Open access peer-reviewed chapter

Polyphenols of Salvia miltiorrhiza in Aging-Associated Cardiovascular Diseases and Cancer

Written By

Yu-Chen Cheng, Yu-Chiang Hung and Wen-Long Hu

Submitted: May 21st, 2021 Reviewed: May 31st, 2021 Published: June 24th, 2021

DOI: 10.5772/intechopen.98632

Chapter metrics overview

93 Chapter Downloads

View Full Metrics

Abstract

With the increasing lifespan of human, cardiovascular diseases (CVDs) and cancer are the main diseases leading to the death in the world. Aging is related to a progressive decline in cardiovascular function and structure. While human body suffer from oxidative stress, reactive oxygen species (ROS) are generated as metabolic by-products, which lead to inactivate proteins, damage nucleic acids, and alter the fatty acids of lipids. The accumulation of this oxidative damage contributes to the development of heart disease, diabetes, chronic inflammatory diseases, and cancer. Polyphenols have been widely studied as an anti-oxidant agent in the world. Danshen, the dried root or rhizome of Salvia miltiorrhiza Bunge. is a common Traditional Chinese medicine used in cardiovascular disease and cancer. The main polyphenols in Danshen are phenolic acids (including Salvianolic acids A and B, rosmarinic acid, and their derivatives) and flavonoids. Salvianolic acids have potent anti-oxidative capabilities due to their polyphenolic structure and exhibit cardiovascular protection through mechanisms of ROS scavengers, reduction of leukocyte-endothelial adherence, inhibition of inflammation and indirect regulation of immune function. Salvianolic acids A and B have been reported to owe anti-cancer, anti-inflammatory activities not only through inducing apoptosis, halting cell cycle and adjourning metastasis by targeting multiple deregulated signaling networks of cancer but also sensitizing cancer cells to chemotherapeutic agents.

Keywords

  • Salvia miltiorrhiza
  • polyphenol
  • Traditional Chinese medicine
  • cardiovascular disease
  • cancer

1. Introduction

With the increasing lifespan of human, cardiovascular diseases (CVDs) and cancer are the main diseases leading to the death in the world [1]. Aging is related to a progressive decline in cardiovascular function and structure. The major CVDs include ischemic heart disease, cardiomyopathy, hypertensive heart disease, atrial fibrillation, stroke, aortic aneurysm, rheumatic heart disease, endocarditis, and peripheral arterial disease [2].

There are many oxidants surrounding our environment even persisted inside the human body. While human body suffer from oxidative stress, reactive oxygen species (ROS) are produced from the respiratory chain and leading the electron transfer. Superoxide radical (O2•–) which dismutates from hydrogen peroxide (H 2O2) and molecular oxygen (O2) is a toxic compound after the ROS stimulation [3, 4]. ROS are related to inactivate proteins, damage nucleic acids, and alter the fatty acids of lipids. When those oxidative intracellular components in turn to perturbations in membrane structure and function, those reaction might lead to cell damage. The accumulation of this oxidative damage for a long period of time will leading the development of heart disease, diabetes, chronic inflammatory diseases, cancer, and several neurodegenerative diseases in the aging process.

Polyphenols have been widely studied as an anti-oxidant agent in the world. They are common nutrient antioxidants, mainly derived from fruits, vegetables, tea, coffee, cocoa, mushrooms, beverages, and Traditional Chinese medicine [56]. Traditional Chinese medicine (TCM) are widely used for a long time in Asia countries. Most TCM source come from plants, including leaf, stem, roots or whole plants. Polyphenols are content rich in plants, and so are TCM. Danshen, the dried root or rhizome of Salvia miltiorrhizaBunge. is a common TCM used in cardiovascular disease and cancer [7, 8, 9]. Following, we will make a discussion of aging-associated CVDs, cancer and Salvia miltiorrhiza(Danshen).

Advertisement

2. The monographs of aging-associated cardiovascular disease, cancer and Salvia miltiorrhiza

2.1 Aging-associated cardiovascular disease

The epidemic of CVDs has taken on a global dimension. CVDs now represent more than 30% of all deaths worldwide. According to the World Health Report, CVDs were responsible for 15 million annual deaths worldwide. Especially in developing countries, 9 million deaths every year while 2 million deaths in economies in transition [10].

CVD is positive related to human’s age. By 2030, approximately 20% of the population will be aged 65 or older. At that time, the prevalence of CVD will exponential increase due to the fact that additional 27 million people will have hypertension, 8 million coronary heart disease, 4 million stroke and 3 million heart failure [11]. In this age group, CVDs will result in 40% of all deaths and rank as the leading cause and cost triple payment for treatment [12, 13].

Consistently, researchers have found that many of the factors underlying age-related changes in the arteries are also implicated in the development of CVD [14]. The incidence and prevalence of common CVDs such as hypertension, atherosclerosis, coronary and cerebral artery disease are increasing at about age 45 in men and age 55 in women [15]. These diseases may develop to increase in the prevalence of congestive heart failure and stroke during aging.

Aging is accompanied by changes in vascular structure and function, especially in the large arteries [16]. The aging cardiovascular tissues are exemplified by pathological alterations including hypertrophy, altered left ventricular (LV) diastolic function, and diminished LV systolic reverse capacity [17], increased arterial stiffness, and impaired endothelial function.

Endothelial dysfunction [18] is one of the major pathologic change of CVDs, besides, increasing intima media thickness, vascular stiffness [19], vesicular smooth muscle cells hypertrophy and proliferation and increasing vessel diameter are related to aging vessels. Impaired endothelial vasodilation is an early sign of arterial aging before the clinical manifestations of vascular dysfunction [20]. As endothelial cells age, they exhibit a reduction in endothelial nitric oxide synthetase (eNOS) activity, reducing the abundance of nitric oxide (NO) [21]. NO is a vasodilator produced by endothelial cells, and related to regulate vascular tone, inhibiting vascular inflammation, thrombotic events, and aberrant cellular proliferation [22].

Aging has also a remarkable effect on the heart [23]. The number of cardiac myocytes lessen while heart weight gains with age. The functional cardiac cell continued loss come with the lower regenerative activity from 1% to 0.4% per year of age 20 to 75 years [24]. Most of researches found no obvious difference between male and female in increasing atrial volume [25] and cardiac fibrosis [26]. Although one study of cardiac extracellular matrix proteins found that senior women had a greater amount of collagen and other extracellular matrix proteins in the LV than senior men [27]. A recent work has clearly demonstrated that age-dependent mitochondrial DNA damage is an important substrate underpinning the pathophysiology of cardiac arrhythmias [28]. Another important pathological feature associated with aging is the calcification of aortic and mitral valves which triggers stenosis/insufficiency resulting in cardiac pressure/volume overload [29].

2.2 Cancer

Cancer is the second leading cause of death globally after ischemic heart disease, accounting for an estimated 9.6 million deaths, or one in six deaths, in 2018 and accounting for nearly 10 million deaths in 2020, but will likely become the first for nearly 18.63 million deaths in 2060 [30, 31]. Lung, prostate, colorectal, stomach and liver cancer are the most common types of cancer in men, while breast, colorectal, lung, cervical and thyroid cancer are the most common among women. It might prevent about one-third to half of cancer death after modifying or avoiding key risk factors and reduce the cancer burden through early detection of cancer. Prevention is the most important and effective long-term strategy for cancer control [32].

Cancer is a multistage process that involves mutational changes and uncontrolled cell proliferation. The etiology of cancer is linked to environmental and genetic inheritance causes. The physical (such as ultraviolet and ionizing radiation), chemical (such as asbestos, components of tobacco smoke, aflatoxin, and arsenic) and biological carcinogens (infections from certain viruses, bacteria, or parasites) may play a role in tumor genesis. The accumulation of molecular damage in DNA, proteins and lipids during the aging progress is also characterized by an increase in intracellular oxidative stress due to the progressive decrease of the intracellular ROS scavenging [33]. Therefore, oxidative stress and the resulting oxidative damage are important contributors to the formation and progression of cancer [34].

2.3 Bioactive components of Salvia miltiorrhiza(Danshen)

Salvia miltiorrhiza(Danshen) belongs to the Lamiaceaefamily. There are at least 49 diterpenoid quinones, more than 36 hydrophilic phenolic acids, and 23 essential oil constituents have been isolated and identified from Danshen [35]. Our previous population-based studies demonstrated that Danshen is the most common herbal drug used to treat ischemic heart disease [36] and ischemic stroke [37].

The predominant bioactive compounds in Danshen contains two major groups of chemicals [8, 38]. The first group includes lipophilic compounds (Terpenoids) such as tanshinone I, tanshinone IIA, acetyltanshinone IIA, cryptotanshinone, isocryptotanshinone, dihydrotanshinone, 15,16-dihydrotanshinone I, and miltirone (Figure 1b). These terpenoids possess a wide range of biological activities including antioxidant [39], antibacterial [40], anti-inflammatory [41], antiatherogenic, neuroprotective [42], antitumor [43, 44], and antidiabetic [39] effects.

Figure 1.

The chemical structures of major (a) lipophilic terpenoids and (b) hydrophilic phenolic acids of Danshen.

The second group includes the hydrophilic phenolic acids such as caffeic acid, danshensu, salvianolic acid A(SalA), salvianolic acid B(SalB), lithospermic acid and lithospermic acid B (Figure 1b). Tanshinones show antibacterial, antioxidant, and antineoplastic activities, whereas phenolic acids possess more antioxidant and anticoagulant activities [45]. The classification of polyphenols mainly includes flavonoids (60%), phenolic acids (30%), and other polyphenols (including stilbenes and lignans) [46]. The main polyphenols in Danshen are phenolic acids (including SalA, SalB, rosmarinic acid, and their derivatives) and flavonoids, which exhibit anti-oxygenation, anti-ischemia–reperfusion injury, anti-thrombosis, anti-tumor, and other therapeutic effects [47]. The main polyphenolic compounds are based on caffeic acid (3,4-dihydroxycinnamic acid), one of the most common phenolic acids, formed from two to four or more caffeic acid units, is one of the most common phenolic acids, frequently exist in fruits, grains, as well as TCM [48].

Advertisement

3. Oxidative stress in aging-associated cardiovascular disease and cancer

3.1 Oxidative stress and aging-associated cardiovascular disease

Decreasing in absolute number of cardiomyocytes due to increased apoptosis and necrosis and decreasing in repopulation of cardiomyocytes from cardiac stem cell reserves were occurred in aging heart [49, 50]. The increase in oxidative stress due to the increase in ROS production with age results in an overall enhancement in the rate of cardiomyocyte death with age. With advancing age, we accumulate mutations in our somatic cells. The expression of such factors as p53, p21, p16, senescence-associated β-galactosidase activity and phosphorylation status of γ-H2Ax are widely used to detect the DNA damage. These biomarkers of aging can be used in cardiac tissue to assess how modulation of longevity genes influences the rate and degree of cardiovascular aging at the cellular level [51, 52].

Many aging-associated CVDs including ischemia/reperfusion, hypertensive heart disease and diabetes are related to oxidative stress and that will exhibit cytokines. In addition, increased ROS-responsive signaling pathways are objective by inflammatory oxidative stress and ROS generative system like unfolded protein response of the endoplasmic reticulum or NADPH oxidase activation [53].

The Apoptosis signal-regulating kinase 1(ASK1)-signalosome regulates p38 MAPK and SAPK/JNK and NFκB signaling networks promote senescence (in vitro) and aging (in vivo, animal models and human cohorts) in response to oxidative stress and inflammation leading to age-associated CVDs. Furthermore, their inhibition delays the onset of these CVDs as well as senescence and aging [53, 54].

The Energy generation from mitochondria is through oxidative phosphorylation and will also increase in ROS production which leads to free radical–imposed damage to macromolecules and cellular component. p66Shc, a mitochondrial adaptor, plays an important role in the generation of ROS and as a molecular effector which may explain how aging is connected with CVD and metabolic disease [55]. Several studies show that increased p66Shc expression with time may promote ROS accumulation with subsequent deregulation of pathways implicated in mitochondrial dysfunction, fat accumulation, insulin resistance and diabetes [56, 57, 58].

The AMPK-SIRT1 pathway is involved in energy metabolism in cell. The functional AMP-activated protein kinase (AMPK) is a heterotrimer consisting of a catalytic alpha (α), a regulatory gamma (γ) and a scaffolding beta (β) subunit and is activated by low cellular energy status [59]. AMPK activates eNOS, and facilitates autophagy and mitophagy, thus preventing mitochondrial insufficiency, inflammation and cellular death [60]. Sirtuin 1 (SIRT1) is a NAD+-dependent class III histone deacetylase (HDAC) that mediates the effects of caloric restriction on lifespan and metabolic pathways in various organisms. SIRT1 prevents cardiovascular aging by activating of eNOS [61].

3.2 Oxidative stress in cancer

Cancer is a multistage process defined by at least three stages: initiation, promotion, and progression [62]. ROS from both endogenous and exogenous sources result in increased oxidative stress in the cell. Oxidative stress modulates gene expression of downstream targets involved in DNA repair, cell proliferation and in part through activation or inhibition of transcription factors and second messengers. The role of single nuclear polymorphism for oxidative DNA repair and enzymatic antioxidants is important in determining the potential human cancer risk [34].

ROS regulates tumor development including following steps: transformation [63], survival [64], proliferation [65], invasion [66], metastasis [67], and angiogenesis [68]. One study showed the oxidative stress may be positive correlation with lung cancer staging [69]. In breast carcinomas, 8-OHdG (a most widely used fingerprint of radical attack towards DNA) might be increased 8- to 17-fold in breast primary tumors compared with non-malignant breast tissue [70].

H2O2 plays an important role in carcinogenesis because it is capable of diffusing throughout the mitochondria and across cell membranes and producing many types of cellular injury [71]. ROS may down-regulate the expression of the DNA mismatch repair genes (mutS homolog 2 and 6) and inhibit its enzymatic activity. ROS also induce the expression of DNA methyltransferases, leading to a total hypermethylation of the genome [72]. DNA methylation silence several tumor suppressor genes promoter, such as adenomatous polyposis coli (APC), cyclin-dependent kinase inhibitor-2 (CDKN-2), breast cancer susceptibility gene 1 (BRCA1), retinoblastoma protein (Rb), and the DNA mismatch repair gene, human mutL homolog 1 (hMLH1) [73, 74].

However, it is interesting that oxidative stress induces cancer, but also exists opposite condition. When ROS produced in large excess, they endanger the viability of the cancer cells, through the sustained activation of the cell cycle inhibitors [75]. To protect themselves from ROS-mediated toxicity, many types of cancers enhance the intrinsic antioxidant defenses, which make them dependent on the efficacy of a given ROS-detoxifying system. This poses an attractive target for anticancer therapy by using prooxidants or inhibiting of a chosen antioxidant system [76]. Whether ROS promote tumor cell survival or act as anti-tumorigenic agents depends on the cell and tissues, the location of ROS production, and the concentration of individual ROS.

Advertisement

4. Mechanisms of Salvia miltiorrhizain aging-associated CVD and cancer

4.1 Therapeutic properties of Danshen in aging-associated CVD

Salvianolic acids, especially SalA and SalB, have potent anti-oxidative capabilities due to their polyphenolic structure. The cardiovascular protection of salvianolic acids include the following mechanisms: ROS scavengers, reduction of leukocyte-endothelial adherence, inhibition of inflammation and metalloproteinases expression from aortic smooth muscle cells, and indirect regulation of immune function, and also competitive binding to target proteins to interrupt protein–protein interactions [77].

SalA inhibits oxidative stress directly by scavenging the free radicals to improve the endothelial dysfunction [78], vascular smooth muscle cell proliferation [79], pulmonary arterial hypertension [80], and cardiac fibrosis. SalA can chelate Cu2+ and inhibit Cu2+-promoted oxidation of low-density lipoprotein to reduce the production of malondialdehyde which is the final product of polyunsaturated fatty acids peroxidation in a cell-free system [81]. Interesting, there is a study showed both Salvianolic acid and tanshinone contribute to the cardioprotective effect of Danshen. Tanshinone mainly inhibits intracellular calcium and cell adhesion pathways at an early stage after ischemic injury whereas Salvianolic acid acts mainly by decreasing apoptosis [82].

SalB protects human endothelial progenitor cells against oxidative stress-mediated dysfunction by modulating Akt/mTOR/4EBP1, p38 MAPK/ATF2, and ERK1/2 signaling pathways and prevents oxidative-induced endothelial dysfunction via down-regulated NADPH oxidase 4 and eNOS expression [18].

Cardiac fibrosis is a chronic harmful result of hypertension which may further advance to heart failure and increased matrix metalloproteinase-9 (MMP-9) contributes to the underlying mechanism. In neonatal cardiac fibroblast, SalA inhibited fibroblast migration, blocked myofibroblast transformation, inhibited secretion of intercellular adhesion molecule (ICAM), interleukin-6 (IL-6) and soluble vascular cell adhesion molecule-1 (sVCAM-1) as well as collagen induced by MMP-9. The inhibition on MMP-9 by SalA was further confirmed in cultured cardiac H9c2 cell overexpressing MMP-9 in vitro and in heart of spontaneously hypertensive rats (SHR) in vivo [83]. SalA targeted transgelin and had a protective effect on myocardium by stabilizing the transgelin-actin complex, modulating the reorganization of the actin cytoskeleton, facilitating F-actin bundling, further enhancing the contractility and blood flows of coronary arteries, and improving outcomes of myocardial ischemia [84]. SalB facilitates angiogenesis and alleviated cardiac fibrosis and cardiac remodeling in diabetic cardiomyopathy by suppressing insulin-like growth factor-binding protein 3 (IGFBP3) [85]. SalB can alleviate Ang II-induced cardiac fibrosis via suppressing the NF-κB pathway in vitro [86]. It is reported that treatment with 5% water-soluble extract of Danshen which contained SalB for 12 weeks lowers blood cholesterol and reduces atherosclerotic plaque formation in diet-induced hypercholesterolemic rabbits, which is associated with its ROS scavenging capacity (Table 1) [87].

ComponentPathology of CVDMechanismReferences
Salvianolic acid AEndothelial dysfunction⊕ microvascular remodeling[78]
Vascular smooth muscle cell proliferation⊕ p21 expression via cAMP/PKA/CREB signaling cascade[79]
Pulmonary arterial hypertension↓ right ventricular systolic pressure
↓ hypertrophic damage of myocardium, parenchymal injury and collagen deposition in the lungs
[80]
Lipid oxidationchelate Cu2+ and ⊝ Cu2+-mediated oxidation of LDL
↓ reducing MDA
[81]
hypertension⊝ MMP-9[83]
myocardial ischemiastabilize the transgelin-actin complex
modulate the reorganization of the actin cytoskeleton
⊕ F-actin bundling,
↑ contractility and blood flows of coronary arteries
[84]
Salvianolic acid bEndothelial dysfunctionmodulating Akt/mTOR/4EBP1, p38 MAPK/ATF2
↑ ERK1/2 signaling pathways
↓ Nox4 and eNOS
[18]
Atherosclerotic plaque formation↓ LDL
⊝ atherosclerotic plaque formation
⊕ scavenging ROS
[87]
Cardiac fibrosis⊝ fibroblast migration and myofibroblast transformation
↓ ICAM, IL-6 and sVCAM-1
⊝ MMP-9
⊝ NF-κB pathway
[86]
Diabetic cardiomyopathy⊕ angiogenesis and cardiac remodeling
↓ cardiac fibrosis
⊝ IGFBP3
[85]

Table 1.

The main antioxidative mechanisms of Salvia miltiorrhiza(Danshen) in CVD.

↑: increase; ↓: decrease; ↔: no change; ⊝: inhibit; ⊕: promote. cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP-response element binding protein; LDL, low-density lipoprotein; MDA, malondialdehyde; MMP-9, Matrix metallopeptidase 9; Akt, protein kinase B; mTOR, mechanistic target of rapamycin; 4EBP1, Eukaryotic translation initiation factor 4E-binding protein 1; p38 MAPK, mitogen-activated protein kinases; ATF2, Activating Transcription Factor 2; ERK1, extracellular signal-regulated kinase 1; Nox4, NADPH oxidase 4; eNOS, Endothelial Nitric Oxide Synthase; ROS, reactive oxygen species; ICAM, intercellular adhesion molecule; IL-6, interleukin-6; sVCAM-1, soluble vascular cell adhesion molecule-1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IGFBP3, insulin-like growth factor-binding protein 3.

Homocysteine (Hcy), a by-product of methionine metabolism, may lead to hyperhomocysteinemia which is the risk factors responsible for the development of several vascular diseases (thromboembolism, atherosclerosis, stroke, vascular diseases and dementia). The aqueous extracts of Danshen against vascular atherosclerotic lesions though inhibiting Hcy-induced rat smooth muscle cell line(A10) growth via the PKC/MAPK-dependent pathway, attenuated carbonyl-modification of specific cytoskeleton and chaperone proteins leading to cell type transformation, also, scavenging of ROS and subsequent modulation of protein carbonylation to inhibit cell proliferation [88]. Another study demonstrated the protective effect of Danshen extract against the Hcy-induced adverse effect on human umbilical vein endothelial cell and showed different effectiveness in protection according to the following descending order: Danshen aqueous extract, 3-(3,4-dihydroxy-phenyl)-2-hydroxy-propionic acid (Danshensu), protocatechuic acid, catechin and protocatechualdehyde [89]. Danshensu decreases foam cell formation by reducing the expression of TNFα, ICAM-1, and ET-1 while increasing NO production, thus protecting the vascular endothelium from injury [90]. SalA markedly attenuated induction of MKP-3(mitogen-activated protein kinase phosphatases 3) and inhibition of eNOS expression and NO formation under endothelial ischemia/reperfusion condition [91].

Some clinical studies reported that the Danshen preparations in combination with Western medicine were more effective for treatment of various CVDs including angina pectoris, myocardial infarction, hypertension, hyperlipidemia, and pulmonary heart diseases [92]. Our previous series studies showed the most common used single Chinese herbal products which prescribed by TCM Doctors during 2000–2010 in Taiwan is Danshen (16.50% in ischemic stroke; 29.30% in ischemic heart disease; 3.95% in atrill fibrillation; 5.13% in heart failure) [36, 37, 93, 94]. There was nearly one-third lower stroke risk in ischemic heart disease patients with combination TCM than patients with non-TCM treatment (95% CI = 0.11–0.84, P = .02). The higher survival rate (P < .001) and the lower incidence of hemorrhagic stroke (P = .04) in ischemic heart disease patients with TCM treatment was reported [95]. Compared to non-TCM users, the stroke risk was significantly lower in TCM users with atrial fibrillation who were female or younger than 65 years, but not in males, people more than 65 years old, or people with comorbidities [93]. One randomized controlled trial showed Salvia MiltiorrhizaDepside Salt combined with aspirin is a clinically effective and safe intervention to treat adults aged 35 and older with stable angina pectoris without adverse drug reactions such as bleeding tendency occurred [96].

4.2 Therapeutic properties of Danshen in cancer

SalA and SalB have been reported to owe anti-cancer, anti-inflammatory and cardioprotective activities not only through inducing apoptosis, halting cell cycle and adjourning metastasis by targeting multiple deregulated signaling networks of cancer but also sensitizing cancer cells to chemo-drugs [97].

Acting to protect the organism against these harmful pro-oxidants is a complex system of enzymatic antioxidants (e.g., superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase, catalase) and nonenzymatic antioxidants (e.g., glutathione, vitamins C and D) [98].

SalA elevated ROS levels, downregulated P-glycoprotein, and triggered apoptosis by increasing caspase-3 activity and upregulating Bax expression, while downregulating Bcl-2 expression and disrupting the mitochondrial membrane potential in multidrug resistance MCF-7 human breast cancer cells [99]. In lung cancer, SalA could increase the chemotherapeutic efficacy of cisplatin by enhanced sensitivity to cisplatin in A549/DDP cells mainly through suppression of the c-met/AKT/mTOR signaling pathway [100]. In addition, SalA considerably suppressed the migrative and invasive activity of human NPC cells but not presented cytotoxicity. In SalA-treated NPC cells, the activity and expression of matrix metalloproteinase-2 (MMP-2), a key regulator of cancer cell invasion, were reduced. Additionally, the presence of high concentrations of SalA dramatically abolished the activation of focal adhesion kinase (FAK) and moderately inhibited the phosphorylation of Src and ERK in NPC cells [101].

The anti-tumor effect of SalB is via inhibiting the expression of glucosylceramide and GM3 synthases, and then increases the ceramide accumulation and ceramide-mediated Triple-negative breast cancer cell apoptosis [102]. One study indicated SalB induced cell death and triggered autophagy in HCT116 and HT29 cells in a dose-dependent manner, and it is as a novel autophagy inducer in colorectal cancer cells through the suppression of AKT/mTOR pathway [103]. Besides, SalB reduced the cytotoxicity of doxorubicin through scavenging ROS generated by doxorubicin in HepG2 cells and enhance the expression of SOD and decrease that of NADPH oxidase, which resulted in the elimination of ROS [104]. Sal-B regulated proliferation, epithelial-mesenchymal transition (EMT) and apoptosis to reduce the resistance to cisplatin via AKT/mTOR pathway in cisplatin-resistant gastric cancer cells [105].

Rosmarinic acid (RA) inhibited non-small cell lung cancer (NSCLC) by inducing G1 phase cell cycle arrest, apoptosis and the sensitivity of cisplatin-resistant cell via activating MAPK, enhancing p21 and p53 expression, and inhibiting the expression of P-gp and MDR1 [106]. RA reverses cisplatin resistance of NSCLS by activating the MAPK signaling pathway.

Most of the currently available chemotherapeutic and radiotherapeutic agents kill cancer cells by increasing ROS stress. Thus, both ROS-elevating and ROS-eliminating strategies have been developed for cancer therapy. As we know either chemotherapy or radiotherapy was usually associate with uncomfortable side-effects which are burdens to clinical physicians. Our previous researches find the aqueous extract of Danshen has shown anticancer as well as antioxidant effects, besides, it could prevent or mitigate the causative cardiomyopathy through controlling multiple targets without compromising the efficacy of chemotherapy (Table 2) [108, 109].

ComponentCancerMechanismReferences
Salvianolic acid ANon-small cell lung cancer↑ efficacy of DDP
⊝c-met/AKT/mTOR signaling pathway
[100]
Breast cancer↑ ROS in resistant cells
↑ apoptosis via caspase-3 activity, disrupted mitochondrial membrane potential, ↓ Bcl-2 and
↑ Bax in the resistant cells
↓ P-glycoprotein
[99]
Nasopharyngeal carcinoma↓ MMP-2
⊝ FAK, Src, and ERK pathways
[101]
Salvianolic acid BColorectal cancer⊕ cancer cell death and autophagy
⊝ AKT/mTOR pathway
[103]
Head and neck carcinoma⊝ COX-2/PGE-2 pathway
⊕ the promotion of apoptosis
⊕ angiogenesis.
[107]
Hepatocellular cancer↓ cytotoxicity of doxorubicin
↓ ROS by enhancing the expression of SOD and decreasing NADPH oxidase
[104]
Gastric cancer↓ the resistance to DDP via AKT/mTOR pathway[105]

Table 2.

The therapeutic effect mechanism of polyphenols of Salvia miltiorrhiza(Danshen) in common cancers.

↑: increase; ↓: decrease; ↔: no change; ⊝: inhibit; ⊕: promote. ROS, reactive oxygen species; DDP, cisplatin; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; Bcl-2, B-cell lymphoma 2; Bax, Bcl-2-associated X protein; FAK, focal Adhesion Kinase; ERK, extracellular signal regulated kinase; COX-2/PGE-2; SOD; NADPH.

Advertisement

5. Conclusion

The current epidemiologic data show the incremental trend of CVD and cancer prevalence, mortality as well as disease burden expected in the next 40 years. The prevention of disease becomes the main lesson from now on to the future. Danshen plays a role as anti-oxidative agent and its therapeutic effects in diseases including age-associated CVDs and cancer are confirmed in many studies. Traditional Chinese medicine might be an option for treatment.

Advertisement

Conflict of interest

The authors declare no conflict of interest.

Advertisement

Abbreviations

CVDCardiovascular disease
ROSReactive oxygen species
TCMTraditional Chinese medicine
LVLeft ventricular
eNOSEndothelial nitric oxide synthetase
NONitric oxide
SalASalvianolic acid A
SalBSalvianolic acid B
AMPKAMP-activated protein kinase
SIRT1Sirtuin 1
MMP-9Matrix metalloproteinase-9
HcyHomocysteine
SODSuperoxide dismutase
RARosmarinic acid
NSCLCNon-small cell lung cancer

References

  1. 1. World Health Organization. The top 10 causes of death [Internet]. World Health Organization; [cited 2020 Dec 9]. Available from:https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
  2. 2. Moran AE, Roth GA, Narula J, Mensah GA. 1990-2010 global cardiovascular disease atlas. Global heart. 2014;9(1):3-16
  3. 3. Imlay JA. Cellular defenses against superoxide and hydrogen peroxide. Annual review of biochemistry. 2008;77:755-776
  4. 4. Kiley PJ, Storz G. Exploiting thiol modifications. PLoS biology. 2004;2(11):e400
  5. 5. Song FL, Gan RY, Zhang Y, Xiao Q, Kuang L, Li HB. Total phenolic contents and antioxidant capacities of selected chinese medicinal plants. International journal of molecular sciences. 2010;11(6):2362-2372
  6. 6. Cai Y, Luo Q, Sun M, Corke H. Antioxidant activity and phenolic compounds of 112 traditional Chinese medicinal plants associated with anticancer. Life sciences. 2004;74(17):2157-2184
  7. 7. Wu CF, Bohnert S, Thines E, Efferth T. Cytotoxicity of Salvia miltiorrhiza Against Multidrug-Resistant Cancer Cells. The American journal of Chinese medicine. 2016;44(4):871-894
  8. 8. Hung YC, Pan TL, Hu WL. Roles of Reactive Oxygen Species in Anticancer Therapy with Salvia miltiorrhiza Bunge. Oxidative medicine and cellular longevity. 2016;2016:5293284
  9. 9. Cheng YC, Sheen JM, Hu WL, Hung YC. Polyphenols and Oxidative Stress in Atherosclerosis-Related Ischemic Heart Disease and Stroke. Oxidative medicine and cellular longevity. 2017;2017:8526438
  10. 10. The World Health Report 1997--conquering suffering, enriching humanity. World health forum. 1997;18(3-4):248-260
  11. 11. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123(8):933-944
  12. 12. North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circulation research. 2012;110(8):1097-1108
  13. 13. Fleg JL, Aronow WS, Frishman WH. Cardiovascular drug therapy in the elderly: benefits and challenges. Nature reviews Cardiology. 2011;8(1):13-28
  14. 14. Kovacic JC, Moreno P, Hachinski V, Nabel EG, Fuster V. Cellular senescence, vascular disease, and aging: Part 1 of a 2-part review. Circulation. 2011;123(15):1650-1660
  15. 15. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a "set up" for vascular disease. Circulation. 2003;107(1):139-146
  16. 16. Safar ME. Arterial aging--hemodynamic changes and therapeutic options. Nature reviews Cardiology. 2010;7(8):442-449
  17. 17. Chen C, Sung KT, Shih SC, Liu CC, Kuo JY, Hou CJ, et al. Age, Gender and Load-Related Influences on Left Ventricular Geometric Remodeling, Systolic Mid-Wall Function, and NT-ProBNP in Asymptomatic Asian Population. PloS one. 2016;11(6):e0156467
  18. 18. Tang Y, Jacobi A, Vater C, Zou X, Stiehler M. Salvianolic acid B protects human endothelial progenitor cells against oxidative stress-mediated dysfunction by modulating Akt/mTOR/4EBP1, p38 MAPK/ATF2, and ERK1/2 signaling pathways. Biochemical pharmacology. 2014;90(1):34-49
  19. 19. Collins JA, Munoz JV, Patel TR, Loukas M, Tubbs RS. The anatomy of the aging aorta. Clinical anatomy (New York, NY). 2014;27(3):463-466
  20. 20. El Assar M, Angulo J, Rodríguez-Mañas L. Oxidative stress and vascular inflammation in aging. Free radical biology & medicine. 2013;65:380-401
  21. 21. Collins C, Tzima E. Hemodynamic forces in endothelial dysfunction and vascular aging. Experimental gerontology. 2011;46(2-3):185-188
  22. 22. Heffernan KS, Fahs CA, Ranadive SM, Patvardhan EA. L-arginine as a nutritional prophylaxis against vascular endothelial dysfunction with aging. Journal of cardiovascular pharmacology and therapeutics. 2010;15(1):17-23
  23. 23. Stern S, Behar S, Gottlieb S. Cardiology patient pages. Aging and diseases of the heart. Circulation. 2003;108(14):e99-101
  24. 24. Dai DF, Chen T, Johnson SC, Szeto H, Rabinovitch PS. Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxidants & redox signaling. 2012;16(12):1492-1526
  25. 25. Medrano G, Hermosillo-Rodriguez J, Pham T, Granillo A, Hartley CJ, Reddy A, et al. Left Atrial Volume and Pulmonary Artery Diameter Are Noninvasive Measures of Age-Related Diastolic Dysfunction in Mice. The journals of gerontology Series A, Biological sciences and medical sciences. 2016;71(9):1141-1150
  26. 26. Dzeshka MS, Lip GY, Snezhitskiy V, Shantsila E. Cardiac Fibrosis in Patients With Atrial Fibrillation: Mechanisms and Clinical Implications. Journal of the American College of Cardiology. 2015;66(8):943-959
  27. 27. Dworatzek E, Baczko I, Kararigas G. Effects of aging on cardiac extracellular matrix in men and women. Proteomics Clinical applications. 2016;10(1):84-91
  28. 28. Baris OR, Ederer S, Neuhaus JF, von Kleist-Retzow JC, Wunderlich CM, Pal M, et al. Mosaic Deficiency in Mitochondrial Oxidative Metabolism Promotes Cardiac Arrhythmia during Aging. Cell metabolism. 2015;21(5):667-677
  29. 29. Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation. 2005;111(24):3316-3326
  30. 30. Mattiuzzi C, Lippi G. Current Cancer Epidemiology. Journal of epidemiology and global health. 2019;9(4):217-222
  31. 31. World Health Organization. Projections of mortality and causes of death, 2016 to 2060 [internet]. World Health Organization; [cited 2019 Jul 9]. Available from:https://www.who.int/healthinfo/global_burden_disease/projections/en/
  32. 32. World Health Organization. Cancer [Internet]. Lyon: World Health Organization; 2020 [cited 2021 Mar 3]. Available from:https://www.who.int/news-room/fact-sheets/detail/cancer
  33. 33. Minelli A, Bellezza I, Conte C, Culig Z. Oxidative stress-related aging: A role for prostate cancer? Biochimica et biophysica acta. 2009;1795(2):83-91
  34. 34. Klaunig JE. Oxidative Stress and Cancer. Current pharmaceutical design. 2018;24(40):4771-4778
  35. 35. Pang H, Wu L, Tang Y, Zhou G, Qu C, Duan JA. Chemical Analysis of the Herbal Medicine Salviae miltiorrhizae Radix et Rhizoma (Danshen). Molecules (Basel, Switzerland). 2016;21(1):51
  36. 36. Hung YC, Tseng YJ, Hu WL, Chen HJ, Li TC, Tsai PY, et al. Demographic and Prescribing Patterns of Chinese Herbal Products for Individualized Therapy for Ischemic Heart Disease in Taiwan: Population-Based Study. PloS one. 2015;10(8):e0137058
  37. 37. Hung IL, Hung YC, Wang LY, Hsu SF, Chen HJ, Tseng YJ, et al. Chinese Herbal Products for Ischemic Stroke. The American journal of Chinese medicine. 2015;43(7):1365-1379
  38. 38. Chen X, Guo J, Bao J, Lu J, Wang Y. The anticancer properties of Salvia miltiorrhiza Bunge (Danshen): a systematic review. Medicinal research reviews. 2014;34(4):768-794
  39. 39. Orgah JO, He S, Wang Y, Jiang M, Wang Y, Orgah EA, et al. Pharmacological potential of the combination of Salvia miltiorrhiza (Danshen) and Carthamus tinctorius (Honghua) for diabetes mellitus and its cardiovascular complications. Pharmacological research. 2020;153:104654
  40. 40. Chen BC, Ding ZS, Dai JS, Chen NP, Gong XW, Ma LF, et al. New Insights Into the Antibacterial Mechanism of Cryptotanshinone, a Representative Diterpenoid Quinone From Salvia miltiorrhiza Bunge. Frontiers in microbiology. 2021;12:647289
  41. 41. Cui S, Chen S, Wu Q, Chen T, Li S. A network pharmacology approach to investigate the anti-inflammatory mechanism of effective ingredients from Salvia miltiorrhiza. International immunopharmacology. 2020;81:106040
  42. 42. Zhang XZ, Qian SS, Zhang YJ, Wang RQ. Salvia miltiorrhiza: A source for anti-Alzheimer's disease drugs. Pharmaceutical biology. 2016;54(1):18-24
  43. 43. Zhang Y, Jiang P, Ye M, Kim SH, Jiang C, Lü J. Tanshinones: sources, pharmacokinetics and anti-cancer activities. International journal of molecular sciences. 2012;13(10):13621-13666
  44. 44. Pan TL, Hung YC, Wang PW, Chen ST, Hsu TK, Sintupisut N, et al. Functional proteomic and structural insights into molecular targets related to the growth inhibitory effect of tanshinone IIA on HeLa cells. Proteomics. 2010;10(5):914-929
  45. 45. Wang X, Morris-Natschke SL, Lee KH. New developments in the chemistry and biology of the bioactive constituents of Tanshen. Medicinal research reviews. 2007;27(1):133-148
  46. 46. Neveu V, Perez-Jiménez J, Vos F, Crespy V, du Chaffaut L, Mennen L, et al. Phenol-Explorer: an online comprehensive database on polyphenol contents in foods. Database: the journal of biological databases and curation. 2010;2010:bap024
  47. 47. Wang J, Xu J, Gong X, Yang M, Zhang C, Li M. Biosynthesis, Chemistry, and Pharmacology of Polyphenols from Chinese Salvia Species: A Review. Molecules (Basel, Switzerland). 2019;24(1)
  48. 48. Jiang RW, Lau KM, Hon PM, Mak TC, Woo KS, Fung KP. Chemistry and biological activities of caffeic acid derivatives from Salvia miltiorrhiza. Current medicinal chemistry. 2005;12(2):237-246
  49. 49. Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circulation research. 1991;68(6):1560-1568
  50. 50. Goldspink DF, Burniston JG, Tan LB. Cardiomyocyte death and the ageing and failing heart. Experimental physiology. 2003;88(3):447-458
  51. 51. Szczesny B, Bhakat KK, Mitra S, Boldogh I. Age-dependent modulation of DNA repair enzymes by covalent modification and subcellular distribution. Mechanisms of ageing and development. 2004;125(10-11):755-765
  52. 52. Mah LJ, El-Osta A, Karagiannis TC. GammaH2AX as a molecular marker of aging and disease. Epigenetics. 2010;5(2):129-136
  53. 53. Papaconstantinou J. The Role of Signaling Pathways of Inflammation and Oxidative Stress in Development of Senescence and Aging Phenotypes in Cardiovascular Disease. Cells. 2019;8(11)
  54. 54. Costantino S, Paneni F, Cosentino F. Ageing, metabolism and cardiovascular disease. The Journal of physiology. 2016;594(8):2061-2073
  55. 55. Paneni F, Cosentino F. p66 Shc as the engine of vascular aging. Current vascular pharmacology. 2012;10(6):697-699
  56. 56. Paneni F, Costantino S, Cosentino F. p66(Shc)-induced redox changes drive endothelial insulin resistance. Atherosclerosis. 2014;236(2):426-429
  57. 57. Rota M, LeCapitaine N, Hosoda T, Boni A, De Angelis A, Padin-Iruegas ME, et al. Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circulation research. 2006;99(1):42-52
  58. 58. Franzeck FC, Hof D, Spescha RD, Hasun M, Akhmedov A, Steffel J, et al. Expression of the aging gene p66Shc is increased in peripheral blood monocytes of patients with acute coronary syndrome but not with stable coronary artery disease. Atherosclerosis. 2012;220(1):282-286
  59. 59. Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing research reviews. 2012;11(2):230-241
  60. 60. Lesniewski LA, Zigler MC, Durrant JR, Donato AJ, Seals DR. Sustained activation of AMPK ameliorates age-associated vascular endothelial dysfunction via a nitric oxide-independent mechanism. Mechanisms of ageing and development. 2012;133(5):368-371
  61. 61. Stein S, Matter CM. Protective roles of SIRT1 in atherosclerosis. Cell cycle (Georgetown, Tex). 2011;10(4):640-647
  62. 62. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free radical biology & medicine. 2010;49(11):1603-1616
  63. 63. Jackson AL, Loeb LA. The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutation research. 2001;477(1-2):7-21
  64. 64. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261-1274
  65. 65. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nature cell biology. 2002;4(5):E131-E136
  66. 66. Roebuck KA. Oxidant stress regulation of IL-8 and ICAM-1 gene expression: differential activation and binding of the transcription factors AP-1 and NF-kappaB (Review). International journal of molecular medicine. 1999;4(3):223-230
  67. 67. Westermarck J, Kähäri VM. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 1999;13(8):781-792
  68. 68. Folkman J. Tumor angiogenesis. Advances in cancer research. 1985;43:175-203
  69. 69. Xiang M, Feng J, Geng L, Yang Y, Dai C, Li J, et al. Sera total oxidant/antioxidant status in lung cancer patients. Medicine. 2019;98(37):e17179
  70. 70. Marnett LJ. Oxyradicals and DNA damage. Carcinogenesis. 2000;21(3):361-370
  71. 71. Matés JM, Sánchez-Jiménez FM. Role of reactive oxygen species in apoptosis: implications for cancer therapy. The international journal of biochemistry & cell biology. 2000;32(2):157-170
  72. 72. Schetter AJ, Heegaard NH, Harris CC. Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis. 2010;31(1):37-49
  73. 73. Fleisher AS, Esteller M, Harpaz N, Leytin A, Rashid A, Xu Y, et al. Microsatellite instability in inflammatory bowel disease-associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1. Cancer research. 2000;60(17):4864-4868
  74. 74. Das PM, Singal R. DNA methylation and cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2004;22(22):4632-4642
  75. 75. Prasad S, Gupta SC, Pandey MK, Tyagi AK, Deb L. Oxidative Stress and Cancer: Advances and Challenges. Oxidative medicine and cellular longevity. 2016;2016:5010423
  76. 76. Firczuk M, Bajor M, Graczyk-Jarzynka A, Fidyt K, Goral A, Zagozdzon R. Harnessing altered oxidative metabolism in cancer by augmented prooxidant therapy. Cancer letters. 2020;471:1-11
  77. 77. Ho JH, Hong CY. Salvianolic acids: small compounds with multiple mechanisms for cardiovascular protection. Journal of biomedical science. 2011;18(1):30
  78. 78. Teng F, Yin Y, Cui Y, Deng Y, Li D, Cho K, et al. Salvianolic acid A inhibits endothelial dysfunction and vascular remodeling in spontaneously hypertensive rats. Life sciences. 2016;144:86-93
  79. 79. Sun L, Zhao R, Zhang L, Zhang W, He G, Yang S, et al. Prevention of vascular smooth muscle cell proliferation and injury-induced neointimal hyperplasia by CREB-mediated p21 induction: An insight from a plant polyphenol. Biochemical pharmacology. 2016;103:40-52
  80. 80. Chen YC, Yuan TY, Zhang HF, Wang DS, Yan Y, Niu ZR, et al. Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model. Acta pharmacologica Sinica. 2016;37(6):772-782
  81. 81. Liu YL, Liu GT. [Inhibition of human low-density lipoprotein oxidation by salvianolic acid-A]. Yao xue xue bao = Acta pharmaceutica Sinica. 2002;37(2):81-85
  82. 82. Wang X, Wang Y, Jiang M, Zhu Y, Hu L, Fan G, et al. Differential cardioprotective effects of salvianolic acid and tanshinone on acute myocardial infarction are mediated by unique signaling pathways. Journal of ethnopharmacology. 2011;135(3):662-671
  83. 83. Jiang B, Li D, Deng Y, Teng F, Chen J, Xue S, et al. Salvianolic acid A, a novel matrix metalloproteinase-9 inhibitor, prevents cardiac remodeling in spontaneously hypertensive rats. PloS one. 2013;8(3):e59621
  84. 84. Zhong W, Sun B, Gao W, Qin Y, Zhang H, Huai L, et al. Salvianolic acid A targeting the transgelin-actin complex to enhance vasoconstriction. EBioMedicine. 2018;37:246-258
  85. 85. Li CL, Liu B, Wang ZY, Xie F, Qiao W, Cheng J, et al. Salvianolic acid B improves myocardial function in diabetic cardiomyopathy by suppressing IGFBP3. Journal of molecular and cellular cardiology. 2020;139:98-112
  86. 86. Wang C, Luo H, Xu Y, Tao L, Chang C, Shen X. Salvianolic Acid B-Alleviated Angiotensin II Induces Cardiac Fibrosis by Suppressing NF-κB Pathway In Vitro. Medical science monitor: international medical journal of experimental and clinical research. 2018;24:7654-7664
  87. 87. Wu YJ, Hong CY, Lin SJ, Wu P, Shiao MS. Increase of vitamin E content in LDL and reduction of atherosclerosis in cholesterol-fed rabbits by a water-soluble antioxidant-rich fraction of Salvia miltiorrhiza. Arteriosclerosis, thrombosis, and vascular biology. 1998;18(3):481-486
  88. 88. Hung YC, Wang PW, Pan TL. Functional proteomics reveal the effect of Salvia miltiorrhiza aqueous extract against vascular atherosclerotic lesions. Biochimica et biophysica acta. 2010;1804(6):1310-1321
  89. 89. Chan K, Chui SH, Wong DY, Ha WY, Chan CL, Wong RN. Protective effects of Danshensu from the aqueous extract of Salvia miltiorrhiza (Danshen) against homocysteine-induced endothelial dysfunction. Life sciences. 2004;75(26):3157-3171
  90. 90. Yang RX, Huang SY, Yan FF, Lu XT, Xing YF, Liu Y, et al. Danshensu protects vascular endothelia in a rat model of hyperhomocysteinemia. Acta pharmacologica Sinica. 2010;31(10):1395-1400
  91. 91. Yang D, Xie P, Liu Z. Ischemia/reperfusion-induced MKP-3 impairs endothelial NO formation via inactivation of ERK1/2 pathway. PloS one. 2012;7(7):e42076
  92. 92. Ren J, Fu L, Nile SH, Zhang J, Kai G. Salvia miltiorrhiza in Treating Cardiovascular Diseases: A Review on Its Pharmacological and Clinical Applications. Frontiers in pharmacology. 2019;10:753
  93. 93. Hung YC, Cheng YC, Muo CH, Chiu HE, Liu CT, Hu WL. Adjuvant Chinese Herbal Products for Preventing Ischemic Stroke in Patients with Atrial Fibrillation. PloS one. 2016;11(7):e0159333
  94. 94. Tsai MY, Hu WL, Lin CC, Lee YC, Chen SY, Hung YC, et al. Prescription pattern of Chinese herbal products for heart failure in Taiwan: A population-based study. International journal of cardiology. 2017;228:90-96
  95. 95. Cheng YC, Lu CN, Hu WL, Hsu CY, Su YC, Hung YC. Decreased stroke risk with combined traditional Chinese and western medicine in patients with ischemic heart disease: A real-world evidence. Medicine. 2020;99(42):e22654
  96. 96. Lyu J, Xue M, Li J, Lyu W, Wen Z, Yao P, et al. Clinical effectiveness and safety of salvia miltiorrhiza depside salt combined with aspirin in patients with stable angina pectoris: A multicenter, pragmatic, randomized controlled trial. Phytomedicine: international journal of phytotherapy and phytopharmacology. 2021;81:153419
  97. 97. Qin T, Rasul A, Sarfraz A, Sarfraz I, Hussain G, Anwar H, et al. Salvianolic acid A & B: potential cytotoxic polyphenols in battle against cancer via targeting multiple signaling pathways. International journal of biological sciences. 2019;15(10):2256-2264
  98. 98. Sies H. Oxidative stress: from basic research to clinical application. The American journal of medicine. 1991;91(3c):31s-38s
  99. 99. Wang X, Wang C, Zhang L, Li Y, Wang S, Wang J, et al. Salvianolic acid A shows selective cytotoxicity against multidrug-resistant MCF-7 breast cancer cells. Anti-cancer drugs. 2015;26(2):210-223
  100. 100. Tang XL, Yan L, Zhu L, Jiao DM, Chen J, Chen QY. Salvianolic acid A reverses cisplatin resistance in lung cancer A549 cells by targeting c-met and attenuating Akt/mTOR pathway. Journal of pharmacological sciences. 2017;135(1):1-7
  101. 101. Chuang CY, Ho YC, Lin CW, Yang WE, Yu YL, Tsai MC, et al. Salvianolic acid A suppresses MMP-2 expression and restrains cancer cell invasion through ERK signaling in human nasopharyngeal carcinoma. Journal of ethnopharmacology. 2020;252:112601
  102. 102. Sha W, Zhou Y, Ling ZQ, Xie G, Pang X, Wang P, et al. Antitumor properties of Salvianolic acid B against triple-negative and hormone receptor-positive breast cancer cells via ceramide-mediated apoptosis. Oncotarget. 2018;9(91):36331-36343
  103. 103. Jing Z, Fei W, Zhou J, Zhang L, Chen L, Zhang X, et al. Salvianolic acid B, a novel autophagy inducer, exerts antitumor activity as a single agent in colorectal cancer cells. Oncotarget. 2016;7(38):61509-61519
  104. 104. Kan S, Cheung WM, Zhou Y, Ho WS. Enhancement of doxorubicin cytotoxicity by tanshinone IIA in HepG2 human hepatoma cells. Planta medica. 2014;80(1):70-76
  105. 105. Wang J, Ma Y, Guo M, Yang H, Guan X. Salvianolic acid B suppresses EMT and apoptosis to lessen drug resistance through AKT/mTOR in gastric cancer cells. Cytotechnology. 2021;73(1):49-61
  106. 106. Liao XZ, Gao Y, Sun LL, Liu JH, Chen HR, Yu L, et al. Rosmarinic acid reverses non-small cell lung cancer cisplatin resistance by activating the MAPK signaling pathway. Phytotherapy research: PTR. 2020;34(5):1142-1153
  107. 107. Zhao Y, Guo Y, Gu X. Salvianolic Acid B, a potential chemopreventive agent, for head and neck squamous cell cancer. Journal of oncology. 2011;2011:534548
  108. 108. Hung YC, Wang PW, Lin TY, Yang PM, You JS, Pan TL. Functional Redox Proteomics Reveal That Salvia miltiorrhiza Aqueous Extract Alleviates Adriamycin-Induced Cardiomyopathy via Inhibiting ROS-Dependent Apoptosis. Oxidative medicine and cellular longevity. 2020;2020:5136934
  109. 109. You JS, Pan TL, Lee YS. Protective effects of Danshen (Salvia miltiorrhiza) on adriamycin-induced cardiac and hepatic toxicity in rats. Phytotherapy research: PTR. 2007;21(12):1146-1152

Written By

Yu-Chen Cheng, Yu-Chiang Hung and Wen-Long Hu

Submitted: May 21st, 2021 Reviewed: May 31st, 2021 Published: June 24th, 2021