are downregulated in several types of tumors, such as prostate cancer and colon cancer (Bossi and Sacchi 2007). Therefore, reactivating p53 is an important strategy for tumor therapy. Taken together, these findings suggest that tan IIA may increase the level of H3K27me1 and H3K4m2 on the p53 promoter by targeting LSD1, which activates p53, thereby promoting tumor cell cycle arrest and apoptosis.

Histone acetylation

Histone acetylation is a reversible and homeostatic process regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) (Attoub et al., 2011). Studies have reported abnormal acetylation levels in certain tumors (Zhao and Shilatifard 2019). Histone lysine residues are hyperacetylated in drug-resistant prostate cancer, acute myeloid leukemia, gastrointestinal stromal tumors, lymphomas, and TNBC (He et al., 2021), whereas acetylation levels are decreased in ovarian cancer, colon cancer, liver cancer, and skin cancer (Wu et al., 2020). Overexpression of HDAC is present in tumors with low acetylation levels, indicating that targeting HDAC may be a strategy for treatment of these tumors (Li and Seto 2016). To date, numerous HDAC inhibitors are in various stages of clinical research; vorinostat (SAHA), beristatin (PXD101), and bilestat (LBH589) are approved for the clinical treatment of cutaneous T cell lymphoma, peripheral T cell lymphoma and multiple myeloma, respectively (Ho et al., 2020), and other HDAC inhibitors have been investigated in clinical trials for the treatment of various cancers (Ono et al., 2018; Xie et al., 2018). S. miltiorrhiza bioactive compounds have been found to target histone deacetyltransferases (HDACs) and identified as potential inhibitors of HDACs. Tan IIA suppresses the expression and enzymatic activity of HDAC1, HDAC3, HDAC4, and HDAC8, which increases histone 3 acetylation and RNA polymerase II recruitment to the Nrf2 transcription start site, thereby inhibiting TPA-induced JB6 P+ cell neoplastic transformation (Wang et al., 2014). In contrast, LUT increases the enrichment of H3K27ac in the promoter region of Nrf2 by downregulating HDAC1, HDAC2, HDAC3, HDAC6, and HDAC7 expression and enzymatic activity, further promoting the transcriptional activity of the Nrf2 gene, which in turn inhibits the cellular activity of HCT116 (Zuo et al., 2018).

The level of acetylation is closely related to tumor stage, metastasis, and invasion as well as prognosis (He et al., 2021). Aurora A is a mitotic S/T kinase involved in the process of cell division, and the expression of aurora A is elevated in various tumors (Meraldi et al., 2004). Tan I reduces the level of histone acetylation at the aurora A DNA promoter region, which downregulates aurora A and ultimately inhibits the growth of breast cancer cells (Gong et al., 2012). Furthermore, LUT reduces the level of H3K27ac and H3K56ac at the MMP9 promoter region by inactivating the Akt/mTOR signaling pathway, thereby inhibiting metastasis of AR-positive TNBC (Wu et al., 2021).

Ubiquitination

Ubiquitination is an important post-translational modification mediated by ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3) (Cockram et al., 2021). Abnormal ubiquitination alters intracellular physiological functions, leading to the initiation and development of cancer (Pellegrino et al., 2022). For example, overexpression of the E3 ligase, mouse double minute 2 (MDM2), mediates ubiquitination of p53 and promotes proteasomal degradation of p53, which inhibits p53 function, leading to tumorigenesis and cancer cell progression (Wang et al., 2017). It has been reported that tan IIA induces ubiquitous degradation of the anti-apoptotic protein, Mcl-1, through targeting the EGFR-Akt signaling pathway, which induces NSCC cell apoptosis (Gao et al., 2020). Tan IIA promotes the FBW7 E3 ligase-mediated ubiquitination degradation of c-Myc, which induces OSCC cell apoptosis (Chen et al., 2020a; Li et al., 2020). Moreover, tan I and DHT activate the Nrf2 pathway by reducing Nrf2 ubiquitination, thereby maintaining redox homeostasis of skin fibroblasts and HBE cells (Tao et al., 2013a; Tao et al., 2013).

In summary, S. miltiorrhiza bioactive compounds suppress tumor growth and development by regulating DNA methylation, histone methylation, acetylation, and ubiquitination to silence tumor suppressors or promote oncogenes (Figure 4).

FIGURE 4

Future prospects

Currently, chemotherapy and radiotherapy are the main methods for the clinical treatment of tumors, but these methods have serious shortcomings, such as resistance and toxic side effects. Thus, combination therapy may be important to improve tumor sensitivity. We previously demonstrated that the bioactive compounds of S. miltiorrhiza inhibit cancer cell proliferation, induce apoptosis, suppress metastasis, and suppress invasion. Thus, we speculate that S. miltiorrhiza bioactive compounds may be used as adjuvant drugs to improve the sensitivity of drug-resistant tumors.

At present, drug resistance is one of the major barriers to cancer treatment, which limits the efficacy of chemotherapy drugs, leading to tumor recurrence, metastasis, and cell death resistance (Haider et al., 2020). Doxorubicin (Dox) and paclitaxel are first-line treatments for patients with metastatic and early-stage breast cancer (Abu Samaan, Samec et al., 2019; Jamialahmadi et al., 2021). However, it has been reported that patients develop resistance to these drugs during the treatment of breast cancer, greatly affecting the efficacy of the drugs (Rivera and Gomez 2010). Moreover, platinum drugs, such as cisplatin and oxaliplatin (OXA), induce DNA damage in tumor cells; they are mainly used in the treatment of ovarian cancer, but their efficacy is severely limited due to drug resistance (Pujade-Lauraine et al., 2019). Studies have found that the bioactive compounds of S. miltiorrhiza have potential roles in reversing resistance and enhancing chemotherapeutic drug sensitivity. For example, tan IIA increases the sensitivity of OXA-resistant CRC cells to OXA by regulating the Akt/ERK signaling pathway, thereby enhancing the anti-proliferation effect and inducing apoptosis in SW480/OXA and HT29/OXA cells (Zhang et al., 2019b). Furthermore, CPT/DHT reduces the P-glycoprotein (P-gp) mRNA and protein levels as well as inhibits P-gp ATPase activity of SW620 Ad300 cells (Hu et al., 2014). Moreover, tan IIA reduces the accumulation of β-catenin in the nucleus by repressing β-catenin nuclear translocation, which enhances Dox inhibition of MCF-7/Dox cell proliferation and migration (Li et al., 2021). Adenosine triphosphate (ATP)-binding cassette (ABC) transporters, such as P-gp, breast cancer resistance protein (BCRP), and multidrug resistance-related protein 1 (MRP1), catalyze the transduction of structurally diverse compounds across cell membranes via ATP-dependent transport (Zahra et al., 2020). Because ABC transporters are overexpressed in tumor cells, they pump out the chemotherapeutic drugs, thereby inducing tumor cells to acquire drug resistance (Choi and Yu 2014). It has been reported that tan IIA downregulates the expression of P-gp, BCRP, and MRP1, further promoting intracellular accumulation of Dox, which induces apoptosis and suppresses proliferation of MCF7/Dox cells, thereby alleviating the inhibitory effect of Dox on the hematopoietic function and Dox-induced cardiotoxicity and nephrotoxicity (Li et al., 2019).

S. miltiorrhiza bioactive compounds not only increase the sensitivity of drug-resistant cells to chemotherapeutic drugs but also synergistically inhibit tumor development. Bai et al. reported that tan IIA combined with 5-FU represses the activation of NF-κB and inhibits CRC cell proliferation (Bai et al., 2016). Furthermore, tan IIA and Dox cotreatment decreases the activity of the VEGF/PI3K/Akt signaling pathway, which promotes apoptosis and induces cell cycle arrest, thereby suppressing proliferation, metastasis, and invasion of A549 cells (Xie et al., 2016). Moreover, tan I and paclitaxel cooperate to promote apoptosis and accelerate cell senescence, thereby inhibiting proliferation and metastasis of ovarian cancer cells (A2780 and ID-8 cells) (Zhou et al., 2020). In addition, the combination of LUT and OXA induces apoptosis and cell cycle arrest as well as inhibits proliferation of SGC-7901 gastric cancer cells (Ren et al., 2020).

Radiotherapy is an effective method of cancer treatment, but the resistance and side effects of radiation therapy affect its efficacy. Therefore, sensitizers that kill tumor cells improve the efficacy of radiotherapy (Chevalier 2020). Tan IIA combined with irradiation reduces histone H3 (S10) phosphorylation in ionizing radiation-resistant cell lines (CAL27-IR and SCC25-IR cells), and this combination enhances irradiation-induced DNA damage and promotes apoptosis, thereby inhibiting tumor growth in vivo and in vitro (Li et al., 2021). Moreover, tan IIA increases radiation-induced ROS production and induces autophagy, which in turn increases the sensitivity of OSCC cells (SCC090 cells) to radiation (Ding et al., 2016). Pro-oncogenic protein phosphoribosyl pyrophosphate aminotransferase is an essential enzyme that catalyzes the first step in purine biosynthesis and promotes the increase in purine metabolism in cancer cells, and its overexpression promotes cancer cell proliferation and invasion. Tan I downregulates the expression of PPAT, which in turn enhances the radiosensitivity of radiation-resistant lung cancer cells (H358-IR and H157-IR cells), thereby inhibiting cell proliferation (Yan et al., 2018).

In summary, the bioactive compounds of S. miltiorrhiza target miRNAs and epigenetic enzymes as well as function to inhibit cancer cell proliferation, induce cell cycle arrest, induce apoptosis, trigger autophagy, suppress metastasis, and suppress invasion (Figure 5). Moreover, S. miltiorrhiza bioactive compounds have multiple roles as adjuvant drugs in chemotherapy and radiotherapy as follows: 1) improve the sensitivity of drug-resistant cells to chemotherapeutic drugs; 2) work together with chemotherapeutic drugs to enhance the therapeutic effect; and 3) combine with radiotherapy to improve the effect of radiotherapy (Table 2). Thus, S. miltiorrhiza bioactive compounds have an antitumor effect and potential application prospects in tumor treatment and adjuvant medicine. In addition, one critical mechanism of S. miltiorrhiza bioactive compounds in suppressing cancer initiation and progression is through targeting miRNAs, including miR-125b, miRNA-122, and miRNA-384, which are present in various cancer cells, suggesting that these miRNAs may play important roles in cancer progression. The pharmacological activity and mechanism of S. miltiorrhiza bioactive compounds are continually being elucidated, thereby supporting their potential application in future clinical cancer therapies.

FIGURE 5

References

• 1

  Abu SamaanT. M.SamecM.LiskovaA.KubatkaP.BüsselbergD. (2019). Paclitaxel's mechanistic and clinical effects on breast cancer. Biomolecules9 (12), E789. 10.3390/biom9120789

  • CrossRef
  • Google Scholar

• 2

  AliA.ZhangP.LiangfangY.WensheS.WangH.LinX.et al (2015). KLF17 empowers TGF-β/Smad signaling by targeting Smad3-dependent pathway to suppress tumor growth and metastasis during cancer progression. Cell Death Dis.6 (3), e1681. 10.1038/cddis.2015.48

  • CrossRef
  • Google Scholar

• 3

  Ali SyedaZ.LangdenS. S. S.MunkhzulC.LeeM.SongS. J. (2020). Regulatory mechanism of MicroRNA expression in cancer. Int. J. Mol. Sci.21 (5), E1723. 10.3390/ijms21051723

  • CrossRef
  • Google Scholar

• 4

  AllegriL.CapriglioneF.MaggisanoV.DamanteG.BaldanF. (2021). Effects of dihydrotanshinone I on proliferation and invasiveness of paclitaxel-resistant anaplastic thyroid cancer cells. Int. J. Mol. Sci.22 (15), 8083. 10.3390/ijms22158083

  • CrossRef
  • Google Scholar

• 5

  AnsonD. M.WilcoxR. M.HusemanE. D.StumpT. A.ParisR. L.DarkwahB. O.et al (2018). Luteolin decreases epidermal growth factor receptor-mediated cell proliferation and induces apoptosis in glioblastoma cell lines. Basic Clin. Pharmacol. Toxicol.123 (6), 678–686. 10.1111/bcpt.13077

  • CrossRef
  • Google Scholar

• 6

  AttoubS.HassanA. H.VanhoeckeB.IratniR.TakahashiT.GabenA. M.et al (2011). Inhibition of cell survival, invasion, tumor growth and histone deacetylase activity by the dietary flavonoid luteolin in human epithelioid cancer cells. Eur. J. Pharmacol.651 (1-3), 18–25. 10.1016/j.ejphar.2010.10.063

  • CrossRef
  • Google Scholar

• 7

  BachmannI. M.HalvorsenO. J.CollettK.StefanssonI. M.StraumeO.HaukaasS. A.et al (2006). EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J. Clin. Oncol.24 (2), 268–273. 10.1200/JCO.2005.01.5180

  • CrossRef
  • Google Scholar

• 8

  BaiY.ZhangL.FangX.YangY. (2016). Tanshinone IIA enhances chemosensitivity of colon cancer cells by suppressing nuclear factor-κB. Exp. Ther. Med.11 (3), 1085–1089. 10.3892/etm.2016.2984

  • CrossRef
  • Google Scholar

• 9

  BejaranoF.ChangC. H.SunK.HagenJ. W.DengW. M.LaiE. C. (2021). A comprehensive in vivo screen for anti-apoptotic miRNAs indicates broad capacities for oncogenic synergy. Dev. Biol.475, 10–20. 10.1016/j.ydbio.2021.02.010

  • CrossRef
  • Google Scholar

• 10

  BhattacharjeeS.DashwoodR. H. (2020). Epigenetic regulation of NRF2/KEAP1 by phytochemicals. Antioxidants (Basel)9 (9), E865. 10.3390/antiox9090865

  • CrossRef
  • Google Scholar

• 11

  BirdA. P. (1986). CpG-rich islands and the function of DNA methylation. Nature321 (6067), 209–213. 10.1038/321209a0

  • CrossRef
  • Google Scholar

• 12

  BossiG.SacchiA. (2007). Restoration of wild-type p53 function in human cancer: Relevance for tumor therapy. Head. Neck29 (3), 272–284. 10.1002/hed.20529

  • CrossRef
  • Google Scholar

• 13

  CaoD.ZhuG. Y.LuY.YangA.ChenD.HuangH. J.et al (2020). Luteolin suppresses epithelial-mesenchymal transition and migration of triple-negative breast cancer cells by inhibiting YAP/TAZ activity. Biomed. Pharmacother.129, 110462. 10.1016/j.biopha.2020.110462

  • CrossRef
  • Google Scholar

• 14

  CaoY. F.WangS. F.LiX.ZhangY. L.QiaoY. J. (2018). The anticancer mechanism investigation of Tanshinone II(A) by pharmacological clustering in protein network. BMC Syst. Biol.12 (1), 90. 10.1186/s12918-018-0606-6

  • CrossRef
  • Google Scholar

• 15

  CaoY.LuK.XiaY.WangY.WangA.ZhaoY. (2022). Danshensu attenuated epithelial-mesenchymal transformation and chemoresistance of colon cancer cells induced by platelets. Front. Biosci.27 (5), 160. 10.31083/j.fbl2705160

  • CrossRef
  • Google Scholar

• 16

  ChanH. L.MoreyL. (2019). Emerging roles for polycomb-group proteins in stem cells and cancer. Trends biochem. Sci.44 (8), 688–700. 10.1016/j.tibs.2019.04.005

  • CrossRef
  • Google Scholar

• 17

  ChenJ.DingC.ChenY.HuW.LuY.WuW.et al (2020). ACSL4 promotes hepatocellular carcinoma progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis. Oncogenesis9 (4), 42. 10.1038/s41389-020-0226-z

  • CrossRef
  • Google Scholar

• 18

  ChenJ.ShiD. Y.LiuS. L.ZhongL. (2012). Tanshinone IIA induces growth inhibition and apoptosis in gastric cancer in vitro and in vivo. Oncol. Rep.27 (2), 523–528. 10.3892/or.2011.1524

  • CrossRef
  • Google Scholar

• 19

  ChenQ.LuoJ.WuC.LuH.CaiS.BaoC.et al (2020a). The miRNA-149-5p/MyD88 axis is responsible for ursolic acid-mediated attenuation of the stemness and chemoresistance of non-small cell lung cancer cells. Environ. Toxicol.35 (5), 561–569. 10.1002/tox.22891

  • CrossRef
  • Google Scholar

• 20

  ChenT.LiX. F.WangJ. F.ZhouS.FangF. (2018). Effects of luteolin on proliferation and programmed cell death of human multiple myeloma cell RPMI-8226. Zhongguo Shi Yan Xue Ye Xue Za Zhi26 (5), 1425–1429. 10.7534/j.issn.1009-2137.2018.05.028

  • CrossRef
  • Google Scholar

• 21

  ChenX.GuoJ.BaoJ.LuJ.WangY. (2014). The anticancer properties of salvia miltiorrhiza bunge (danshen): A systematic review. Med. Res. Rev.34 (4), 768–794. 10.1002/med.21304

  • CrossRef
  • Google Scholar

• 22

  ChevalierF. (2020). Counteracting radio-resistance using the optimization of radiotherapy. Int. J. Mol. Sci.21 (5), E1767. 10.3390/ijms21051767

  • CrossRef
  • Google Scholar

• 23

  ChiuS. C.HuangS. Y.ChenS. P.SuC. C.ChiuT. L.PangC. Y. (2013). Tanshinone IIA inhibits human prostate cancer cells growth by induction of endoplasmic reticulum stress in vitro and in vivo. Prostate Cancer Prostatic Dis.16 (4), 315–322. 10.1038/pcan.2013.38

  • CrossRef
  • Google Scholar

• 24

  ChoiY. H.YuA. M. (2014). ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development. Curr. Pharm. Des.20 (5), 793–807. 10.2174/138161282005140214165212

  • CrossRef
  • Google Scholar

• 25

  CockramP. E.KistM.PrakashS.ChenS. H.WertzI. E.VucicD. (2021). Ubiquitination in the regulation of inflammatory cell death and cancer. Cell Death Differ.28 (2), 591–605. 10.1038/s41418-020-00708-5

  • CrossRef
  • Google Scholar

• 26

  DingL.DingL.WangS.WangS.WangW.WangW.et al (2017). Tanshinone IIA affects autophagy and apoptosis of glioma cells by inhibiting phosphatidylinositol 3-kinase/akt/mammalian target of rapamycin signaling pathway. Pharmacology99 (3-4), 188–195. 10.1159/000452340

  • CrossRef
  • Google Scholar

• 27

  DingL.WangS.QuX.WangJ. (2016). Tanshinone IIA sensitizes oral squamous cell carcinoma to radiation due to an enhanced autophagy. Environ. Toxicol. Pharmacol.46, 264–269. 10.1016/j.etap.2016.07.021

  • CrossRef
  • Google Scholar

• 28

  DuanR.DuW.GuoW. (2020). EZH2: A novel target for cancer treatment. J. Hematol. Oncol.13 (1), 104. 10.1186/s13045-020-00937-8

  • CrossRef
  • Google Scholar

• 29

  EdatharaP. M.ChintalapallyS.MakaniV. K. K.PantC.YerramsettyS.DR. M.et al (2021). Inhibitory role of oleanolic acid and esculetin in HeLa cells involve multiple signaling pathways. Gene771, 145370. 10.1016/j.gene.2020.145370

  • CrossRef
  • Google Scholar

• 30

  EstellerM. (2008). Epigenetics in cancer. N. Engl. J. Med.358 (11), 1148–1159. 10.1056/NEJMra072067

  • CrossRef
  • Google Scholar

• 31

  FangB.ChenX.WuM.KongH.ChuG.ZhouZ.et al (2018). Luteolin inhibits angiogenesis of the M2-like TAMs via the downregulation of hypoxia inducible factor-1α and the STAT3 signalling pathway under hypoxia. Mol. Med. Rep.18 (3), 2914–2922. 10.3892/mmr.2018.9250

  • CrossRef
  • Google Scholar

• 32

  FangZ. Y.ZhangM.LiuJ. N.ZhaoX.ZhangY. Q.FangL. (2020). Tanshinone IIA: A review of its anticancer effects. Front. Pharmacol.11, 611087. 10.3389/fphar.2020.611087

  • CrossRef
  • Google Scholar

• 33

  FuL.HanB.ZhouY.RenJ.CaoW.PatelG.et al (2020). The anticancer properties of tanshinones and the pharmacological effects of their active ingredients. Front. Pharmacol.11, 193. 10.3389/fphar.2020.00193

  • CrossRef
  • Google Scholar

• 34

  FuL. Q.DuW. L.CaiM. H.YaoJ. Y.ZhaoY. Y.MouX. Z. (2020a). The roles of tumor-associated macrophages in tumor angiogenesis and metastasis. Cell. Immunol.353, 104119. 10.1016/j.cellimm.2020.104119

  • CrossRef
  • Google Scholar

• 35

  FunderburkS. F.WangQ. J.YueZ. (2010). The Beclin 1-VPS34 complex--at the crossroads of autophagy and beyond. Trends Cell Biol.20 (6), 355–362. 10.1016/j.tcb.2010.03.002

  • CrossRef
  • Google Scholar

• 36

  GanL.XuM.HuaR.TanC.ZhangJ.GongY.et al (2018). The polycomb group protein EZH2 induces epithelial-mesenchymal transition and pluripotent phenotype of gastric cancer cells by binding to PTEN promoter. J. Hematol. Oncol.11 (1), 9. 10.1186/s13045-017-0547-3

  • CrossRef
  • Google Scholar

• 37

  GaoF.LiM.LiuW.LiW. (2020). Inhibition of EGFR signaling and activation of mitochondrial apoptosis contribute to tanshinone IIA-mediated tumor suppression in non-small cell lung cancer cells. Onco. Targets. Ther.13, 2757–2769. 10.2147/OTT.S246606

  • CrossRef
  • Google Scholar

• 38

  GaoG.GeR.LiY.LiuS. (2019). Luteolin exhibits anti-breast cancer property through up-regulating miR-203. Artif. Cells Nanomed. Biotechnol.47 (1), 3265–3271. 10.1080/21691401.2019.1646749

  • CrossRef
  • Google Scholar

• 39

  GongL.DiC.XiaX.WangJ.ChenG.ShiJ.et al (2016). AKT/mTOR signaling pathway is involved in salvianolic acid B-induced autophagy and apoptosis in hepatocellular carcinoma cells. Int. J. Oncol.49 (6), 2538–2548. 10.3892/ijo.2016.3748

  • CrossRef
  • Google Scholar

• 40

  GongY.LiY.AbdolmalekyH. M.LiL.ZhouJ. R. (2012). Tanshinones inhibit the growth of breast cancer cells through epigenetic modification of Aurora A expression and function. PLoS One7 (4), e33656. 10.1371/journal.pone.0033656

  • CrossRef
  • Google Scholar

• 41

  GuoY.LiY.WangF. F.XiangB.HuangX. O.MaH. B.et al (2019). The combination of Nutlin-3 and Tanshinone IIA promotes synergistic cytotoxicity in acute leukemic cells expressing wild-type p53 by co-regulating MDM2-P53 and the AKT/mTOR pathway. Int. J. Biochem. Cell Biol.106, 8–20. 10.1016/j.biocel.2018.10.008

  • CrossRef
  • Google Scholar

• 42

  GuoY.LiY.XiangB.HuangX. O.MaH. B.WangF. F.et al (2017). Nutlin-3 plus tanshinone IIA exhibits synergetic anti-leukemia effect with imatinib by reactivating p53 and inhibiting the AKT/mTOR pathway in Ph+ ALL. Biochem. J.474 (24), 4153–4170. 10.1042/BCJ20170386

  • CrossRef
  • Google Scholar

• 43

  HaiderT.PandeyV.BanjareN.GuptaP. N.SoniV. (2020). Drug resistance in cancer: Mechanisms and tackling strategies. Pharmacol. Rep.72 (5), 1125–1151. 10.1007/s43440-020-00138-7

  • CrossRef
  • Google Scholar

• 44

  HanC.WeiY.WangX.BaC.ShiW. (2019). Protective effect of Salvia miltiorrhiza polysaccharides on liver injury in chickens. Poult. Sci.98 (9), 3496–3503. 10.3382/ps/pez153

  • CrossRef
  • Google Scholar

• 45

  HanG.WangY.LiuT.GaoJ.DuanF.ChenM.et al (2022). Salvianolic acid B acts against non-small cell lung cancer A549 cells via inactivation of the MAPK and Smad2/3 signaling pathways. Mol. Med. Rep.25 (5), 184. 10.3892/mmr.2022.12700

  • CrossRef
  • Google Scholar

• 46

  HeZ. X.WeiB. F.ZhangX.GongY. P.MaL. Y.ZhaoW. (2021). Current development of CBP/p300 inhibitors in the last decade. Eur. J. Med. Chem.209, 112861. 10.1016/j.ejmech.2020.112861

  • CrossRef
  • Google Scholar

• 47

  HoT. C. S.ChanA. H. Y.GanesanA. (2020). Thirty years of HDAC inhibitors: 2020 insight and hindsight. J. Med. Chem.63 (21), 12460–12484. 10.1021/acs.jmedchem.0c00830

  • CrossRef
  • Google Scholar

• 48

  HuT.ToK. K.WangL.ZhangL.LuL.ShenJ.et al (2014). Reversal of P-glycoprotein (P-gp) mediated multidrug resistance in colon cancer cells by cryptotanshinone and dihydrotanshinone of Salvia miltiorrhiza. Phytomedicine21 (11), 1264–1272. 10.1016/j.phymed.2014.06.013

  • CrossRef
  • Google Scholar

• 49

  HuT.WangL.ZhangL.LuL.ShenJ.ChanR. L.et al (2015). Sensitivity of apoptosis-resistant colon cancer cells to tanshinones is mediated by autophagic cell death and p53-independent cytotoxicity. Phytomedicine22 (5), 536–544. 10.1016/j.phymed.2015.03.010

  • CrossRef
  • Google Scholar

• 50

  HuaH.KongQ.ZhangH.WangJ.LuoT.JiangY. (2019). Targeting mTOR for cancer therapy. J. Hematol. Oncol.12 (1), 71. 10.1186/s13045-019-0754-1

  • CrossRef
  • Google Scholar

• 51

  HuangS. Y.ChangS. F.LiaoK. F.ChiuS. C. (2017). Tanshinone IIA inhibits epithelial-mesenchymal transition in bladder cancer cells via modulation of STAT3-CCL2 signaling. Int. J. Mol. Sci.18 (8), E1616. 10.3390/ijms18081616

  • CrossRef
  • Google Scholar

• 52

  HuangY.YuS. H.ZhenW. X.ChengT.WangD.LinJ. B.et al (2021). Tanshinone I, a new EZH2 inhibitor restricts normal and malignant hematopoiesis through upregulation of MMP9 and ABCG2. Theranostics11 (14), 6891–6904. 10.7150/thno.53170

  • CrossRef
  • Google Scholar

• 53

  HuangY.YuanK.TangM.YueJ.BaoL.WuS.et al (2021a). Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras-Raf-MAPK signalling. J. Cell. Mol. Med.25 (3), 1480–1492. 10.1111/jcmm.16237

  • CrossRef
  • Google Scholar

• 54

  HuangY.ZhouZ.ZhangJ.HaoZ.HeY.WuZ.et al (2021b). lncRNA MALAT1 participates in metformin inhibiting the proliferation of breast cancer cell. J. Cell. Mol. Med.25 (15), 7135–7145. 10.1111/jcmm.16742

  • CrossRef
  • Google Scholar

• 55

  IidaK.NaikiT.Naiki-ItoA.SuzukiS.KatoH.NozakiS.et al (2020). Luteolin suppresses bladder cancer growth via regulation of mechanistic target of rapamycin pathway. Cancer Sci.111 (4), 1165–1179. 10.1111/cas.14334

  • CrossRef
  • Google Scholar

• 56

  IorioM. V.CroceC. M. (2012). MicroRNA dysregulation in cancer: Diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol. Med.4 (3), 143–159. 10.1002/emmm.201100209

  • CrossRef
  • Google Scholar

• 57

  JamialahmadiK.ZahedipourF.KarimiG. (2021). The role of microRNAs on doxorubicin drug resistance in breast cancer. J. Pharm. Pharmacol.73 (8), 997–1006. 10.1093/jpp/rgaa031

  • CrossRef
  • Google Scholar

• 58

  JanardhanA.KatheraC.DarsiA.AliW.HeL.YangY.et al (2018). Prominent role of histone lysine demethylases in cancer epigenetics and therapy. Oncotarget9 (76), 34429–34448. 10.18632/oncotarget.24319

  • CrossRef
  • Google Scholar

• 59

  JiangX.WangJ.DengX.XiongF.ZhangS.GongZ.et al (2020). The role of microenvironment in tumor angiogenesis. J. Exp. Clin. Cancer Res.39 (1), 204. 10.1186/s13046-020-01709-5

  • CrossRef
  • Google Scholar

• 60

  JieensinueS.ZhuH.LiG.DongK.LiangM.LiY. (2018). Tanshinone IIA reduces SW837 colorectal cancer cell viability via the promotion of mitochondrial fission by activating JNK-Mff signaling pathways. BMC Cell Biol.19 (1), 21. 10.1186/s12860-018-0174-z

  • CrossRef
  • Google Scholar

• 61

  JinL.ChenC.HuangL.BuL.ZhangL.YangQ. (2021). Salvianolic acid A blocks vasculogenic mimicry formation in human non-small cell lung cancer via PI3K/Akt/mTOR signalling. Clin. Exp. Pharmacol. Physiol.48 (4), 508–514. 10.1111/1440-1681.13464

  • CrossRef
  • Google Scholar

• 62

  JinW. (2020). Role of JAK/STAT3 signaling in the regulation of metastasis, the transition of cancer stem cells, and chemoresistance of cancer by epithelial-mesenchymal transition. Cells9 (1), E217. 10.3390/cells9010217

  • CrossRef
  • Google Scholar

• 63

  JungD. Y.KimJ. H.JungM. H. (2020). Anti-obesity effects of tanshinone I from salvia miltiorrhiza bunge in mice fed a high-fat diet through inhibition of early adipogenesis. Nutrients12 (5), E1242. 10.3390/nu12051242

  • CrossRef
  • Google Scholar

• 64

  KanS.CheungW. M.ZhouY.HoW. S. (2014). Enhancement of doxorubicin cytotoxicity by tanshinone IIA in HepG2 human hepatoma cells. Planta Med.80 (1), 70–76. 10.1055/s-0033-1360126

  • CrossRef
  • Google Scholar

• 65

  KanwalR.GuptaK.GuptaS. (2015). Cancer epigenetics: An introduction. Methods Mol. Biol.1238, 3–25. 10.1007/978-1-4939-1804-1_1

  • CrossRef
  • Google Scholar

• 66

  KarabiyikC.VicinanzaM.SonS. M.RubinszteinD. C. (2021). Glucose starvation induces autophagy via ULK1-mediated activation of PIKfyve in an AMPK-dependent manner. Dev. Cell56 (13), 1961–1975.e5. 10.1016/j.devcel.2021.05.010

  • CrossRef
  • Google Scholar

• 67

  KarakaidosP.VerigosJ.MagklaraA. (2019). LSD1/KDM1A, a gate-keeper of cancer stemness and a promising therapeutic target. Cancers (Basel)11 (12), E1821. 10.3390/cancers11121821

  • CrossRef
  • Google Scholar

• 68

  KashyapA.UmarS. M.DevJ. R. A.PrasadC. P. (2021). Dihydrotanshinone-I modulates epithelial mesenchymal transition (EMT) thereby impairing migration and clonogenicity of triple negative breast cancer cells. Asian pac. J. Cancer Prev.22 (7), 2177–2184. 10.31557/APJCP.2021.22.7.2177

  • CrossRef
  • Google Scholar

• 69

  KeeleyE. C.MehradB.StrieterR. M. (2010). CXC chemokines in cancer angiogenesis and metastases. Adv. Cancer Res.106, 91–111. 10.1016/S0065-230X(10)06003-3

  • CrossRef
  • Google Scholar

• 70

  KimH.RamirezC. N.SuZ. Y.KongA. N. (2016). Epigenetic modifications of triterpenoid ursolic acid in activating Nrf2 and blocking cellular transformation of mouse epidermal cells. J. Nutr. Biochem.33, 54–62. 10.1016/j.jnutbio.2015.09.014

  • CrossRef
  • Google Scholar

• 71

  KimJ.KunduM.ViolletB.GuanK. L. (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol.13 (2), 132–141. 10.1038/ncb2152

  • CrossRef
  • Google Scholar

• 72

  KimK.ShinE. A.JungJ. H.ParkJ. E.KimD. S.ShimB. S.et al (2018). Ursolic acid induces apoptosis in colorectal cancer cells partially via upregulation of MicroRNA-4500 and inhibition of JAK2/STAT3 phosphorylation. Int. J. Mol. Sci.20 (1), E114. 10.3390/ijms20010114

  • CrossRef
  • Google Scholar

• 73

  KumarV.RadinD.LeonardiD. (2019). Studies examining the synergy between Dihydrotanshinone and Temozolomide against MGMT+ glioblastoma cells in vitro: Predicting interactions with the blood-brain barrier. Biomed. Pharmacother.109, 386–390. 10.1016/j.biopha.2018.10.069

  • CrossRef
  • Google Scholar

• 74

  LakshminarasimhanR.LiangG. (2016). The role of DNA methylation in cancer. Adv. Exp. Med. Biol.945, 151–172. 10.1007/978-3-319-43624-1_7

  • CrossRef
  • Google Scholar

• 75

  LeeH. P.LiuY. C.ChenP. C.TaiH. C.LiT. M.FongY. C.et al (2017). Tanshinone IIA inhibits angiogenesis in human endothelial progenitor cells in vitro and in vivo. Oncotarget8 (65), 109217–109227. 10.18632/oncotarget.22649

  • CrossRef
  • Google Scholar

• 76

  LeeW. D.LiangY. J.ChenB. H. (2016). Effects of tanshinone nanoemulsion and extract on inhibition of lung cancer cells A549. Nanotechnology27 (49), 495101. 10.1088/0957-4484/27/49/495101

  • CrossRef
  • Google Scholar

• 77

  LeeY. S.DuttaA. (2009). MicroRNAs in cancer. Annu. Rev. Pathol.4, 199–227. 10.1146/annurev.pathol.4.110807.092222

  • CrossRef
  • Google Scholar

• 78

  LiC.WangQ.ShenS.WeiX.LiG. (2019). HIF-1α/VEGF signaling-mediated epithelial-mesenchymal transition and angiogenesis is critically involved in anti-metastasis effect of luteolin in melanoma cells. Phytother. Res.33 (3), 798–807. 10.1002/ptr.6273

  • CrossRef
  • Google Scholar

• 79

  LiG.ShanC.LiuL.ZhouT.ZhouJ.HuX.et al (2015). Tanshinone IIA inhibits HIF-1α and VEGF expression in breast cancer cells via mTOR/p70S6K/RPS6/4E-BP1 signaling pathway. PLoS One10 (2), e0117440. 10.1371/journal.pone.0117440

  • CrossRef
  • Google Scholar

• 80

  LiK.LaiH. (2017). TanshinoneIIA enhances the chemosensitivity of breast cancer cells to doxorubicin through down-regulating the expression of MDR-related ABC transporters. Biomed. Pharmacother.96, 371–377. 10.1016/j.biopha.2017.10.016

  • CrossRef
  • Google Scholar

• 81

  LiK.LiuW.ZhaoQ.WuC.FanC.LaiH.et al (2019a). Combination of tanshinone IIA and doxorubicin possesses synergism and attenuation effects on doxorubicin in the treatment of breast cancer. Phytother. Res.33 (6), 1658–1669. 10.1002/ptr.6353

  • CrossRef
  • Google Scholar

• 82

  LiL.ZhangZ. H.ZhaoW. D. (2009). Apoptosis of MR2 cells induced by Tanshinone II A combined with arsenic trioxide. Sichuan Da Xue Xue Bao Yi Xue Ban.40 (5), 812–816.

  • Google Scholar

• 83

  LiM.GaoF.ZhaoQ.ZuoH.LiuW.LiW. (2020). Tanshinone IIA inhibits oral squamous cell carcinoma via reducing Akt-c-Myc signaling-mediated aerobic glycolysis. Cell Death Dis.11 (5), 381. 10.1038/s41419-020-2579-9

  • CrossRef
  • Google Scholar

• 84

  LiM.LiuH.ZhaoQ.HanS.ZhouL.LiuW.et al (2021). Targeting Aurora B kinase with Tanshinone IIA suppresses tumor growth and overcomes radioresistance. Cell Death Dis.12 (2), 152. 10.1038/s41419-021-03434-z

  • CrossRef
  • Google Scholar

• 85

  LiQ.ZhangJ.LiangY.MuW.HouX.MaX.et al (2018). Tanshinone l exhibits anticancer effects in human endometrial carcinoma HEC-1-A cells via mitochondrial mediated apoptosis, cell cycle arrest and inhibition of JAK/STAT signalling pathway. J. buon23 (4), 1092–1096.

  • Google Scholar

• 86

  LiS.WuC.FanC.ZhangP.YuG.LiK. (2021a). Tanshinone II A improves the chemosensitivity of breast cancer cells to doxorubicin by inhibiting β-catenin nuclear translocation. J. Biochem. Mol. Toxicol.35 (1), e22620. 10.1002/jbt.22620

  • CrossRef
  • Google Scholar

• 87

  LiS.WuR.WangL.Dina KuoH. C.SargsyanD.ZhengX.et al (2022). Triterpenoid ursolic acid drives metabolic rewiring and epigenetic reprogramming in treatment/prevention of human prostate cancer. Mol. Carcinog.61 (1), 111–121. 10.1002/mc.23365

  • CrossRef
  • Google Scholar

• 88

  LiX.JiaQ.ZhouY.JiangX.SongL.WuY.et al (2022a). Tanshinone IIA attenuates the stemness of breast cancer cells via targeting the miR-125b/STARD13 axis. Exp. Hematol. Oncol.11 (1), 2. 10.1186/s40164-022-00255-4

  • CrossRef
  • Google Scholar

• 89

  LiX.LiZ.LiX.LiuB.LiuZ. (2017). Mechanisms of Tanshinone II a inhibits malignant melanoma development through blocking autophagy signal transduction in A375 cell. BMC Cancer17 (1), 357. 10.1186/s12885-017-3329-y

  • CrossRef
  • Google Scholar

• 90

  LiY.ChenY. (2019). AMPK and autophagy. Adv. Exp. Med. Biol.1206, 85–108. 10.1007/978-981-15-0602-4_4

  • CrossRef
  • Google Scholar

• 91

  LiY.SetoE. (2016). HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb. Perspect. Med.6 (10), a026831. 10.1101/cshperspect.a026831

  • CrossRef
  • Google Scholar

• 92

  LiZ. M.XuS. W.LiuP. Q. (2018a). Salvia miltiorrhizaBurge (danshen): A golden herbal medicine in cardiovascular therapeutics. Acta Pharmacol. Sin.39 (5), 802–824. 10.1038/aps.2017.193

  • CrossRef
  • Google Scholar

• 93

  LiangY. Y.WanX. H.NiuF. J.XieS. M.GuoH.YangY. Y.et al (2020). Salvia plebeia R. Br, an overview about its traditional uses, chemical constituents, pharmacology and modern applications. Biomed. Pharmacother.121, 109589. 10.1016/j.biopha.2019.109589

  • CrossRef
  • Google Scholar

• 94

  LinH.ZhengL.LiS.XieB.CuiB.XiaA.et al (2018). Cytotoxicity of Tanshinone IIA combined with Taxol on drug-resist breast cancer cells MCF-7 through inhibition of Tau. Phytother. Res.32 (4), 667–671. 10.1002/ptr.6014

  • CrossRef
  • Google Scholar

• 95

  LinL. L.HsiaC. R.HsuC. L.HuangH. C.JuanH. F. (2015). Integrating transcriptomics and proteomics to show that tanshinone IIA suppresses cell growth by blocking glucose metabolism in gastric cancer cells. BMC Genomics16 (1), 41. 10.1186/s12864-015-1230-0

  • CrossRef
  • Google Scholar

• 96

  LiuJ. J.LiuW. D.YangH. Z.ZhangY.FangZ. G.LiuP. Q.et al (2010). Inactivation of PI3k/Akt signaling pathway and activation of caspase-3 are involved in tanshinone I-induced apoptosis in myeloid leukemia cells in vitro. Ann. Hematol.89 (11), 1089–1097. 10.1007/s00277-010-0996-z

  • CrossRef
  • Google Scholar

• 97

  LiuT.XuJ.YanH. L.ChengF. C.LiuX. J. (2019). Luteolin suppresses teratoma cell growth and induces cell apoptosis via inhibiting bcl-2. Oncol. Res.27 (7), 773–778. 10.3727/096504018X15208986577685

  • CrossRef
  • Google Scholar

• 98

  LiuX.ZouH.ZhaoY.ChenH.LiuT.WuZ.et al (2020). Tanshinone inhibits NSCLC by downregulating AURKA through let-7a-5p. Front. Genet.11, 838. 10.3389/fgene.2020.00838

  • CrossRef
  • Google Scholar

• 99

  LiuY.LinF.ChenY.WangR.LiuJ.JinY.et al (2020a). Cryptotanshinone inhibites bladder cancer cell proliferation and promotes apoptosis via the PTEN/PI3K/AKT pathway. J. Cancer11 (2), 488–499. 10.7150/jca.31422

  • CrossRef
  • Google Scholar

• 100

  LuM.WangC.WangJ. (2016). Tanshinone I induces human colorectal cancer cell apoptosis: The potential roles of Aurora A-p53 and survivin-mediated signaling pathways. Int. J. Oncol.49 (2), 603–610. 10.3892/ijo.2016.3565

  • CrossRef
  • Google Scholar

• 101

  LuX.LiY.YangW.TaoM.DaiY.XuJ.et al (2021). Inhibition of NF-κB is required for oleanolic acid to downregulate PD-L1 by promoting DNA demethylation in gastric cancer cells. J. Biochem. Mol. Toxicol.35 (1), e22621. 10.1002/jbt.22621

  • CrossRef
  • Google Scholar

• 102

  MaS.MengZ.ChenR.GuanK. L. (2019). The hippo pathway: Biology and pathophysiology. Annu. Rev. Biochem.88, 577–604. 10.1146/annurev-biochem-013118-111829

  • CrossRef
  • Google Scholar

• 103

  MaZ. L.ZhangB. J.WangD. T.LiX.WeiJ. L.ZhaoB. T.et al (2015). Tanshinones suppress AURKA through up-regulation of miR-32 expression in non-small cell lung cancer. Oncotarget6 (24), 20111–20120. 10.18632/oncotarget.3933

  • CrossRef
  • Google Scholar

• 104

  MacklinP. S.McAuliffeJ.PughC. W.YamamotoA. (2017). Hypoxia and HIF pathway in cancer and the placenta. Placenta56, 8–13. 10.1016/j.placenta.2017.03.010

  • CrossRef
  • Google Scholar

• 105

  ManY.YangL.ZhangD.BiY. (2016). Cryptotanshinone inhibits lung tumor growth by increasing CD4(+) T cell cytotoxicity through activation of the JAK2/STAT4 pathway. Oncol. Lett.12 (5), 4094–4098. 10.3892/ol.2016.5123

  • CrossRef
  • Google Scholar

• 106

  MandalS.GamitN.VarierL.DharmarajanA.WarrierS. (2021). Inhibition of breast cancer stem-like cells by a triterpenoid, ursolic acid, via activation of Wnt antagonist, sFRP4 and suppression of miRNA-499a-5p. Life Sci.265, 118854. 10.1016/j.lfs.2020.118854

  • CrossRef
  • Google Scholar

• 107

  MelincoviciC. S.BoşcaA. B.ŞuşmanS.MărgineanM.MihuC.IstrateM.et al (2018). Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom. J. Morphol. Embryol.59 (2), 455–467.

  • Google Scholar

• 108

  MensM. M. J.GhanbariM. (2018). Cell cycle regulation of stem cells by MicroRNAs. Stem Cell Rev. Rep.14 (3), 309–322. 10.1007/s12015-018-9808-y

  • CrossRef
  • Google Scholar

• 109

  MeraldiP.HondaR.NiggE. A. (2004). Aurora kinases link chromosome segregation and cell division to cancer susceptibility. Curr. Opin. Genet. Dev.14 (1), 29–36. 10.1016/j.gde.2003.11.006

  • CrossRef
  • Google Scholar

• 110

  MohrA. M.MottJ. L. (2015). Overview of microRNA biology. Semin. Liver Dis.35 (1), 3–11. 10.1055/s-0034-1397344

  • CrossRef
  • Google Scholar

• 111

  Naiki-ItoA.NaikiT.KatoH.IidaK.EtaniT.NagayasuY.et al (2020). Recruitment of miR-8080 by luteolin inhibits androgen receptor splice variant 7 expression in castration-resistant prostate cancer. Carcinogenesis41 (8), 1145–1157. 10.1093/carcin/bgz193

  • CrossRef
  • Google Scholar

• 112

  NieZ. Y.ZhaoM. H.ChengB. Q.PanR. F.WangT. R.QinY.et al (2020). Tanshinone IIA regulates human AML cell proliferation, cell cycle, and apoptosis through miR-497-5p/AKT3 axis. Cancer Cell Int.20, 379. 10.1186/s12935-020-01468-5

  • CrossRef
  • Google Scholar

• 113

  NizamutdinovaI. T.LeeG. W.LeeJ. S.ChoM. K.SonK. H.JeonS. J.et al (2008). Tanshinone I suppresses growth and invasion of human breast cancer cells, MDA-MB-231, through regulation of adhesion molecules. Carcinogenesis29 (10), 1885–1892. 10.1093/carcin/bgn151

  • CrossRef
  • Google Scholar

• 114

  NoguchiS.SaitoA.NagaseT. (2018). YAP/TAZ signaling as a molecular link between fibrosis and cancer. Int. J. Mol. Sci.19 (11), E3674. 10.3390/ijms19113674

  • CrossRef
  • Google Scholar

• 115

  OnoH.SowaY.HorinakaM.IizumiY.WatanabeM.MoritaM.et al (2018). The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway. Breast Cancer Res. Treat.171 (1), 43–52. 10.1007/s10549-018-4815-x

  • CrossRef
  • Google Scholar

• 116

  PanJ.CaiX.ZhengX.ZhuX.FengJ.WangX. (2022). Luteolin inhibits viability, migration, angiogenesis and invasion of non-small cell lung cancer vascular endothelial cells via miR-133a-3p/purine rich element binding protein B-mediated MAPK and PI3K/Akt signaling pathways. Tissue Cell75, 101740. 10.1016/j.tice.2022.101740

  • CrossRef
  • Google Scholar

• 117

  PanT. L.HungY. C.WangP. W.ChenS. T.HsuT. K.SintupisutN.et al (2010). Functional proteomic and structural insights into molecular targets related to the growth inhibitory effect of tanshinone IIA on HeLa cells. Proteomics10 (5), 914–929. 10.1002/pmic.200900178

  • CrossRef
  • Google Scholar

• 118

  PanY.ChenL.LiR.LiuY.NanM.HouL. (2021). Tanshinone IIa induces autophagy and apoptosis via PI3K/Akt/mTOR Axis in acute promyelocytic leukemia NB4 cells. Evid. Based. Complement. Altern. Med.2021, 3372403. 10.1155/2021/3372403

  • CrossRef
  • Google Scholar

• 119

  PanY.LiuG.ZhouF.SuB.LiY. (2018). DNA methylation profiles in cancer diagnosis and therapeutics. Clin. Exp. Med.18 (1), 1–14. 10.1007/s10238-017-0467-0

  • CrossRef
  • Google Scholar

• 120

  ParkS. H.ParkH. S.LeeJ. H.ChiG. Y.KimG. Y.MoonS. K.et al (2013). Induction of endoplasmic reticulum stress-mediated apoptosis and non-canonical autophagy by luteolin in NCI-H460 lung carcinoma cells. Food Chem. Toxicol.56, 100–109. 10.1016/j.fct.2013.02.022

  • CrossRef
  • Google Scholar

• 121

  ParzychK. R.KlionskyD. J. (2014). An overview of autophagy: Morphology, mechanism, and regulation. Antioxid. Redox Signal.20 (3), 460–473. 10.1089/ars.2013.5371

  • CrossRef
  • Google Scholar

• 122

  PastushenkoI.BlanpainC. (2019). EMT transition states during tumor progression and metastasis. Trends Cell Biol.29 (3), 212–226. 10.1016/j.tcb.2018.12.001

  • CrossRef
  • Google Scholar

• 123

  PatriarcaC.PiniG. M.ContiG. (2020). Invasion and metastasis: A historical perspective. Pathologica112 (4), 229–233. 10.32074/1591-951X-111

  • CrossRef
  • Google Scholar

• 124

  PellegrinoN. E.GuvenA.GrayK.ShahP.KastureG.NastkeM. D.et al (2022). The next frontier: Translational development of ubiquitination, SUMOylation, and NEDDylation in cancer. Int. J. Mol. Sci.23 (7), 3480. 10.3390/ijms23073480

  • CrossRef
  • Google Scholar

• 125

  PistrittoG.TrisciuoglioD.CeciC.GarufiA.D'OraziG. (2016). Apoptosis as anticancer mechanism: Function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY)8 (4), 603–619. 10.18632/aging.100934

  • CrossRef
  • Google Scholar

• 126

  PotočnjakI.ŠimićL.GobinI.VukelićI.DomitrovićR. (2020). Antitumor activity of luteolin in human colon cancer SW620 cells is mediated by the ERK/FOXO3a signaling pathway. Toxicol. Vitro66, 104852. 10.1016/j.tiv.2020.104852

  • CrossRef
  • Google Scholar

• 127

  Pujade-LauraineE.BanerjeeS.PignataS. (2019). Management of platinum-resistant, relapsed epithelial ovarian cancer and new drug perspectives. J. Clin. Oncol.37 (27), 2437–2448. 10.1200/JCO.19.00194

  • CrossRef
  • Google Scholar

• 128

  QiH.ChenZ.QinY.WangX.ZhangZ.LiY. (2022). Tanshinone IIA inhibits cell growth by suppressing SIX1-induced aerobic glycolysis in non-small cell lung cancer cells. Oncol. Lett.23 (6), 184. 10.3892/ol.2022.13304

  • CrossRef
  • Google Scholar

• 129

  QiP.LiY.LiuX.JafariF. A.ZhangX.SunQ.et al (2019). Cryptotanshinone suppresses non-small cell lung cancer via microRNA-146a-5p/EGFR Axis. Int. J. Biol. Sci.15 (5), 1072–1079. 10.7150/ijbs.31277

  • CrossRef
  • Google Scholar

• 130

  QianJ.CaoY.ZhangJ.LiL.WuJ.WeiG.et al (2020). Tanshinone IIA induces autophagy in colon cancer cells through MEK/ERK/mTOR pathway. Transl. Cancer Res.9 (11), 6919–6928. 10.21037/tcr-20-1963

  • CrossRef
  • Google Scholar

• 131

  QinT.ZhuW.KanX.LiL.WuD. (2022). Luteolin attenuates the chemoresistance of osteosarcoma through inhibiting the PTN/β-catenin/MDR1 signaling axis by upregulating miR-384. J. Bone Oncol.34, 100429. 10.1016/j.jbo.2022.100429

  • CrossRef
  • Google Scholar

• 132

  QiuY.LiC.WangQ.ZengX.JiP. (2018). Tanshinone IIA induces cell death via Beclin-1-dependent autophagy in oral squamous cell carcinoma SCC-9 cell line. Cancer Med.7 (2), 397–407. 10.1002/cam4.1281

  • CrossRef
  • Google Scholar

• 133

  QuerfurthH.LeeH. K. (2021). Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration. Mol. Neurodegener.16 (1), 44. 10.1186/s13024-021-00428-5

  • CrossRef
  • Google Scholar

• 134

  RenJ.FuL.NileS. H.ZhangJ.KaiG. (2019). Salvia miltiorrhiza in treating cardiovascular diseases: A review on its pharmacological and clinical applications. Front. Pharmacol.10, 753. 10.3389/fphar.2019.00753

  • CrossRef
  • Google Scholar

• 135

  RenL. Q.LiQ.ZhangY. (2020). Luteolin suppresses the proliferation of gastric cancer cells and acts in synergy with oxaliplatin. Biomed. Res. Int.2020, 9396512. 10.1155/2020/9396512

  • CrossRef
  • Google Scholar

• 136

  RenX.WangC.XieB.HuL.ChaiH.DingL.et al (2017). Tanshinone IIA induced cell death via miR30b-p53-PTPN11/SHP2 signaling pathway in human hepatocellular carcinoma cells. Eur. J. Pharmacol.796, 233–241. 10.1016/j.ejphar.2016.11.046

  • CrossRef
  • Google Scholar

• 137

  RiveraE.GomezH. (2010). Chemotherapy resistance in metastatic breast cancer: The evolving role of ixabepilone. Breast Cancer Res.12 (2), S2. 10.1186/bcr2573

  • CrossRef
  • Google Scholar

• 138

  RodriguesC.BL.LalloM. A.PerezE. C. (2020). The controversial role of autophagy in tumor development: A systematic review. Immunol. Invest.49 (4), 386–396. 10.1080/08820139.2019.1682600

  • CrossRef
  • Google Scholar

• 139

  Rodríguez-ParedesM.EstellerM. (2011). Cancer epigenetics reaches mainstream oncology. Nat. Med.17 (3), 330–339. 10.1038/nm.2305

  • CrossRef
  • Google Scholar

• 140

  RotiliD.MaiA. (2011). Targeting histone demethylases: A new avenue for the fight against cancer. Genes Cancer2 (6), 663–679. 10.1177/1947601911417976

  • CrossRef
  • Google Scholar

• 141

  RupaimooleR.SlackF. J. (2017). MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov.16 (3), 203–222. 10.1038/nrd.2016.246

  • CrossRef
  • Google Scholar

• 142

  RussellR. C.TianY.YuanH.ParkH. W.ChangY. Y.KimJ.et al (2013). ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell Biol.15 (7), 741–750. 10.1038/ncb2757

  • CrossRef
  • Google Scholar

• 143

  RyuS.ParkS.LimW.SongG. (2019). Effects of luteolin on canine osteosarcoma: Suppression of cell proliferation and synergy with cisplatin. J. Cell. Physiol.234 (6), 9504–9514. 10.1002/jcp.27638

  • CrossRef
  • Google Scholar

• 144

  Salinas-ArellanoE.Pérez-VásquezA.Rivero-CruzI.Torres-ColinR.González-AndradeM.Rangel-GrimaldoM.et al (2020). Flavonoids and terpenoids with PTP-1B inhibitory properties from the infusion of salvia amarissima ortega. Molecules25 (15), E3530. 10.3390/molecules25153530

  • CrossRef
  • Google Scholar

• 145

  SandovalJ.HeynH.MoranS.Serra-MusachJ.PujanaM. A.BibikovaM.et al (2011). Validation of a DNA methylation microarray for 450, 000 CpG sites in the human genome. Epigenetics6 (6), 692–702. 10.4161/epi.6.6.16196

  • CrossRef
  • Google Scholar

• 146

  ShanY. F.ShenX.XieY. K.ChenJ. C.ShiH. Q.YuZ. P.et al (2009). Inhibitory effects of tanshinone II-A on invasion and metastasis of human colon carcinoma cells. Acta Pharmacol. Sin.30 (11), 1537–1542. 10.1038/aps.2009.139

  • CrossRef
  • Google Scholar

• 147

  ShangS.HuaF.HuZ. W. (2017). The regulation of β-catenin activity and function in cancer: Therapeutic opportunities. Oncotarget8 (20), 33972–33989. 10.18632/oncotarget.15687

  • CrossRef
  • Google Scholar

• 148

  ShinE. A.SohnE. J.WonG.ChoiJ. U.JeongM.KimB.et al (2014). Upregulation of microRNA135a-3p and death receptor 5 plays a critical role in Tanshinone I sensitized prostate cancer cells to TRAIL induced apoptosis. Oncotarget5 (14), 5624–5636. 10.18632/oncotarget.2152

  • CrossRef
  • Google Scholar

• 149

  SohnE. J.WonG.LeeJ.YoonS. W.LeeI.KimH. J.et al (2016). Blockage of epithelial to mesenchymal transition and upregulation of let 7b are critically involved in ursolic acid induced apoptosis in malignant mesothelioma cell. Int. J. Biol. Sci.12 (11), 1279–1288. 10.7150/ijbs.13453

  • CrossRef
  • Google Scholar

• 150

  SongQ.YangL.HanZ.WuX.LiR.ZhouL.et al (2020). Tanshinone IIA inhibits epithelial-to-mesenchymal transition through hindering β-arrestin1 mediated β-catenin signaling pathway in colorectal cancer. Front. Pharmacol.11, 586616. 10.3389/fphar.2020.586616

  • CrossRef
  • Google Scholar

• 151

  SuC. C. (2012). Tanshinone IIA potentiates the efficacy of 5-FU in Colo205 colon cancer cells in vivo through downregulation of P-gp and LC3-II. Exp. Ther. Med.3 (3), 555–559. 10.3892/etm.2011.441

  • CrossRef
  • Google Scholar

• 152

  SuC. Y.MingQ. L.RahmanK.HanT.QinL. P. (2015). Salvia miltiorrhiza: Traditional medicinal uses, chemistry, and pharmacology. Chin. J. Nat. Med.13 (3), 163–182. 10.1016/S1875-5364(15)30002-9

  • CrossRef
  • Google Scholar

• 153

  SuL. J.ZhangJ. H.GomezH.MuruganR.HongX.XuD.et al (2019). Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxid. Med. Cell. Longev.2019, 5080843. 10.1155/2019/5080843

  • CrossRef
  • Google Scholar

• 154

  SuhailY.CainM. P.VanajaK.KurywchakP. A.LevchenkoA.KalluriR.et al (2019). Systems biology of cancer metastasis. Cell Syst.9 (2), 109–127. 10.1016/j.cels.2019.07.003

  • CrossRef
  • Google Scholar

• 155

  SuiH.ZhaoJ.ZhouL.WenH.DengW.LiC.et al (2017). Tanshinone IIA inhibits β-catenin/VEGF-mediated angiogenesis by targeting TGF-β1 in normoxic and HIF-1α in hypoxic microenvironments in human colorectal cancer. Cancer Lett.403, 86–97. 10.1016/j.canlet.2017.05.013

  • CrossRef
  • Google Scholar

• 156

  SunC.HanB.ZhaiY.ZhaoH.LiX.QianJ.et al (2022). Dihydrotanshinone I inhibits ovarian tumor growth by activating oxidative stress through Keap1-mediated Nrf2 ubiquitination degradation. Free Radic. Biol. Med.180, 220–235. 10.1016/j.freeradbiomed.2022.01.015

  • CrossRef
  • Google Scholar

• 157

  SunS.ZhuL.LaiM.ChengR.GeY. (2021). Tanshinone I inhibited growth of human chronic myeloid leukemia cells via JNK/ERK mediated apoptotic pathways. Braz J. Med. Biol. Res.54 (8), e10685. 10.1590/1414-431X2020e10685

  • CrossRef
  • Google Scholar

• 158

  SungH.FerlayJ.SiegelR. L.LaversanneM.SoerjomataramI.JemalA.et al (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca. Cancer J. Clin.71 (3), 209–249. 10.3322/caac.21660

  • CrossRef
  • Google Scholar

• 159

  TaoL.XuM.DaiX.NiT.LiD.JinF.et al (2018). Polypharmacological profiles underlying the antitumor property of salvia miltiorrhiza root (danshen) interfering with NOX-dependent neutrophil extracellular traps. Oxid. Med. Cell. Longev.2018, 4908328. 10.1155/2018/4908328

  • CrossRef
  • Google Scholar

• 160

  TaoS.JustinianoR.ZhangD. D.WondrakG. T. (2013). The Nrf2-inducers tanshinone I and dihydrotanshinone protect human skin cells and reconstructed human skin against solar simulated UV. Redox Biol.1 (1), 532–541. 10.1016/j.redox.2013.10.004

  • CrossRef
  • Google Scholar

• 161

  TaoS.ZhengY.LauA.JaramilloM. C.ChauB. T.LantzR. C.et al (2013a). Tanshinone I activates the Nrf2-dependent antioxidant response and protects against As(III)-induced lung inflammation in vitro and in vivo. Antioxid. Redox Signal.19 (14), 1647–1661. 10.1089/ars.2012.5117

  • CrossRef
  • Google Scholar

• 162

  TianH.LiY.MeiJ.CaoL.YinJ.LiuZ.et al (2021). Effects of Salvia miltiorrhiza extract on lung adenocarcinoma. Exp. Ther. Med.22 (2), 794. 10.3892/etm.2021.10226

  • CrossRef
  • Google Scholar

• 163

  TianQ. T.DingC. Y.SongS. S.WangY. Q.ZhangA.MiaoZ. H. (2018). New tanshinone I derivatives S222 and S439 similarly inhibit topoisomerase I/II but reveal different p53-dependency in inducing G2/M arrest and apoptosis. Biochem. Pharmacol.154, 255–264. 10.1016/j.bcp.2018.05.006

  • CrossRef
  • Google Scholar

• 164

  TongW.GuoJ.YangC. (2020). Tanshinone II A enhances pyroptosis and represses cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway. Biosci. Rep.40 (4), BSR20200259. 10.1042/BSR20200259

  • CrossRef
  • Google Scholar

• 165

  TsaiK. J.TsaiH. Y.TsaiC. C.ChenT. Y.HsiehT. H.ChenC. L.et al (2021). Luteolin inhibits breast cancer stemness and enhances chemosensitivity through the nrf2-mediated pathway. Molecules26 (21), 6452. 10.3390/molecules26216452

  • CrossRef
  • Google Scholar

• 166

  TungN. H.NakajimaK.UtoT.HaiN. T.LongD. D.OhtaT.et al (2017). Bioactive triterpenes from the root of salvia miltiorrhiza bunge. Phytother. Res.31 (9), 1457–1460. 10.1002/ptr.5877

  • CrossRef
  • Google Scholar

• 167

  VerschootenL.BarretteK.Van KelstS.Rubio RomeroN.ProbyC.De VosR.et al (2012). Autophagy inhibitor chloroquine enhanced the cell death inducing effect of the flavonoid luteolin in metastatic squamous cell carcinoma cells. PLoS One7 (10), e48264. 10.1371/journal.pone.0048264

  • CrossRef
  • Google Scholar

• 168

  WangC.LiQ.XiaoB.FangH.HuangB.HuangF.et al (2021). Luteolin enhances the antitumor efficacy of oncolytic vaccinia virus that harbors IL-24 gene in liver cancer cells. J. Clin. Lab. Anal.35 (3), e23677. 10.1002/jcla.23677

  • CrossRef
  • Google Scholar

• 169

  WangH.LuoY.QiaoT.WuZ.HuangZ. (2018). Luteolin sensitizes the antitumor effect of cisplatin in drug-resistant ovarian cancer via induction of apoptosis and inhibition of cell migration and invasion. J. Ovarian Res.11 (1), 93. 10.1186/s13048-018-0468-y

  • CrossRef
  • Google Scholar

• 170

  WangH.SuX.FangJ.XinX.ZhaoX.GaurU.et al (2018a). Tanshinone IIA attenuates insulin like growth factor 1 -induced cell proliferation in PC12 cells through the PI3K/Akt and MEK/ERK pathways. Int. J. Mol. Sci.19 (9), E2719. 10.3390/ijms19092719

  • CrossRef
  • Google Scholar

• 171

  WangJ.LiY.WangX.JiangC. (2012). Ursolic acid inhibits proliferation and induces apoptosis in human glioblastoma cell lines U251 by suppressing TGF-β1/miR-21/PDCD4 pathway. Basic Clin. Pharmacol. Toxicol.111 (2), 106–112. 10.1111/j.1742-7843.2012.00870.x

  • CrossRef
  • Google Scholar

• 172

  WangJ.MaY.GuoM.YangH.GuanX. (2021a). Salvianolic acid B suppresses EMT and apoptosis to lessen drug resistance through AKT/mTOR in gastric cancer cells. Cytotechnology73 (1), 49–61. 10.1007/s10616-020-00441-4

  • CrossRef
  • Google Scholar

• 173

  WangJ. Y.ChenL. J. (2019). The role of miRNAs in the invasion and metastasis of cervical cancer. Biosci. Rep.39 (3), BSR20181377. 10.1042/BSR20181377

  • CrossRef
  • Google Scholar

• 174

  WangL.HuT.ShenJ.ZhangL.ChanR. L.LuL.et al (2015). Dihydrotanshinone I induced apoptosis and autophagy through caspase dependent pathway in colon cancer. Phytomedicine22 (12), 1079–1087. 10.1016/j.phymed.2015.08.009

  • CrossRef
  • Google Scholar

• 175

  WangL.YeungJ. H.HuT.LeeW. Y.LuL.ZhangL.et al (2013). Dihydrotanshinone induces p53-independent but ROS-dependent apoptosis in colon cancer cells. Life Sci.93 (8), 344–351. 10.1016/j.lfs.2013.07.007

  • CrossRef
  • Google Scholar

• 176

  WangL.ZhangC.GuoY.SuZ. Y.YangY.ShuL.et al (2014). Blocking of JB6 cell transformation by tanshinone IIA: Epigenetic reactivation of Nrf2 antioxidative stress pathway. Aaps J.16 (6), 1214–1225. 10.1208/s12248-014-9666-8

  • CrossRef
  • Google Scholar

• 177

  WangM.ZengX.LiS.SunZ.YuJ.ChenC.et al (2019). A novel tanshinone analog exerts anti-cancer effects in prostate cancer by inducing cell apoptosis, arresting cell cycle at G2 phase and blocking metastatic ability. Int. J. Mol. Sci.20 (18), E4459. 10.3390/ijms20184459

  • CrossRef
  • Google Scholar

• 178

  WangQ. L.TaoY. Y.YuanJ. L.ShenL.LiuC. H. (2010). Salvianolic acid B prevents epithelial-to-mesenchymal transition through the TGF-beta1 signal transduction pathway in vivo and in vitro. BMC Cell Biol.11, 31. 10.1186/1471-2121-11-31

  • CrossRef
  • Google Scholar

• 179

  WangR.LuoZ.ZhangH.WangT. (2019a). Tanshinone IIA reverses gefitinib-resistance in human non-small-cell lung cancer via regulation of VEGFR/Akt pathway. Onco. Targets. Ther.12, 9355–9365. 10.2147/OTT.S221228

  • CrossRef
  • Google Scholar

• 180

  WangS.ZhaoY.AguilarA.BernardD.YangC. Y. (2017). Targeting the MDM2-p53 protein-protein interaction for new cancer therapy: Progress and challenges. Cold Spring Harb. Perspect. Med.7 (5), a026245. 10.1101/cshperspect.a026245

  • CrossRef
  • Google Scholar

• 181

  WangX. P.WangP. F.BaiJ. Q.GaoS.WangY. H.QuanL. N.et al (2019b). Investigating the effects and possible mechanisms of danshen- honghua herb pair on acute myocardial ischemia induced by isoproterenol in rats. Biomed. Pharmacother.118, 109268. 10.1016/j.biopha.2019.109268

  • CrossRef
  • Google Scholar

• 182

  WangX.YangY.LiuX.GaoX. (2020). Pharmacological properties of tanshinones, the natural products from Salvia miltiorrhiza. Adv. Pharmacol.87, 43–70. 10.1016/bs.apha.2019.10.001

  • CrossRef
  • Google Scholar

• 183

  WangX.ZhangL.DaiQ.SiH.ZhangL.EltomS. E.et al (2021b). Combined luteolin and indole-3-carbinol synergistically constrains erα-positive breast cancer by dual inhibiting estrogen receptor alpha and cyclin-dependent kinase 4/6 pathway in cultured cells and xenograft mice. Cancers (Basel)13 (9), 2116. 10.3390/cancers13092116

  • CrossRef
  • Google Scholar

• 184

  WangY.JinW.WangJ. (2021c). Tanshinone IIA regulates microRNA-125b/foxp3/caspase-1 signaling and inhibits cell viability of nasopharyngeal carcinoma. Mol. Med. Rep.23 (5), 371. 10.3892/mmr.2021.12010

  • CrossRef
  • Google Scholar

• 185

  WangY.ZhangY.ChenX.HongY.WuZ. (2018b). Combined treatment with myo-inositol and luteolin selectively suppresses growth of human lung cancer A549 cells possibly by suppressing activation of PDK1 and Akt. Nan Fang. Yi Ke Da Xue Xue Bao38 (11), 1378–1383. 10.12122/j.issn.1673-4254.2018.11.17

  • CrossRef
  • Google Scholar

• 186

  WooJ.KimH. Y.ByunB. J.ChaeC. H.LeeJ. Y.RyuS. Y.et al (2014). Biological evaluation of tanshindiols as EZH2 histone methyltransferase inhibitors. Bioorg. Med. Chem. Lett.24 (11), 2486–2492. 10.1016/j.bmcl.2014.04.010

  • CrossRef
  • Google Scholar

• 187

  WuC. Y.HsiehC. Y.HuangK. E.ChangC.KangH. Y. (2012). Cryptotanshinone down-regulates androgen receptor signaling by modulating lysine-specific demethylase 1 function. Int. J. Cancer131 (6), 1423–1434. 10.1002/ijc.27343

  • CrossRef
  • Google Scholar

• 188

  WuD.QiuY.JiaoY.QiuZ.LiuD. (2020). Small molecules targeting HATs, HDACs, and BRDs in cancer therapy. Front. Oncol.10, 560487. 10.3389/fonc.2020.560487

  • CrossRef
  • Google Scholar

• 189

  WuH. T.LinJ.LiuY. E.ChenH. F.HsuK. W.LinS. H.et al (2021). Luteolin suppresses androgen receptor-positive triple-negative breast cancer cell proliferation and metastasis by epigenetic regulation of MMP9 expression via the AKT/mTOR signaling pathway. Phytomedicine.81, 153437. 10.1016/j.phymed.2020.153437

  • CrossRef
  • Google Scholar

• 190

  WuJ.XuH.ZhangL.ZhangX. (2016). Radix astragali and tanshinone help carboplatin inhibit B16 tumor cell growth. Technol. Cancer Res. Treat.15 (4), 583–588. 10.1177/1533034615588682

  • CrossRef
  • Google Scholar

• 191

  WuS.SunC.TianD.LiY.GaoX.HeS.et al (2015). Expression and clinical significances of Beclin1, LC3 and mTOR in colorectal cancer. Int. J. Clin. Exp. Pathol.8 (4), 3882–3891.

  • Google Scholar

• 192

  XiangF.PanC.KongQ.WuR.JiangJ.ZhanY.et al (2014). Ursolic acid inhibits the proliferation of gastric cancer cells by targeting miR-133a. Oncol. Res.22 (5-6), 267–273. 10.3727/096504015X14410238486685

  • CrossRef
  • Google Scholar

• 193

  XieJ.LiuJ. H.LiuH.LiaoX. Z.ChenY.LinM. G.et al (2016). Tanshinone IIA combined with adriamycin inhibited malignant biological behaviors of NSCLC A549 cell line in a synergistic way. BMC Cancer16 (1), 899. 10.1186/s12885-016-2921-x

  • CrossRef
  • Google Scholar

• 194

  XieR.LiY.TangP.YuanQ. (2018). Design, synthesis and biological evaluation of novel 2-aminobenzamides containing dithiocarbamate moiety as histone deacetylase inhibitors and potent antitumor agents. Eur. J. Med. Chem.143, 320–333. 10.1016/j.ejmech.2017.08.041

  • CrossRef
  • Google Scholar

• 195

  XinM.HaoY.HuangG.WangX.LiangZ.MiaoJ.et al (2020). The efficacy and safety of salvianolic acids on acute cerebral infarction treatment: A protocol for systematic review and meta analysis. Med. Baltim.99 (23), e20059. 10.1097/MD.0000000000020059

  • CrossRef
  • Google Scholar

• 196

  XuP.WuQ.LuD.YuJ.RaoY.KouZ.et al (2020). A systematic study of critical miRNAs on cells proliferation and apoptosis by the shortest path. BMC Bioinforma.21 (1), 396. 10.1186/s12859-020-03732-x

  • CrossRef
  • Google Scholar

• 197

  XuQ. F.PengH. P.LuX. R.HuY.XuZ. H.XuJ. K. (2021). Oleanolic acid regulates the Treg/Th17 imbalance in gastric cancer by targeting IL-6 with miR-98-5p. Cytokine148, 155656. 10.1016/j.cyto.2021.155656

  • CrossRef
  • Google Scholar

• 198

  XuZ.ChenL.XiaoZ.ZhuY.JiangH.JinY.et al (2018). Potentiation of the anticancer effect of doxorubicinin drug-resistant gastric cancer cells by tanshinone IIA. Phytomedicine51, 58–67. 10.1016/j.phymed.2018.05.012

  • CrossRef
  • Google Scholar

• 199

  XuZ.HanX.OuD.LiuT.LiZ.JiangG.et al (2020a). Targeting PI3K/AKT/mTOR-mediated autophagy for tumor therapy. Appl. Microbiol. Biotechnol.104 (2), 575–587. 10.1007/s00253-019-10257-8

  • CrossRef
  • Google Scholar

• 200

  XueJ.JinX.WanX.YinX.FangM.LiuT.et al (2019). Effects and mechanism of tanshinone II A in proliferation, apoptosis, and migration of human colon cancer cells. Med. Sci. Monit.25, 4793–4800. 10.12659/MSM.914446

  • CrossRef
  • Google Scholar

• 201

  YanY.SuW.ZengS.QianL.ChenX.WeiJ.et al (2018). Effect and mechanism of tanshinone I on the radiosensitivity of lung cancer cells. Mol. Pharm.15 (11), 4843–4853. 10.1021/acs.molpharmaceut.8b00489

  • CrossRef
  • Google Scholar

• 202

  YangP. W.LuZ. Y.PanQ.ChenT. T.FengX. J.WangS. M.et al (2019). MicroRNA-6809-5p mediates luteolin-induced anticancer effects against hepatoma by targeting flotillin 1. Phytomedicine57, 18–29. 10.1016/j.phymed.2018.10.027

  • CrossRef
  • Google Scholar

• 203

  YangY.LiuL.ZhangX.JiangX.WangL. (2020). Tanshinone IIA prevents rifampicin-induced liver injury by regulating BSEP/NTCP expression via epigenetic activation of NRF2. Liver Int.40 (1), 141–154. 10.1111/liv.14262

  • CrossRef
  • Google Scholar

• 204

  YaoX.JiangW.YuD.YanZ. (2019). Luteolin inhibits proliferation and induces apoptosis of human melanoma cells in vivo and in vitro by suppressing MMP-2 and MMP-9 through the PI3K/AKT pathway. Food Funct.10 (2), 703–712. 10.1039/c8fo02013b

  • CrossRef
  • Google Scholar

• 205

  YaoY.RaoC.ZhengG.WangS. (2019a). Luteolin suppresses colorectal cancer cell metastasis via regulation of the miR-384/pleiotrophin axis. Oncol. Rep.42 (1), 131–141. 10.3892/or.2019.7136

  • CrossRef
  • Google Scholar

• 206

  YeT.ZhuS.ZhuY.FengQ.HeB.XiongY.et al (2016). Cryptotanshinone induces melanoma cancer cells apoptosis via ROS-mitochondrial apoptotic pathway and impairs cell migration and invasion. Biomed. Pharmacother.82, 319–326. 10.1016/j.biopha.2016.05.015

  • CrossRef
  • Google Scholar

• 207

  YeY. T.ZhongW.SunP.WangD.WangC.HuL. M.et al (2017). Apoptosis induced by the methanol extract of Salvia miltiorrhiza Bunge in non-small cell lung cancer through PTEN-mediated inhibition of PI3K/Akt pathway. J. Ethnopharmacol.200, 107–116. 10.1016/j.jep.2016.12.051

  • CrossRef
  • Google Scholar

• 208

  YouS.HeX.WangM.MaoL.ZhangL. (2020). Tanshinone IIA suppresses glioma cell proliferation, migration and invasion both in vitro and in vivo partially through miR-16-5p/talin-1 (TLN1) Axis. Cancer Manag. Res.12, 11309–11320. 10.2147/CMAR.S256347

  • CrossRef
  • Google Scholar

• 209

  YuF.LuZ.ChenB.WuX.DongP.ZhengJ. (2015). Salvianolic acid B-induced microRNA-152 inhibits liver fibrosis by attenuating DNMT1-mediated Patched1 methylation. J. Cell. Mol. Med.19 (11), 2617–2632. 10.1111/jcmm.12655

  • CrossRef
  • Google Scholar

• 210

  YuF.YuC.LiF.ZuoY.WangY.YaoL.et al (2021). Wnt/β-catenin signaling in cancers and targeted therapies. Signal Transduct. Target. Ther.6 (1), 307. 10.1038/s41392-021-00701-5

  • CrossRef
  • Google Scholar

• 211

  YuS.GuoL.YanB.YuanQ.ShanL.ZhouL.et al (2022). Tanshinol suppresses osteosarcoma by specifically inducing apoptosis of U2-OS cells through p53-mediated mechanism. J. Ethnopharmacol.292, 115214. 10.1016/j.jep.2022.115214

  • CrossRef
  • Google Scholar

• 212

  YunS. M.JungJ. H.JeongS. J.SohnE. J.KimB.KimS. H. (2014). Tanshinone IIA induces autophagic cell death via activation of AMPK and ERK and inhibition of mTOR and p70 S6K in KBM-5 leukemia cells. Phytother. Res.28 (3), 458–464. 10.1002/ptr.5015

  • CrossRef
  • Google Scholar

• 213

  YuxianX.FengT.RenL.ZhengcaiL. (2009). Tanshinone II-A inhibits invasion and metastasis of human hepatocellular carcinoma cells in vitro and in vivo. Tumori95 (6), 789–795. 10.1177/030089160909500623

  • CrossRef
  • Google Scholar

• 214

  ZachariM.GanleyI. G. (2017). The mammalian ULK1 complex and autophagy initiation. Essays Biochem.61 (6), 585–596. 10.1042/EBC20170021

  • CrossRef
  • Google Scholar

• 215

  ZahraR.FurqanM.UllahR.MithaniA.SaleemR. S. Z.FaisalA. (2020). A cell-based high-throughput screen identifies inhibitors that overcome P-glycoprotein (Pgp)-mediated multidrug resistance. PLoS One15 (6), e0233993. 10.1371/journal.pone.0233993

  • CrossRef
  • Google Scholar

• 216

  ZeisbergM.NeilsonE. G. (2009). Biomarkers for epithelial-mesenchymal transitions. J. Clin. Invest.119 (6), 1429–1437. 10.1172/JCI36183

  • CrossRef
  • Google Scholar

• 217

  ZengZ.ZhangH.WangX.LiuK.LiT.SunS.et al (2018). Salvianolic acid B suppresses cell proliferation and induces apoptosis in osteosarcoma through p38-mediated reactive oxygen species generation. Oncol. Lett.15 (2), 2679–2685. 10.3892/ol.2017.7609

  • CrossRef
  • Google Scholar

• 218

  ZhangB.MaZ.LiX.ZhangC.ShaoY.LiuZ.et al (2016a). Tanshinones suppress non-small cell lung cancer through up-regulating miR-137. Acta Biochim. Biophys. Sin.48 (8), 768–770. 10.1093/abbs/gmw053

  • CrossRef
  • Google Scholar

• 219

  ZhangG.YangY. M.MengW. T.ZhouJ. (2010). Apoptosis of NB4 cells induced by Tanshinone II A combined with arsenic trioxide. Sichuan Da Xue Xue Bao Yi Xue Ban.41 (1), 57–61.

  • Google Scholar

• 220

  ZhangH. S.ZhangF. J.LiH.LiuY.DuG. Y.HuangY. H. (2016b). Tanshinone ⅡA inhibits human esophageal cancer cell growth through miR-122-mediated PKM2 down-regulation. Arch. Biochem. Biophys.598, 50–56. 10.1016/j.abb.2016.03.031

  • CrossRef
  • Google Scholar

• 221

  ZhangK.LiJ.MengW.XingH.YangY. (2016c). Tanshinone IIA inhibits acute promyelocytic leukemia cell proliferation and induces their apoptosis in vivo. Blood Cells Mol. Dis.56 (1), 46–52. 10.1016/j.bcmd.2015.10.007

  • CrossRef
  • Google Scholar

• 222

  ZhangL.LinW.ChenX.WeiG.ZhuH.XingS. (2019). Tanshinone IIA reverses EGF- and TGF-β1-mediated epithelial-mesenchymal transition in HepG2 cells via the PI3K/Akt/ERK signaling pathway. Oncol. Lett.18 (6), 6554–6562. 10.3892/ol.2019.11032

  • CrossRef
  • Google Scholar

• 223

  ZhangL.LiuQ.HuangL.YangF.LiuA.ZhangJ. (2020). Combination of lapatinib and luteolin enhances the therapeutic efficacy of lapatinib on human breast cancer through the FOXO3a/NQO1 pathway. Biochem. Biophys. Res. Commun.531 (3), 364–371. 10.1016/j.bbrc.2020.07.049

  • CrossRef
  • Google Scholar

• 224

  ZhangM.WangR.TianJ.SongM.ZhaoR.LiuK.et al (2021). Targeting LIMK1 with luteolin inhibits the growth of lung cancer in vitro and in vivo. J. Cell. Mol. Med.25 (12), 5560–5571. 10.1111/jcmm.16568

  • CrossRef
  • Google Scholar

• 225

  ZhangR. W.LiuZ. G.XieY.WangL. X.LiM. C.SunX. (2016d). In vitro inhibition of invasion and metastasis in colon cancer cells by TanIIA. Genet. Mol. Res.15 (3). 10.4238/gmr.15039008

  • CrossRef
  • Google Scholar

• 226

  ZhangW.LiuC.LiJ.LuY.LiH.ZhuangJ.et al (2022). Tanshinone IIA: New perspective on the anti-tumor mechanism of A traditional natural medicine. Am. J. Chin. Med.50 (1), 209–239. 10.1142/S0192415X22500070

  • CrossRef
  • Google Scholar

• 227

  ZhangX.ZhouY.GuY. E. (2019a). Tanshinone IIA induces apoptosis of ovarian cancer cells in vitro and in vivo through attenuation of PI3K/AKT/JNK signaling pathways. Oncol. Lett.17 (2), 1896–1902. 10.3892/ol.2018.9744

  • CrossRef
  • Google Scholar

• 228

  ZhangY.GeT.XiangP.ZhouJ.TangS.MaoH.et al (2019b). Tanshinone IIA reverses oxaliplatin resistance in human colorectal cancer via inhibition of ERK/Akt signaling pathway. Onco. Targets. Ther.12, 9725–9734. 10.2147/OTT.S217914

  • CrossRef
  • Google Scholar

• 229

  ZhangY.GengY.HeJ.WuD.ZhangT.XueL.et al (2019c). Tanshinone IIA induces apoptosis and autophagy in acute monocytic leukemia via downregulation of PI3K/Akt pathway. Am. J. Transl. Res.11 (5), 2995–3006.

  • Google Scholar

• 230

  ZhangY.GuoS.FangJ.PengB.ZhangY.CaoT. (2018). Tanshinone IIA inhibits cell proliferation and tumor growth by downregulating STAT3 in human gastric cancer. Exp. Ther. Med.16 (4), 2931–2937. 10.3892/etm.2018.6562

  • CrossRef
  • Google Scholar

• 231

  ZhangY.JiangP.YeM.KimS. H.JiangC.LüJ. (2012). Tanshinones: Sources, pharmacokinetics and anti-cancer activities. Int. J. Mol. Sci.13 (10), 13621–13666. 10.3390/ijms131013621

  • CrossRef
  • Google Scholar

• 232

  ZhaoW.FengH.GuoS.HanY.ChenX. (2017). Danshenol A inhibits TNF-α-induced expression of intercellular adhesion molecule-1 (ICAM-1) mediated by NOX4 in endothelial cells. Sci. Rep.7 (1), 12953. 10.1038/s41598-017-13072-1

  • CrossRef
  • Google Scholar

• 233

  ZhaoX.LiuM.LiD. (2015). Oleanolic acid suppresses the proliferation of lung carcinoma cells by miR-122/Cyclin G1/MEF2D axis. Mol. Cell. Biochem.400 (1-2), 1–7. 10.1007/s11010-014-2228-7

  • CrossRef
  • Google Scholar

• 234

  ZhaoY. X.LuoD.ZhangY. H.ShenB.WangB. X.SunZ. F. (2017a). The effect of tanshinone ⅡA potentiates the effects of Cisplatin in Fadu cells in vitro through downregulation of survivin. Lin. Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi31 (10), 781–784. 10.13201/j.issn.1001-1781.2017.10.011

  • CrossRef
  • Google Scholar

• 235

  ZhaoZ.ShilatifardA. (2019). Epigenetic modifications of histones in cancer. Genome Biol.20 (1), 245. 10.1186/s13059-019-1870-5

  • CrossRef
  • Google Scholar

• 236

  ZhengL.GuanZ. J.PanW. T.DuT. F.ZhaiY. J.GuoJ. (2018). Tanshinone suppresses arecoline-induced epithelial-mesenchymal transition in oral submucous fibrosis by epigenetically reactivating the p53 pathway. Oncol. Res.26 (3), 483–494. 10.3727/096504017X14941825760362

  • CrossRef
  • Google Scholar

• 237

  ZhengL.ZhangY.LiuG.ChengS.ZhangG.AnC.et al (2020). Tanshinone I regulates autophagic signaling via the activation of AMP-activated protein kinase in cancer cells. Anticancer. Drugs31 (6), 601–608. 10.1097/CAD.0000000000000908

  • CrossRef
  • Google Scholar

• 238

  ZhouJ.JiangY. Y.ChenH.WuY. C.ZhangL. (2020). Tanshinone I attenuates the malignant biological properties of ovarian cancer by inducing apoptosis and autophagy via the inactivation of PI3K/AKT/mTOR pathway. Cell Prolif.53 (2), e12739. 10.1111/cpr.12739

  • CrossRef
  • Google Scholar

• 239

  ZhouJ.JiangY. Y.WangH. P.ChenH.WuY. C.WangL.et al (2020a). Natural compound Tan-I enhances the efficacy of Paclitaxel chemotherapy in ovarian cancer. Ann. Transl. Med.8 (12), 752. 10.21037/atm-20-4072

  • CrossRef
  • Google Scholar

• 240

  ZhouJ.JiangY. Y.WangX. X.WangH. P.ChenH.WuY. C.et al (2020b). Tanshinone IIA suppresses ovarian cancer growth through inhibiting malignant properties and angiogenesis. Ann. Transl. Med.8 (20), 1295. 10.21037/atm-20-5741

  • CrossRef
  • Google Scholar

• 241

  ZhouL.SuiH.WangT.JiaR.ZhangZ.FuJ.et al (2020c). Tanshinone IIA reduces secretion of pro-angiogenic factors and inhibits angiogenesis in human colorectal cancer. Oncol. Rep.43 (4), 1159–1168. 10.3892/or.2020.7498

  • CrossRef
  • Google Scholar

• 242

  ZhouX.LvL.TanY.ZhangZ.WeiS.XiaoS. (2021). Tanshinone IIA sensitizes TRAIL-induced apoptosis in glioblastoma through inducing the expression of death receptors (and suppressing STAT3 activation). Brain Res.1766, 147515. 10.1016/j.brainres.2021.147515

  • CrossRef
  • Google Scholar

• 243

  ZouS.TongQ.LiuB.HuangW.TianY.FuX. (2020). Targeting STAT3 in cancer immunotherapy. Mol. Cancer19 (1), 145. 10.1186/s12943-020-01258-7

  • CrossRef
  • Google Scholar

• 244

  ZuoQ.WuR.XiaoX.YangC.YangY.WangC.et al (2018). The dietary flavone luteolin epigenetically activates the Nrf2 pathway and blocks cell transformation in human colorectal cancer HCT116 cells. J. Cell. Biochem.119 (11), 9573–9582. 10.1002/jcb.27275

  • CrossRef
  • Google Scholar