Therapeutic Potential of Ginsenosides in Anthracycline-Induced Cardiotoxicity
Abstract
:1. Introduction
2. Mechanisms and Prevention of Anthracycline Cardiotoxicity
2.1. Classification of the AIC
2.2. Mechanisms Associated with the AIC
2.2.1. Oxidative-Stress-Mediated AIC
2.2.2. ANTs Induce Cardiomyocyte Death
2.2.3. DNA TOP 2β-Mediated Cardiotoxicity
2.3. Clinical Management of AIC
3. Classification of Ginsenosides and Their Therapeutic Effects on Cardiovascular Diseases
3.1. Classification of Ginsenosides
3.2. Ginsenosides Used to Treat Cardiovascular Diseases
4. Therapeutic Effects and Mechanisms of Ginsenosides in AIC
4.1. Ginsenosides Inhibit Oxidative Stress
Ginsenosides | Models | Disease | Mechanism | Reference |
---|---|---|---|---|
Rg3 | Angiotensin II (Ang II)-induced cardiac hypertrophy in vitro; in vivo transverse aortic constriction constructs a rat model of cardiac hypertrophy. | Hypertensive Cardiac Hypertrophy (HCH); Myocarditis (MC) | ANP, BNP, and β-MHC ↓; myocardial fibrosis-related proteins (MyHc, CollagenI, and TGF-β1) ↓; upregulation of Nrf2/HO-1, SIRT1 pathway; downregulation of NF-κB pathway; Regulation of Nrf2/HO-1, SIRT1/NF-κB pathway inhibits inflammation and oxidative stress. | [98] |
Rg5 | Ang II induces cardiac inflammation and remodeling. | IL-1β, IL-16, TNF ↓; p-JNK ↓; AP-1 ↓; Inhibition of the JNK/AP-1 pathway blocks inflammation. | [99] | |
Rb3 | Ang II injury to cardiomyocytes. | NADPH ↓; ROS ↓; NOX-2, NOX-4, p67 ↓; NO, NOS ↑; Reversing NADPH overexpression to resist oxidative damage. | [82] | |
F1 | A mouse model of atherosclerosis constructed by feeding a high-fat diet. | Atherosclerosis | LOX-1, TLR4 ↓; MPO ↓; G-CSF, ICAM-1, MIP-1δ, IL-1α, IL-15, IL-16 ↓; A20, NF-κB ↓; Mediated A20 inhibition of the NF-κB signaling pathway relieves inflammation. | [100] |
Ginsenosides | Models | Disease | Mechanism | Reference |
---|---|---|---|---|
Rg1 Rd Rk3 Rh1 Rb1 Rd Rc | In vitro cultivation of H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R) injury | MI, HF, Ischemic Cardiomyopathy (ICM) | SOD, GSH-Px, GSH ↑; LDH ↑; Nrf2, HO-1 ↑; TNF-α ↓; Activates Nrf2/HO-1 signaling pathway, inhibits JNK phosphorylation, and regulates Akt and MAPK pathways to prevent oxidative stress | [101,102,103,104,105,106,107] |
Rg1 | In vivo and in vitro ischemia/reperfusion (I/R) injury models | Protection of cardiomyocytes against hypoxia-induced cellular injury by upregulation of HIF-1α through activation of the PI3K/Akt/mTOR pathway | [108] | |
Rb1 Re | Rat myocardial I/R model: H2O2-induced oxidative stress | CK, MDA ↓; LDH ↑; SOD, eNOS, NO ↑; increase NO content to inhibit oxidative stress | [109,110] | |
Rb1 | In vitro H/R model of H9c2 cardiomyocytes | SOD, CAT, GSH-Px ↑; MDA ↓; PARP-1/2 ↑; ERα, ERβ, p-Akt ↑; p-JNK, p-ERK 1/2 ↓; Activation of ER-dependent crosstalk across Akt, JNK, and ERK 1/2 pathways prevents H/R damage | [111] | |
Rg1 | In vitro H/R model of H9c2 cardiomyocytes | CK, LDH ↓; MMP, ATP ↑; Bax/Bcl-2, ROS ↓; GDH ↓; MFN2 ↑; Regulates GDH and MFN2, maintains mitochondrial dynamics to prevent H/R injury | [112] | |
Rg5 | Modeling myocardial ischemia | Promotes Akt translocation, increases mitochondrial hexokinase-II (HK-II) binding to mitochondria; inhibits dynamin-related protein 1 (Drp1) recruitment and mitochondrial fission; mPTP ↓; ATP ↑; Regulation of HK-II and Drp1 increases resistance to hypoxia/reoxygenation injury | [113] | |
Rg2 | Ang II injury to cardiomyocytes | MI | Col-1, Col-3, α-SMA ↓; p-Akt ↑; Masson staining shows Rg2 reduces MI-induced cardiac fibrosis in mice | [114] |
Re | Constructing a rat MI model | P-AMPKα ↑; TGF-β1 ↓; Smad2/3 ↓; FAK, p-PI3K/p110α, p-Akt ↑; Regulation of AMPK/TGF-β1/Smad2/3 and FAK/PI3K p110α/Akt signaling pathways | [115] |
4.2. Inhibition of Ferroptosis by Ginsenosides
4.3. Regulation of Autophagy by Ginseng Saponins
4.4. Inhibitory Effects of Ginsenosides on Pyroptosis
4.5. Inhibition of Apoptosis by Ginsenosides
4.6. Protective Effects of Other Factors on AIC
5. Clinical Applications of Ginseng and Ginsenosides
Ingredients | Disease | Subjects | Outcome | References |
---|---|---|---|---|
Panax ginseng extract (PGE) | The effects of ginseng extract on blood pressure and heart rate | 30 healthy adult subjects. Oral administration of 200 mg of ginseng extract. Monitoring of ECG parameters and blood pressure. | QTc interval prolongation and diastolic blood pressure after 2 h of ingestion. | [181] |
Powder composed of Radix Ginseng, Radix Notoginseng, and Succinum | Coronary artery angina | 116 patients with coronary artery angina pectoris. Randomized double-blind trial of treatment group and control group (compound Danshen tablets). | The general symptoms, physical strength, ECG parameters, and lipid metabolism in the ginseng treatment group were all better than those in the control group. | [188] |
Red ginseng extract | ST-elevation acute myocardial infarction (AMI) | 50 patients with AMI. Measurement of coronary flow reserve (CFR) and changes in absolute numbers of circulating angiogenic cells. | During the 8-month follow-up period, the CFR in the red ginseng group was significantly better than that in the placebo group; CD34+, CXCR4+, and CD117+ levels increased and inflammation slowed down. | [189] |
PGE | The effect of PGE on lipid metabolism—lipid-lowering research | Eight adult male subjects, 6 g/day, 8 weeks. Testing serum MDA, SOD, CAT, serum total cholesterol (TC), triglyceride (TG), LDL, HDL, and other indicators. | MDA, TC, TG, LDL ↓; HDL, SOD, CAT ↑. Lowering blood lipids and antioxidant properties. | [190] |
Korean red ginseng (KRG) | Endothelial function | 16 healthy participants on four occasions were administered: KRG root (3 g), KRG ginsenosides extract, KRG polysaccharides extract, and cornstarch control. Assessment of flow-mediated vasodilatation. | Maximum vasodilation occurred 180 min after taking KRG ginsenoside extract. Improves endothelial function in healthy individuals. | [191] |
Ginsenoside Rg3–enriched Korean red ginseng (Rg3-KRG) | Arterial stiffness and peripheral and central BP | 23 healthy subjects. 400 mg Rg3-KRG extract or 400 mg wheat bran control. Measurement of aortic augmentation index and central BP. | Brachial systolic and diastolic BP ↓. Lowers central and peripheral arterial pressures in healthy adults. | [192] |
Ginseng (Rb1/Rg1) | Blood lipid levels. | Patients with metabolic syndrome, healthy volunteers, postmenopausal women. Meta-analysis. | Total cholesterol, LDL, triglycerides ↓. Regulate blood lipid levels. | [154] |
Ingredients | Disease | Subjects | Outcome | References |
---|---|---|---|---|
Shenmai injection (SMI) | CAD and CHF. Efficacy and safety. | 240 patients with CHF complicated by CAD. CHF standard treatment drugs and SMI (100 mL/day). 1 week. Endpoints: NYHA functional classification, SF-36. Heart survey score, traditional Chinese medicines syndrome score, LVEF, and BNP level. | Each endpoint is superior to the placebo group. SMI can further improve the course of patients with CHF complicated by CAD. | [193] |
SMI | Coronary heart disease (CHD) | 40 patients with OPCABG. Injecting SMI before performing OPCABG. Indicators: cardiac output (CO), stroke volume (SV), and the ejection fraction (EF) during surgery. | CO, SV, EF ↑. Improving the safety of anesthesia. | [194] |
Shenmai and compound danshen injection (SM-DS) | Myocardial reperfusion injury after percutaneous coronary intervention (PCI) in patients with acute AMI. | 38 patients with AMI who underwent PCI treatment. SM-DS therapy was used before and after PCI surgery. The integrated left ventricular ejection isometric index (Tei) was determined by echocardiogram. Monitoring MDA, SOD, IL-6, and TNF-α levels. | SOD ↑; MDA, IL-6, TNF-α ↓; The improvement time of the Tei index in the treatment group was earlier than that in the control group. SM-DS could reduce the myocardial reperfusion injury in patients with AMI after PCI. | [195] |
SMI | CHF | 64 patients with CHF. Basic treatment and SMI. 14 days. Tissue Doppler imaging (TDI) monitoring of eft ventricular diastolic function (LVDF) used. | TDI assessment shows that SMI could effectively improve the LVDF in CHF patients. | [196] |
SMI | AMI | Meta-analysis of 50 clinical studies of Shenmai for AMI. | The incidence of cardiac failure, the incidence of HF, shock, and reinfarction ↓. No serious adverse drug reactions (ADRs)/adverse events (AEs) were observed, but post-marketing safety evaluation is still required. | [197] |
Shenfu injection (SFI) | I/RI | 40 patients’ mitral valve replacement (MVR) with cardiopulmonary bypass (CPB). Monitoring systolic SBP, HR, MBP, DBP, and CTn, SOD, and MDA. | MDA, cTnl ↓; SOD ↑. The SBP, MBP, and DBP values and HR were significantly improved in group IV compared with any other groups. | [198] |
Xinyue capsule | CAD | A randomized, double-blind, controlled clinical trial involving 1054 CAD patients undergoing PCI. Conventional treatment and Xinyue capsule (100 mg/day). 24 weeks. Monitoring ADRs during trials. | Xinyue capsule added on conventional treatment reduced the incidence of cardiac death, nonfatal myocardial infarction, and urgent revascularization. | [199] |
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
TfR | Transferrin Receptor | Akt | protein kinase B |
FTH1 | Ferritin Heavy Chain 1 | LC3II | light chain 3II |
IRP1 | Iron Regulatory Protein 1 | Atg | autophagy-related gene |
Bcl-2 | B cell leukemia-2 | caspase | Cysteine-aspartic protease |
NOS | Nitric Oxide Synthase | Mdm2 | Mouse double minute 2 homolog |
GSH | glutathione | CK | creatine kinase |
SOD | superoxide dismutase | LDH | lactate dehydrogenase |
ATP | adenosine triphosphate | GPx | glutathione peroxidase |
eNOS | endothelial nitric oxide synthase | HO-1 | heme oxygenase 1 |
PI3K | phosphatidylinositol 3-kinase | AST | aspartate transaminase |
TGF-β | transforming growth factor-β | COL-IV | Collagen Type IV |
VEGF | Vascular Endothelial Growth Factor | MPO | Myeloperoxidase |
TNF-α | tumor necrosis factor-α | G-CSF | Granulocyte Colony-Stimulating Factor |
MMP | Matrix Metalloproteinases | GDH | Glutamate Dehydrogenase |
α-SMA | α-Smooth Muscle Actin | TLR4 | Toll-like receptor 4 |
FAK | Focal Adhesion Kinase | SIRT1 | sirtuin 1 |
p62 | ubiquitin-binding protein p62 | A20 | A20 Zinc Finger Protein |
GPX4 | Glutathione Peroxidase 4 | SIRT3 | sirtuin 3 |
ANP | atrial natriuretic peptide | MyHc | myosin heavy chain |
β-MHC | β-myosin heavy chain | 4-HNE | 4-Hydroxy-2-nonenal |
GSSG | Glutathione disulfide | Cyt-c | cytochrome c |
NF-κB | Nuclear Factor-Kappa B | Col | Collagen type |
PARP | Poly (ADP—Ribose) Polymerase | LC3 | light chain 3 |
JNK | c-Jun N-terminal Kinase | MFN2 | Mitofusin 2 |
AP-1 | Activator Protein-1 | Collagen I | Collagen Type I |
PINK1 | PTEN induced putative kinase 1 | NOX | NADPH oxidase |
GSK-3β | Glycogen synthase kinase 3β | ER | Estrogen Receptor |
ARE | Antioxidant Response Element | ERK | Extracellular Signal-Regulated Kinases |
RhoA | Ras homolog gene family, member A | MIP-1δ | Macrophage Inflammatory Protein-1δ |
Bax | Bcl-2-associated X apoptosis regulator | H-keap1 | kelch-like ECH-associated protein 1 |
ICAM-1 | Intercellular Adhesion Molecule-1 | Bad | Bcl-2 associated death promoter |
VPS | Vacuolar protein sorting 34 | HIF-1α | Hypoxia-Inducible Factor-1α |
MAPK | Mitogen-Activated Protein Kinase | Smad 2/3 | Mothers against decapentaplegic homolog 2/3 |
Ras | Rat sarcoma virus oncogene homolog | EHA | European Hematology Association Guidelines |
NIX | Nip3—like protein X | FUNDC1 | FUN14 Domain—containing 1 |
SLC7A11 | Solute Carrier Family 7 Member 11 | FIP200 | 200—kDa FAK—family interacting protein |
COL1A1 | Collagen Type I Alpha 1 Chain | ATG14L | Autophagy—related 14 |
FADD | Fas—associated death domain protein | SLC7A11 | Solute Carrier Family 7 Member 11 |
mTOR | mechanistic target of rapamycin | ETC | Electron Transport Chain |
DMT1 | Divalent Metal Transporter 1 | FPN | Ferroportin |
PUMA | p53—upregulated modulator of apoptosis | BNIP3 | Bcl—2/adenovirus E1B 19kDa—interacting protein 3 |
ESC | European Society of Cardiology Guidelines | PGC-1α | Peroxisome proliferator-activated receptor gamma coactivator 1α |
TRADD | Tumor Necrosis Factor Receptor 1—associated Death Domain protein | ABCB1 | ATP—Binding Cassette Sub—family B Member 1 |
Nrf2 | nuclear factor erythroid 2-related factor 2 | AMPK | adenosine monophosphate-activated protein kinase |
NLRP3 | NOD-like receptor protein-3 GSDME:Gasdermin E | ASC | Apoptosis-associated speck-like protein containing a CARD |
ROCK | Rho-associated coiled-coil containing protein kinase | NOXA | Novel Oxidation—inducible protein in Astrocytes |
NADPH | Nicotinamide Adenine Dinucleotide Phosphate Hydrogen | CSCO | Chinese Society of Clinical Oncology Guidelines |
SERCA | Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase | LOX-1 | Lectin-like Oxidized Low-Density Lipoprotein Receptor-1 |
Apaf1 | Apoptotic Peptidase Activating Factor 1 | ULK1 | unc—51 like autophagy activating kinase 1 |
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Class | -OR of Points | Representative Ginsenosides | |
---|---|---|---|
Dammarane type | Protopanaxadiol (PPD) | C3; C20 | C-K, Rd, Rg3, Rb, Ra1, Ra2, Ra3, Rb, Rc, Rd, Rg3, Rh1, Rh2, Rh3, Rh4, F2 |
Protopanaxatriol (PPT) | C6; C20 | Re, Rf, F1, F3, F4, F5, Rg1, Rg2, Rh1, notoginsenoside R1 | |
Ocotillol type | C24; C20 | ginsenoside R2, notoginsenoside R1, pseudoginsenoside F11 Makonoside-Rs | |
Oleanolic acid type | Ro, Ri |
Animal Model | Treatment Protocol | Autophagy Marker Change | Effects of Autophagy Targeting | Reference |
---|---|---|---|---|
Male C57BL/6 mice. 8–10 weeks old. DOX 20 mg/kg i.p. weekly. | Gavage administration of Rb1 (40 mg/kg/day). | LC3-I, p62 ↓. | Inhibiting autophagy | [116,122] |
H/R treatment, H9c2 cardiomyocytes | Rg1 (100 μmol/L), 24 h. | LC3-II, Beclin-1, p62 ↓, inhibiting AMPK pathway. | Inhibiting autophagy | [123] |
Male rats weighing 280–320 g. Balloon-injury. | Gavage administration of Re 12.5/25 mg/kg, 2 weeks. | ERK1/2, LC3-I, p62 ↓ | Inhibiting autophagy | [124] |
Mouse primary peritoneal macrophages. ox-LDL (100 μg/mL)–24 h. | Ox-LDL and 10/20/40/80 μM Rb1(24 h). | AMPK, LC3-II ↑; SQSTM1/p62 degradation. | Rb1 rescues autophagy flux, inducing autophagy. | [125] |
ICR male mice. Coronary artery ligation (CAL). | Rb1 6 mg/kg i.p. after 20 min of CAL. | PINK1,Parkin,LC3-II/LC3-I ↑, p62 ↓ to increase degradation. | Rb1 exerts cardioprotective functions through activation of mitophagy via AMPKα pathway. | [126] |
C57BL/6 male mice (9–11 weeks old). Left anterior descending coronary artery (LAD). 28 days. | Gavage administration of Rg1 (20 mg/kg). | LC3-II ↑, p62 ↓ GRg1 significantly increases SIRT1 expression and activates the PINK1/Parkin signaling pathway. | Rg1 enhances mitochondrial autophagy and alleviates HF. | [127] |
Male Sprague Dawley (SD) rats. The left anterior descending branch-ligated HF rat model. OGD/R H9c2 cell model. | Gavage administration of Rb2 (10 mg/kg, 20 mg/kg, daily for 3 days) | miR-216a-5p ↓, LC3B II/I, Beclin1 ↑. | Rb2 promotes autophagy treatment for HF. | [130] |
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Bai, R.; Zhao, Z.; Han, X.; Shang, M.; Liu, G.; Xu, F.; Cai, S. Therapeutic Potential of Ginsenosides in Anthracycline-Induced Cardiotoxicity. Molecules 2025, 30, 2527. https://doi.org/10.3390/molecules30122527
Bai R, Zhao Z, Han X, Shang M, Liu G, Xu F, Cai S. Therapeutic Potential of Ginsenosides in Anthracycline-Induced Cardiotoxicity. Molecules. 2025; 30(12):2527. https://doi.org/10.3390/molecules30122527
Chicago/Turabian StyleBai, Rongrong, Zhigao Zhao, Xing Han, Mingying Shang, Guangxue Liu, Feng Xu, and Shaoqing Cai. 2025. "Therapeutic Potential of Ginsenosides in Anthracycline-Induced Cardiotoxicity" Molecules 30, no. 12: 2527. https://doi.org/10.3390/molecules30122527
APA StyleBai, R., Zhao, Z., Han, X., Shang, M., Liu, G., Xu, F., & Cai, S. (2025). Therapeutic Potential of Ginsenosides in Anthracycline-Induced Cardiotoxicity. Molecules, 30(12), 2527. https://doi.org/10.3390/molecules30122527