Astragalin: A promising herbal compound with broad anticancer potential (Review)

Introduction

In the past decades, the application of certain new research methods and technologies have led to the proposal of new treatments for cancer, mainly neoadjuvant chemotherapy and targeted immunotherapy. Whilst they have often shown improved efficacy in the initial clinical application, they are associated with drug resistance and side effects (1). Therefore, seeking complementary and alternative treatments from traditional herbal medicine has become one new approach in the treatment of cancer. For example, astragalin has attracted widespread attention due to its wide availability, affordable cost, potent anticancer activity and high safety profile. Moreover, astragalin and its derivatives are considered to have definite cytotoxicity (2).

Astragalin, also known as kaempferol-3-O-glucoside (Fig. 1), is a flavonoid compound found in a number of medicinal plants such as Astragalus, Apocynum venetum leaves, Rosaceae, safflower, cassia seed and edible plants such as green tea, legumes, Allium ursinum and Allium victorialis (3). It has been reported to have anti-inflammatory (4), anti-glycemic, anti-adipogenic (5,6), antioxidant (7) and neuroprotective effects (8,9). Modern pharmacological studies have also reported that astragalin and its derivatives have several biological effects on the cardiovascular system (10,11), the endocrine system (12) and cancer (13,14). Furthermore, it has been reported to be associated with the inhibition of proliferation, migration and invasion of tumor cells, induction of apoptosis and inhibition of angiogenesis (3,15).

Figure 1. Molecular structural formula of astragalin. Astragalin is also known as kaempferol 3-O-β-D-glucoside, where kaempferol binds to a glucose unit at the 3-position hydroxyl group and exhibits typical flavonoid glycoside bioactivity. The figure was drawn using the KingDraw platform (version v3.6.5; http://www.kingdraw.com/).

Regarding the anticancer effects of astragalin, previous studies have reported effects of astragalin on specific cancers through in vitro and ex vivo experiments, or network pharmacological analyses (16–18). However, unlike previous literature reports on this topic, the present paper summarizes the anticancer effects of the natural compound Astragalin in several types of cancers, systematically outlining the specific mechanisms of the cancer-inhibiting effects of Astragalin, and suggesting future research directions for Astragalin. The present paper presents a comprehensive and systematic review of the mechanism of action of astragalin and its derivatives in several cancers, with an in-depth exploration to elucidate the potential and possibilities of astragalin for anticancer use. Table I summarizes the mechanism of action of astragalin on several cancers and Fig. 2 presents the specific types of anticancer mechanisms of astragalin.

Figure 2. Astragalin exerts anticancer effects through various mechanisms. The numbers shown for each type of cancer on the right correspond to the mechanism numbers shown on the left. The figure was drawn using Figdraw (version 2.0; http://www.figdraw.com/static/index.html#/).

Table I. Biological effects of astragalin and its derivatives on several cancers.

Table I.

Biological effects of astragalin and its derivatives on several cancers.

A, Lung cancer
Agent	Concentration	Time	Research type	Cell lines/animal	Target	Mechanism	First author/s, year (Refs.)
Astragalin	0, 2.5, 5, 10,	6, 12, 18	In vitro	A549 and	Caspase-3 upregulated, caspase-9	Inhibits cell growth and	Chen et al, 2017 (29)
	20, 40 µg/ml	and 24 h		H1299 cells	upregulated, PI3K downregulated,	promotes apoptosis
	20 or 50 mg/kg	21 days	In vivo	Athymic nude	AKT downregulated, NF-κB	Suppressed tumor growth
				mice	downregulated and Fas downregulated
	0–500 µg/ml	48 h	In vitro	A549 and	p38 MAPK upregulated, caspase-3	Inhibits proliferation,	Jia et al, 2021 (25)
				SCLC-H466	upregulated, caspase-9 upregulated,	induces apoptosis and
				cells	Bax upregulated, Nrf2 downregulated,	non-cytotoxic to normal
					NQO1 downregulated, Bcl-2 down-	cells
					regulated and SOD downregulated
	0, 5, 25, 75 and	12 and	In vitro	A549 cells	Caspase-3 upregulated, caspase-9	Inhibits cell migration,	Xu et al, 2021 (26)
	150 µM	24 h			upregulated, Bax upregulated, Bak	invasion and induces
					upregulated, XIAP downregulated	apoptosis
					and Bcl-xL downregulated
	151×10−3 g/l	24 h	In vitro	A549 cells	Caspase-3 upregulated	Induction of apoptosis	Ribeiro et al, 2021 (33)
B, Ovarian cancer
Agent	Concentration	Time	Research type	Cell lines/animal	Target	Mechanism	First author/s, year (Refs.)
Astragalin	20 and	8 days	In vivo	APP/PS1 mice	LC3BII/LC3BI upregulated, Beclin-1	Reversal of autophagy	Yang et al, 2023 (45)
	40 mg/kg				upregulated, ATG5 upregulated,	or autophagic flux
					ATG12 upregulated, LAMP-1	dysfunction
					upregulated and p62 downregulated
	100 µM	24 h	In vitro	OVCAR-8 and	HIF-1α downregulated, PCNA down-	Inhibition of glycolytic	Song and Fu, 2018 (38)
				SKOV3 cells	regulated, MMP-2 downregulated	pathways, proliferation	and
					and MMP-9 downregulated	and invasion in ovarian	Song and Fu, 2019 (39)
						cancer cells
C, Gastric cancer
Agent	Concentration	Time	Research type	Cell lines/animal	Target	Mechanism	First author/s, year (Refs.)
Astragalin	-	-	In vitro	HGC-27 cells	Bax upregulated, Bad upregulated,	Inhibits cell proliferation,	Chu et al, 2022 (59)
					PI3K downregulated and AKT	induces apoptosis, and
					downregulated	blocks the cell cycle
	0, 20, 40 and	12 h	In vitro	MGC-803,	Bcl-2 downregulated, Bim	Inhibits cell proliferation	Wang et al, 2021 (17)
	80 µM			HGC-27,	upregulated, PI3K downregulated	and migration, induces
				MKN28 cells	and AKT downregulated	apoptosis
	25 and	21 days	In vivo	Xenograft mouse		Reduce tumor size and
	50 mg/kg					inhibit tumor growth
	80 and 160 µM	24 h	In vitro	AGS cells	ppGalNAcT2 downregulated,	Weakens cell viability	Radziejewska et al,
					C1GalT1 downregulated and NF-κB	and induces apoptosis	2022 (58)
					downregulated
	151×10−3 g/l	24 h	In vitro	AGS cells	Caspase-3 upregulated	Induction of apoptosis	Ribeiro et al, 2021 (33)
D, Colorectal cancer
Agent	Concentration	Time	Research type	Cell lines/animal	Target	Mechanism	First author/s, year (Refs.)
Astragalin	20, 40 and	4, 8, 24, 48	In vitro	HCT116 cells	Caspase-3 upregulated, caspase-9	Inhibits cell growth,	Yang et al, 2021 (16)
	80 µg/ml	and 72 h			upregulated, Bax upregulated, p53	migration and
					upregulated, G0/G1 upregulated, CDK2	proliferation, induces
					downregulated, CDK4 downregulated,	apoptosis, induces cell
					TNF-α downregulated and NF-κB	cycle arrest and inhibits
						transcription
	0, 25, 50 or	18 days	In vivo	Xenograft nude	P65 downregulated	Reduce the size and
	75 mg/kg			mouse		volume of the tumor
	25–250 µg/ml	48 h	In vitro	LS180 cells	Caspase-8 upregulated, Bax up-	Inhibits cell proliferation	Augustynowicz et al,
					regulated; MAPK downregulated,	and metabolic activity,	2022 (68)
					p53 downregulated, PI3K-AKT	and induces apoptosis
					downregulated and TGF-β
					downregulated
	0, 15.63, 31.25	24 h	In vitro	HCT-116 and	mTOR downregulated, PI3K down-	Inhibits cell cloning and	Zhai et al, 2022 (69)
	and 62.5 µg/ml			HT-29 cells	regulated and AKT downregulated	promotes apoptosis
	120 mg/kg	22 days	In vivo	HCT-116		Delays tumor growth
				xenograft nude
				mice
	0, 1, 5, 10, 25	24 and 48 h	In vitro	HCT-116 cells	NF-κB downregulated, AKT	Inhibits cell growth and	Tragulpakseerojn et al,
	and 50 µg/ml				downregulated and ERK1/2	proliferation	2017 (70)
					downregulated
E, Breast cancer
Agent	Concentration	Time	Research type	Cell lines/animal	Target	Mechanism	First author/s, year (Refs.)
Astragalin	20 and	24 h	In vitro	MDA-MB-231	GLUT-1 downregulated, LDH-A	Inhibits aerobic glycolysis	Zeb et al, 2024 (77)
	40 µg/ml			cells	downregulated, HK-2 downregulated,	and cell proliferation
					mTOR downregulated and AMPK
					upregulated
	5 and 10 µg/ml	8 h	In vitro	MDA-MB-231	MMP-9 downregulated and NF-κB	Inhibits cell invasion and	Ahn et al, 2019 (82) and
				cells	downregulated	reduces cell metastasis	Shin et al, 2016 (83)
	10 mg/kg	8 days	In vivo	Balb/c mice		Inhibition of cellular lung
						metastasis
F, Kidney cancer
Agent	Concentration	Time	Research type	Cell lines/animal	Target	Mechanism	First author/s, year (Refs.)
Astragalin	10, 20 and	24 h	In vitro	A498 cells	Caspase 3 upregulated, caspase 9	Inhibits cell growth,	Zhu et al, 2019 (89)
	40 µM				upregulated, Bax upregulated, Bcl-2	induces apoptosis and
					downregulated, G2/M upregulated	blocks the cell cycle
					and miR-203 upregulated
G, Melanoma
Agent	Concentration	Time	Research type	Cell lines/animal	Target	Mechanism	First author/s, year (Refs.)
Astragalin	0, 25, 50, and	24, 48, and	In vitro	A375P and	Caspase 3 upregulated, caspase 9 up-	Inhibits cell growth and	You et al, 2017 (96)
	100 µM	72 h		SK-MEL-2 cells	regulated, Bax upregulated, cyclin D1	induces apoptosis
					downregulated, Mcl-1 downregulated
					and SOX10 downregulated
H, Prostate cancer
Agent	Concentration	Time	Research type	Cell lines/animal	Target	Mechanism	First author/s, year (Refs.)
Astragalin	200, 400 and	21 days	In vivo	Xenograft mice	G0/G1 upregulated, p38 MAPK	Inhibits tumor growth and	Kim et al, 2023 (104)
	800 mg/kg				upregulated, MMP-9 downregulated,	reduces tumor weight
					CDK4 downregulated, cyclin D1
					downregulated and cyclin E
	0, 200, 400 and	24 h	In vitro	DU145 and	downregulated	Induces cell cycle arrest
	800 µg/ml			LNCaP cells		and inhibits cell pro-
						liferation and migration
	0–200 µg/ml	24 h	In vitro	DU-145 cells	Caspase 3 upregulated, caspase 8 up-	Destroys organelles,	Koyuncu et al,
					regulated, caspase 9 upregulated, TP53	inhibits cell proliferation	2024 (103)
					upregulated and Bax upregulated	and promotes cell death
I, Liver cancer
Agent	Concentration	Time	Research type	Cell lines/animal	Target	Mechanism	First author/s, year (Refs.)
Astragalin	0, 11 and 33 µM	24, 48 and	In vitro	HCC cells	miR-125b upregulated, HK-2	Inhibits cell proliferation	Li et al, 2017 (109)
		72 h			downregulated and ROS upregulated	and induces cell cycle
						arrest and apoptosis
	0, 10 and	0, 5, 10, 15	in vivo	Nude mice		Inhibits tumor growth,
	20 mg/kg	and 20 days				Inhibits tumor cell
						proliferation in vivo
	5–100 µg/ml	22 h	In vitro	HepG2 and	Bcl-2 downregulated	Inhibits cell viability and	Pirvu et al, 2018 (111)
				L-929 cells		resists cell proliferation
	10–100 µg/ml	24 and 48 h	In vitro	HepG2 cells	TC downregulated, ROS down-	Reduces cell viability,	Zhou et al, 2024 (113)
					regulated, SOD upregulated, GSH,	regulates redox, regulates
					upregulated PI3K upregulated and	cellular glucose and lipid
					p-AKT upregulated	metabolism, and improves
						insulin resistance
J, Leukemia
Agent	Concentration	Time	Research type	Cell lines/animal	Target	Mechanism	First author/s, year (Refs.)
Heptaacetyl	0, 3, 10, 30 and	0, 6, 12 and	In vitro	HL-60 cells	Caspase 3 upregulated, Bcl-2	Inhibition of cell pro-	Burmistrova et al,
derivative of	100 µM	24 h			downregulated, Bax upregulated,	liferation and induction	2011 (117)
astragalin					ERK1/2 upregulated and JNK/SAPK	of apoptosis
					upregulated
K, Neuroblastoma
Agent	Concentration	Time	Research type	Cell lines/animal	Target	Mechanism	First author/s, year (Refs.)
Astragalin	25, 50, 100 and	24 h	In vitro	SK-N-SH cells	MAPK downregulated, ROS down-	Reduces oxidative stress,	Chung et al, 2016 (128)
	200 µg/ml				regulated, HO-1 upregulated, CAT	exerts neuroprotective
					upregulated and SOD2 upregulated	effects and induces
						apoptosis in tumor cells
L, Diffuse large B-cell lymphoma
Agent	Concentration	Time	Research type	Cell lines/animal	Target	Mechanism	First author/s, year (Refs.)
Astragalin	0, 1, 5, 25 and	0, 24, 48	In vitro	OCI-LY8 cells	p53 upregulated, caspase-3	Inhibits cell viability,	Lu et al, 2017 (143)
	125 µg/l	and 72 h			upregulated, Bax upregulated, Bcl-2	inhibits cell growth and
					downregulated, JAK1 downregulated, JAK2-downregulated and STAT3 downregulated	induces apoptosis

[i] Bcl-2, B-cell lymphoma-2; Nrf2, nuclear factor erythroid 2-related factor 2; NQO1, NAD (P)H quinone dehydrogenase 1; SOD, super oxide dismutase; Bak, BCL2-antagonist/killer; XIAP, X-linked inhibitor of apoptosis protein; ATG5, recombinant autophagy related protein 5; ATG12, recombinant autophagy related protein 12; LAMP-1, lysosomal associated membrane protein 1; p62, sequestosome 1; HIF-1α, hypoxia inducible factor-1α; PCNA, proliferating cell nuclear antigen; MMP, matrix metalloproteinase; GLUT-1, glucose transporter protein 1; LDH-A, lactate dehydrogenase A; HK-2, hexokinase 2; Mcl-1, myeloid cell leukemia sequence 1; ROS, reactive oxygen species; GSH, glutathione; HO-1, heme oxygenase 1; CAT, catalase; JAK, Janus kinase; STAT3, signal transducer and activator of transcription 3; AMPK, AMP-activated protein kinase; C1GalT1, core 1 synthase, glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1; miR, microRNA; p-, phosphorylated; SAPK, stress-activated protein kinase; TC, total cholesterol.

Search and selection criteria

The PubMed (https://pubmed.ncbi.nlm.nih.gov/.), Web of Science (https://www.webofscience.com/) and China Knowledge (https://www.cnki.net/) databases were used for data mining using the following search terms: [‘astragalin’ in the Mesh database (title/abstract) or all its synonyms (kaempferol-3-O-glucoside glycoside)] and [‘Neoplasms’ or all its synonyms (cancer) in the Mesh database (title/abstract)]. Articles published between the creation of the database and April 1, 2025, were imported into Zetero 6.0 (https://www.zotero.org/blog/zotero-6/). A total of 89 papers were obtained after removing duplicates.

The inclusion criteria were as follows: i) In vivo and in vitro experiments with astragalin in the treatment of different types of cancer; ii) preclinical trials of astragalin in different types of cancer; iii) clinical trials of astragalin combined with other drugs; and iv) clinical trials of astragalin for different types of cancer. Articles such as meta-analyses, reviews, abstracts, letters and case reports were not included in the present review. The exclusion criteria were as follows: i) Repeated literature and research; ii) irrelevant articles, defined as articles that did not examine the anticancer mechanism of astragalin; and iii) investigation of the anticancer mechanism of a complex that does not contain astragalin in its composition.

Astragalin and several cancers

Astragalin and lung cancer

Lung cancer poses a serious health and economic burden to the global population, with the number of new lung cancer cases expected to reach ~3.8 million by 2050 (19). Issues with current lung cancer treatment include high morbidity and mortality rates, late diagnosis, limited therapeutic options, restrictions on targeted therapies, economic and resource constraints, tumor heterogeneity and drug resistance (20), nutritional and quality of life issues (21), and research and clinical translational challenges (22). Therefore, the option of developing novel therapeutic agents with high safety margins may improve this situation.

Among the existing herbal medicine developments, astragalin is expected to be a safe and reliable novel ingredient due to its potent potency to inhibit the activity of lung cancer cells, impede cell migration, proliferation, invasion and induce apoptosis. Astragalin belongs to the class of lotus leaf flavonoids (LLF), and in vitro studies (23,24) have reported that high concentrations (500 µg/ml) of LLF can notably induce apoptosis in human lung cancer A549 cells (25). LLF increases the content of reactive oxygen species and the level of the oxidative end-product malondialdehyde, and at the same time, reduces superoxide dismutase activity. It upregulates several apoptotic factors including caspase-3 and caspase-9, and inhibits the expression of related factors [such as B-cell lymphoma-2 (Bcl-2) and nuclear factor erythroid 2-related factor 2], thereby achieving an anti-lung cancer effect (25). Astragalin acts on the JAK/STAT pathway to regulate the expression of apoptotic factors and related genes in a dose-dependent manner, causing damage to cellular DNA and augmenting reactive oxygen species to promote apoptosis and inhibit migration and invasion (26). Moreover, in vivo studies (27,28) have reported that astragalin may induce cell death via the aspartase, ERK-1/2, AKT and NF-κB signaling pathways, a process that may be associated with an increased Bax:Bcl-2 ratio (29). Network pharmacological studies (30,31) have also reported that astragalin treatment of lung adenocarcinoma may exert its unique inhibitory effects on cell proliferation, migration and apoptosis through the microRNA (miRNA/miR)-140-3p/3-phosphoinositide dependent protein kinase 1 axis (32). Finally, astragalin has been reported to act on the lung cancer A549 cell line with potent cytotoxicity, activating effector caspase-3 and inducing apoptosis (33).

Astragalin and ovarian cancer

In 2022, ovarian cancer was associated with ~3 million deaths worldwide (34). Whilst current standard treatment regimens have improved patient survival to a certain extent, overall survival remains low due to issues of drug resistance and relapse (35). For example, whilst offering hope for patients with breast cancer gene mutations, poly (ADP-ribose) polymerase inhibitors have limited efficacy, prolonging survival by only a few months, and are associated with resistance (36,37). This has led to the need for the research and development of new treatment modalities and novel drugs. In this process, the active components of traditional Chinese herbs have received attention.

Astragalin has been reported to inhibit cell proliferation and migration and induce apoptosis in ovarian cancer cells by regulating signaling pathways, affecting the expression of specific cytokines and inhibiting the glycolytic pathway. This effect is associated with the upregulation of prolyl hydroxylase domain-containing protein 2 (PHD2) expression and inhibition of hypoxia-inducible factor 1α (HIF-1α) (38,39). PHD2 can act as an oxygen sensor and improve perfusion and oxidization of tumor cells (40), and participates in the programming of macrophage glycolysis (41). HIF-1α is stabilized by binding to hypoxia-responsive element in the anaerobic state, activating key enzymes such as pyruvate dehydrogenase kinase 1 (PDK1) and pyruvate kinase type M2, and inhibiting the tricarboxylic acid cycle, thus shifting glucose metabolism from oxidative phosphorylation to anaerobic glycolysis (42–44). This metabolic reprogramming enhances cell survival. Astragalin inhibits the phosphorylation of related proteins, whereas 3-methyladenine or bafilomycin A1, which act as autophagy inhibitors, can reverse this process. Astragalin can also regulate cellular autophagy by targeting the PI3K/AKT/mTOR signaling pathway (45), a classic signaling pathway in ovarian cancer tumorigenesis, proliferation and progression (46). Thus, astragalin may exert its unique biological effects on ovarian cancer cells.

Astragalin and cervical cancer

Cervical cancer ranks second among malignant neoplastic diseases in women and has a high mortality rate (47). Due to the high resistance to platinum-based chemical drugs, this disease is now often treated with radiotherapy (48); however, this can cause damage to the mucosa of the vagina and urinary tract, which can affect patient quality of life (49). Therefore, it is necessary to explore new therapeutic methods with low toxicity and high safety.

It is conceivable that if astragalin is applied in conjunction with radiotherapy drugs, it may be able to exert neuroprotective effects locally, reduce the discomfort of vaginal and urinary tract mucosa, and improve the quality of life of patients. Astragalin inhibits cell proliferation and accelerates the process of apoptosis in cervical cancer cells by regulating signaling pathways and cellular oxygenation (50). Network pharmacological analysis has reported that, in HeLa cells, astragalin can exert regulatory effects on signaling proteins such as EGFR, STAT3 and cyclin D1, affecting the ErbB and forkhead box protein O signaling pathways. This induces an increase in reactive oxygen species and notably inhibits the proliferation and promoting apoptosis in a manner that is linearly associated with concentration (51). Moreover, astragalin, has been reported to exhibit clear anti-cervical cancer activity (52).

Astragalin and gastric cancer

Gastric cancer is a great challenge to global public health with the fifth highest global incidence rate, the third highest mortality rate and a high rate of metastasis (53). The molecular and phenotypic heterogeneity of gastric cancer is particularly high (54), and >70% of patients with gastric cancer are diagnosed at an intermediate-to-advanced stage, missing the optimal time for treatment, with limited efficacy of chemotherapy, targeted therapies and immunotherapy, and issues of drug resistance and side effects (55,56).

Astragalin has been reported to act as a gastroprotective component (57), demonstrating satisfactory results in inhibiting gastric cancer cell activity and suppressing cell proliferation (58,59). Astragalin may be used in the treatment of undifferentiated gastric cancer as it can inhibit the EGFR/PDK/AKT signaling pathway, arrest the cell cycle at pre-G1 stage, induce apoptosis by upregulating the transcription of BAX and BAD genes whilst downregulating PDK1 and BCL-2, and reduce the expression of PI3K and AKT proteins (59). Astragalin inhibits the PI3K/AKT signaling pathway and induces an increase in the level of apoptosis-related proteins, thereby effectively suppressing the viability of gastric cancer cells and inhibiting the escape of cancer cells (17). The inhibitory effect of astragalin on mucin 1 mRNA was reported to be the strongest among the related proteins, reducing the expression of ppGalNAcT2 mRNA and fucosyltransferase 4 mRNA, and controlling tumor growth and proliferation (58). Similar to in lung cancer A549 cells, astragalin can also act on the gastric cancer AGS cell line through the same mechanism of action (33). Persistent Helicobacter pylori infection is also associated with the development of gastric cancer (60), and astragalin has been reported to bind to potential protein targets and exhibit unique antibacterial activity, preventing gastric cancer by eradicating persistent infection by this bacterium (61).

Astragalin and colorectal cancer

In 2022, the global number of colorectal cancer deaths was ~900,000 (34,62). Conventional treatments have limited success in advanced or metastatic colorectal cancer, and chemotherapeutic agents such as 5-fluorouracil, oxaliplatin and irinotecan are widely used but have notable side effects (63). Advanced technologies and new therapeutic ideas [including targeted drugs, immunotherapy and nanotechnology (64,65)] are not yet available for clinical treatment (66). However, herbs may exert anticancer effects by affecting the intestinal flora and improving the intestinal microenvironment (67). For example, astragalin may weaken the activity of colorectal cancer cells, inhibit their proliferation and induce apoptosis through several mechanisms (16,68).

In vitro and in vivo studies have reported that astragalin targets the NF-κB pathway in a dose-dependent manner to reduce the number of colorectal cancer cells, inhibit their growth, induce apoptosis and block their escape (16,27). Its molecular mechanism includes the following: Increasing the level of pro-apoptotic protein factors caspase 6, 7 and 8, whilst inhibiting the expression of Bcl-2; and inhibiting the concentration of CDK2, CDK4 and cell cycle protein D1, increasing the concentration of P21 and P27, so as to cause stalling of the cell growth cycle and promote the cell death (16). Previous research reported that with increasing time and astragalin concentration, the value-added rate and IC50 value of HCT116 cells decreased (16). Moreover, the ability of astragalin to disrupt cell membranes is proportional to its concentration (68). Molecular docking experiments have also reported that astragalin has a high affinity for amino acid targets in the PI3K/AKT/mTOR pathway and is able to retard the growth of cancer foci (69). Novel biological silver nanoparticles combined with astragalin can precisely target carbonic anhydrase IX enzyme and promote anticancer activity (14). Furthermore, the antiproliferative activity of astragalin may be associated with the inhibition of ERK1/2 phosphorylation (70).

Astragalin and breast cancer

In 2022, there were ~2 million women with breast cancer worldwide (34). Moreover, the incidence of male breast cancer is increasing every year by an average of 1.1% per year, which has been associated with unregulated levels of estrogen receptors (71). Chemotherapy, radiotherapy and endocrine therapy, although effective, are often accompanied by serious side effects, such as nausea, vomiting and bone marrow suppression (72–74). In addition, issues such as lymphoedema and chronic arm complications after breast cancer treatment also seriously affect patient quality of life (75).

Astragalin inhibits the activity of the drug metabolizing enzyme cytochrome P450 family 1 subfamily B member 1 and, in vivo, it inhibits estradiolation to produce the carcinogenic metabolite 4-hydroxy-estradiol (76). Furthermore, astragalin inhibits breast cancer cell activity and proliferation and angiogenesis (18,77). Astragalin can act on AKT, zinc finger E-box binding homeobox 1, VEGF and matrix metallopeptidase (MMP)9 targets to inhibit cell motility and exert anti-angiogenic effects (18). It downregulates the protein expression levels of glucose transporter protein (GLUT)-1, lactate dehydrogenase A and hexokinase 2, activates AMP-activated protein kinase (AMPK) and inhibits mTOR activity, reduces glucose uptake, inhibits glycolysis, and inhibits cell proliferation through the AMPK/mTOR pathway (77). Activation of the estrogen receptor is associated with the development of >50% of invasive breast cancers (78), and astragalin, which exerts therapeutic effects comparable with those of hormones with a high margin of safety, may offer new hope for clinical application (79). Moreover, astragalin may mainly interact with human estrogen receptor α receptors to exert anticancer effects (80), and it can also bind to human epidermal growth factor receptor-2 (HER2) and become a potential inhibitor of HER2 (81). Astragalin may also be an effective therapeutic agent for metastasized advanced breast cancer, and this biological effect may be achieved by reducing the expression of TNF-α, which impairs the expression of MMP-9 (82,83).

Astragalin and kidney cancer

The incidence and mortality of renal cell carcinoma is increasing annually (84). By contrast, conventional therapies including surgery, ablation and radiation face notable challenges, including more extensive surgery, nephrotoxicity and suboptimal therapeutic range (85). Patients undergoing kidney transplant have a markedly increased risk of new cancers due to the use of potent immunosuppressants (86). Furthermore, dysregulated miRNA expression is associated with cancer cell emergence, growth and cellular drug resistance (87). As a renoprotective drug (88), lower doses of astragalin have been reported to upregulate miRNAs in renal cancer cells to impede tumor cell growth, affect the cell cycle and promote apoptosis in renal cancer cells (89). Previous research reported that 20–50 µM astragalin was cytotoxic to all renal cancer cells, especially the A498 cell line, and the therapeutic index value of astragalin treatment for renal cancer was high. It upregulated the RNA levels of tumor suppressor genes, causing cancer cells to stagnate at the G2/M stage. It also upregulated the expression of apoptotic proteins and inhibited the colony formation of renal cancer cells, which was positively associated with the dosage of astragalin (89).

Astragalin and melanoma

Melanoma is an aggressive metastatic cancer, with a 5-year survival rate of only 4.6% (90). Global melanoma incidence and mortality in 2040 will be >150% of what it was in 2020 (91). In recent years, immunotherapy and targeted therapies have achieved a certain degree of efficacy as the first-line recommended drugs (92); however, there is a substantial risk of toxicity and drug resistance (93).

Astragalin is cytotoxic and capable of inducing apoptosis. Mitogen- and stress-activated protein kinase 1 (MSK1) is an enzyme involved in several cancer processes, and in melanoma, high levels of MSK1 are often accompanied by high expression of CREB, and increased activity of the MSK1-CREB pathway promotes cell proliferation and metastasis (94). Astragalin directly binds to and inhibits p38 MAPK activity, antagonizing MSK1 phosphorylation and high levels of γ-H2AX in a time- and dose-dependent manner, thereby reducing precancerous skin lesions (95). Astragalin has also been reported to exert toxic effects on melanocytic tumor A375P and SK-MEL-2 cells, increasing the levels of positive cells and sub-G1 populations, activating cleaved poly(ADP-ribose) polymerase, inhibiting SRY-box transcription factor 10 signaling, acting on cell cycle-related proteins and promoting apoptosis (96). Moreover, astragalin has been reported to upregulate the expression of superoxide dismutase and exhibit skin protection effects (97).

Astragalin and prostate cancer

Prostate cancer ranks second among malignancies in men (34), and it has a high degree of homogeneous lesion heterogeneity, with common point mutations in <30% of the same surgically resected specimen (98). Androgen deprivation therapy is widely used in metastatic hormone-sensitive prostate cancer and improves the quality of life of patients with advanced disease; however, it also affects their cardiovascular health (99). With disease progression, it can further develop into metastatic castration resistant prostate cancer (mCRPC). Docetaxel can prolong the overall survival of patients with mCRPC (100); however, adverse effects, such as neutropenia and neurotoxicity, can occur (101,102).

Astragalin has been reported to have notable biological effects for the treatment of prostate cancer by inhibiting cell proliferation, migration and invasion, and inducing apoptosis (103). Astragaloside, the most abundant component of Cyperus exaltatus var. iwasakii (CE) secondary metabolites, modulates transcription factors and inhibits the expression of MMP-9, thereby inhibiting invasion, migration and proliferation of prostate cancer cells. In vivo studies have also reported that in an allogeneic model, CE inhibits tumor loading (104). Moreover, Jurinea mesopotamica Hand.-Mazz. contains high levels of astragalin, which can destroy cell organelles, promote the generation of reactive oxygen species, increase apoptotic gene expression and transcription, regulate energy metabolism, inhibit cell proliferation and induce cell death (103).

Astragalin and liver cancer

Liver cancer is a common primary cancer and a high-risk site for cancer metastasis (105). Emerging Yttrium 90 microsphere therapy has been reported to have notable efficacy in patients with advanced, non-surgical liver cancer (106); however, this method requires strict pre-operative screening, is relatively expensive and requires a high level of expertise to perform the surgery (107). By contrast, it is advantageous to explore the development of Traditional Chinese Medicine herbal active ingredients. For example, astragalin has been reported to inhibit the activity of hepatocellular carcinoma cells, suppressing their proliferation and inducing apoptosis through several mechanisms (108–110).

In vitro and in vivo experiments have reported that astragalin can promote miR-125b expression, inhibit hexokinase 2 and shrink allogeneic tumors. It can also promote the oxidative phosphorylation of hepatocellular carcinoma cells, reduce glycolysis, generate reactive oxygen species and antagonize apoptotic proteins to serve an anti-cell proliferation role (109,111). Previous research reported that astragalin reduced Bcl-2 levels, promoted Bax expression, cleaved caspase 3, 8 and 9, and exerted anti-hepatocellular carcinoma activity by regulating apoptosis pathway (110). Astragalin has also been reported to inhibit the activity of HepG2 cells (112), as well as serve as a potential complementary treatment for insulin resistance in patients with hepatocellular carcinoma. Its mechanism of action may include activation of insulin receptor substrate 1, PI3K and AKT, and the regulation of glycolipid metabolism and oxidative stress in cancer cells to a certain extent (113).

Astragalin derivatives and leukemia

With 58,903 deaths, China had the highest number of leukemia deaths in the world in 2021 (114). Personalized treatment approaches for leukemia have been developed; however, there are issues of treatment resistance, long-term side effects and quality of life (115). Several studies have reported that Chinese herbal medicine has satisfactory therapeutic effects on myelosuppression (116). For example, astragalin has been reported to inhibit growth and induce apoptosis in leukemia cells (117).

Certain researchers have isolated drug components with anticancer activity and clarified that astragalin is its main antileukemia component (118). The flavonoid derivative astragalin heptaacetate (AHA) can induce cell death through non-specific caspases. AHA has been reported to concentrate and cleave cell chromatin under aerobic conditions, block the cell cycle in the G0-G1 phase and affect the mitochondrial membrane potential. It also has been reported to regulate cytokine expression, activate MAPK, exhibit notable cytotoxicity and induce apoptosis at the organelle level (117).

Astragalin and neuroblastoma (NB)

The development of NB may be associated with the neural spine during embryonic development (119). The disease is highly malignant (120), with >50% of patients presenting with high-risk phenotypes (121) and a 5-year survival rate of <50% (122). The immune microenvironment of NB is complex, with low immunogenicity of tumor-associated antigens and immunosuppressive factors (such as TGF-β and IL-10), hindering the effectiveness of immunotherapy (123). Moreover, the high clinical behavioral heterogeneity of NB makes it more difficult to develop standardized treatment protocols (124,125).

Previous research has reported that mutations associated with the RAS/MAPK pathway are present in the majority of recurrent NBs (126,127). Astragalin exhibits biological effects on this pathway, inhibiting cell activity and inducing apoptosis (128). Furthermore, astragalin pretreatment reverses the cytoprotective effect, which is associated with the inhibition of oxidative stress and phosphorylation of MAPK, as shown by a reduction in the levels of extracellular protein-regulated protein kinases, p38 and c-Jun N-terminal kinase, exerting their cytotoxic effects and inducing apoptosis in NB SK-N-SH cells (128).

Astragalin and oral squamous cell carcinoma (OSCC)

Oral cavity cancer accounts for ~90% of oral malignancies (129). Risk factors for the disease include smoking, alcohol consumption and betel nut consumption (130), and human papillomavirus has also been reported to have an association (131). The disadvantages of traditional treatments include systemic damage, limited efficacy and drug resistance (132). Emerging therapies, such as transoral laser surgery and intensity modulated radiation therapy show potential; however, the popularization and application of these therapies still face technical and economic challenges (133,134). By contrast, herbal medicines have advantages in improving survival, enhancing immune function and reducing the toxicity of chemotherapy (135–137).

Research has demonstrated that the Chinese herbal formulation, FFBZL, composed of Scutellaria barbata D. Don, Astragalus membranaceus and Ligusticum chuanxiong Hort, may be used in the treatment of OSCC; therefore, its molecular mechanisms warrant in-depth exploration. As a crucial component, Astragalus membranaceus exhibits marked antitumor activity in laryngeal squamous cell carcinoma through its extract, total flavonoids of Astragalus, suggesting the potential of its active ingredients (138). Astragalin, one of the key active components of Astragalus membranaceus, currently lacks direct data demonstrating its inhibitory effect on OSCC; however, network pharmacology combined with bioinformatics analysis has revealed that six key ingredients of FFBZL (including components from Astragalus membranaceus) may interact with 820 potential target genes. These targets intersect with OSCC-related target genes, generating 151 common targets (139).

Astragalin and diffuse large B-cell lymphoma (DLBCL)

DLBCL is a common aggressive non-Hodgkin's lymphoma that accounts for 30–40% of all non-Hodgkin's lymphomas (140). The R-CHOP regimen (rituximab + cyclophosphamide + adriamycin + vincristine + prednisone) is the first-line standard of care for DLBCL. However, certain patients still relapse after treatment or transition to refractory cases (141).

Astragalin has been reported to induce apoptosis in DLBCL cells by modulating cytokines (142). A previous study reported that astragalin inhibits DLBCL OCI-LY8 cell viability and disrupts the nucleus to promote the emergence of apoptotic vesicles by affecting the JAK/STAT signaling pathway, upregulating the levels of p53, caspase-3 and Bax, and inhibiting Bcl-2 expression (142).

Discussion

Anticancer mechanisms

Astragalin has notable anticancer effects in several types of cancer. It also scavenges free radicals in the body (143). Furthermore, overexpression of GLUT5 has been reported to lead to marked changes in glucose metabolism and enhance glycolysis, which is a prominent manifestation of cancer cells. This protein is expected to be used as a biomarker for the diagnosis of cancer and as a therapeutic target (144). A derivative of astragalin, astragalin-6-glucoside, has been reported to inhibit GLUT5 (145). Certain studies suggest that it is associated with glycolysis; however, the exact mechanism of action is not clear (146).

Based on a review of the mechanisms of astragalin and its derivatives against several malignant tumors, the anticancer mechanisms of astragalin are summarized as follows: i) Regulation of signaling pathways: Astragalin can regulate the PI3K/AKT, MAPKs, JAK/STAT and NF-κB signaling pathways, miRNA expression and the Notch1 pathway (27,147), which inhibits tumor cell growth and survival (148); ii) induction of apoptosis: Astragalin can cause loss of caspase activity, mutation of p53 gene and imbalance in the regulation of Bcl2 protein, leading to reduced activity and programmed death of cancer cells (149). It also affects mitochondrial function, reduces mitochondrial membrane potential and increases the Bax/Bcl-2 ratio (150). Notably, a study reported that astragalin ameliorated testicular germ cell apoptosis in rats with varicocele by reducing the expression of caspase 3 and the Bax/Bcl-2 ratio (151). Moreover, astragalin reduced intracellular oxidative stress, activated caspase 3, 7 and 9, and promoted programmed cell death in cancer cells, whilst protecting normal cells from oxidative damage, suggesting that it has a dual effect on the human body (7); iii) inhibition of cell proliferation and migration: Astragalin is closely associated with several angiogenesis-related factors (such as prostaglandin-endoperoxide synthase 2, kinase insert domain receptor and MMP9), revealing potential biological effects with angiogenesis and suggesting new ideas for the treatment of tumors in terms of reducing the number of blood vessels (152). Astragalin downregulates the expression of specific protein factors, regulates miRNAs and induces cell cycle arrest (26); and iv) enhancement of drug sensitivity: In a previous study, astragalin was administered with carboplatin and cisplatin over a range of concentrations, and the results demonstrated that astragalin was associated with an improved combined effect in OVCAR-8 and SKOV-3 cells compared with carboplatin or cisplatin alone (39). This indicates that astragalin could enhance the accumulation of chemotherapeutic drugs in tumor cells and reverse resistance to chemotherapeutic drugs.

Advantages for cancer treatment

Astragalin has a wide range of advantages in cancer treatment, especially in the process of cooperating with chemotherapeutic drugs to reduce toxicity and increase efficiency.

Range of effects of astragalin

For different cancer types, astragalin has varied anticancer mechanisms of action, but there are also cross-overlapping mechanisms of effect. In general, they include reducing the growth activity of tumor cells, inhibiting tumor cell angiogenesis, inducing apoptosis, blocking the cell growth cycle, and reprogramming the metabolic process of tumor cells, affecting the proliferation, migration and invasion of tumor cells (58). Moreover, several studies have reported that astragalin does not cause harm to normal human cells (8,153).

Role of astragalin in cancer

Astragalin has shown promising results in different types of cancer. For example, radiotherapy may lead to neurotoxicity (154), cancer-caused fatigue (155) and gastrointestinal impairment, and other therapeutic adverse effects (156,157). However, previous research has suggested that if astragalin is used in combination with chemotherapeutic drugs, the neuroprotective, anti-inflammatory, antioxidant (158,159) and antibacterial effects of astragalin could assist the action of the chemotherapeutic drugs (160). Moreover, research has reported that astragalin is involved in targeting cellular resistance factors (89): It can enhance the accumulation of chemotherapeutic drugs in cells and increase the sensitivity of cells to the drugs, thus reversing cellular resistance (39). However, at present, there is a lack of direct research data on the application of astragalin and chemotherapeutic agents in other cancers. Based on the collection of existing literature, we hypothesize that astragalin can serve a direct inhibitory and blocking role in the growth and metabolism of tumor cells, hindering cell growth, proliferation, invasion and migration, and inducing apoptosis through several mechanisms. At the same time, we hypothesize that it can serve a unique toxicity-reducing and synergistic effect in the standardized radiotherapy process. This gives it the potential to be used as a complementary or alternative treatment to first-line chemotherapeutic agents.

Safety and cost-effectiveness

Absorption, distribution, metabolism, excretion and toxicity model predictions have reported that astragalin is not susceptible to acute hazards or systemic toxicity and, meeting drug safety requirements, may reduce accumulation toxicity to normal tissues through exocytosis mechanisms (153). In A549 lung cancer cells, astragalin had an IC50 of 150 µM (after 72 h treatment) and inhibited 85% of lung cancer cells; however, to the best of our knowledge, at this dose, there is no evidence of toxicity to normal lung bronchial epithelial cells and cell survival was markedly higher compared with that of cancer cells (26). Moreover, the IC50 was 20–50 µM in A498 renal carcinoma cells and ≤110 µM in normal renal cells, indicating that the toxicity to normal cells was notably lower than that to cancer cells (89). Additionally, the IC50 of astragalin-containing extract of Citrus × aurantium was 23.26 µg/ml in colon cancer HCT-116 cells; however, the toxicity in normal lung fibroblasts (WI-38) was low, with no marked IC50 value reported. This suggests that astragalin may have a selective effect on cancer and normal cells (161). Moreover, the aforementioned findings indicate that astragalin has a wide therapeutic window and exhibits notable anticancer activity with a high safety profile for normal cells.

In summary, astragalin has potent antitumor biological effects with little or no toxic effects on normal tissues; however, this needs to be supported by further evidence from numerous future clinical trials.

Shortcomings and prospects

Previous research reported that the absolute oral bioavailability of astragalin in rats was <5% (162). This is mainly due to its molecular structure (higher molecular weight and worse water solubility) (163) and its easy conversion by metabolic enzymes [such as uridine diphosphate-glucuronosyltransferases (UGTs)] in the liver and intestine, which is characterized by rapid absorption and clearance (8). However, improved processing or structural optimization may enhance gastric absorption and delay metabolism, thereby increasing bioavailability (164,165). UGT enzymes have been reported to be key metabolizing enzymes of astragalin in vivo. They include CtUGT3 (166) and AtUGT78D2 (167). Moreover, astragalin is distributed in several organs, with the highest concentration in the gastrointestinal tract. It can also cross the blood-brain barrier (168) and can be detected in the liver, lungs and kidneys (169). However, although there are studies that investigated the pharmacokinetics of astragalin (8,170,171), there is a lack of clinical pharmacokinetic validation, and the pharmacological properties of the metabolites, lower bioavailability and stability enhancement need to be further optimized.

Most of the literature included in the present review involved in vivo or in vitro experiments, which largely fail to provide a comprehensive and systematic picture of the drug effects of astragalin within the complex human environment when used in combination or alone. The lack of clinical data, drug metabolism and pharmacokinetics hinders the development of standardized therapeutic protocols for astragalin. Therefore, before the approval of the marketing of this Chinese medicine monomer and its use in large quantities in patients with cancer, several studies are needed: i) Further elucidation of the antitumor mechanism of astragalin through bioinformatics analyses and well-established cyberpharmacological studies; ii) several human studies on the antitumor effect of astragalin and determination of the standardized course of treatment and dosage; iii) exploration of the pharmacological and toxicological effects of astragalin and the possible adverse reactions; and iv) improvement of the description of the pharmacokinetic profile of astragalin. This will aid in the systematic investigation of the different targets of astragalin in several cancer types and promote the discovery and development of new drugs (Fig. 3). At the same time, treatment protocols that maximize anticancer effects should be assessed for different types of cancer to enhance efficacy and reduce toxic side effects. By analyzing the outcomes of treating different types of patients, the differences in the effects of astragalin on different types of cancers can be explored, and the treatment plan can be refined.

Figure 3. Future research directions of astragalin for cancer treatment. The figure was drawn using Figdraw (version 2.0; http://www.figdraw.com/static/index.html#/).

Therefore, future in-depth studies on astragalin should focus on the advancement of data on the real drug environment in the clinic, as well as data associated with drug metabolism pathways and pharmacokinetics in a standardized manner, with a view to providing an objective basis for the development of new drugs and the update of therapeutic regimens.

Summary

In the research of malignant tumors, the development and utilization of herbal medicines has become a major topic. The results of the present review indicate that astragalin, with its wide and natural sources, strong anticancer activity, high safety value and low cost, has potential to be an alternative drug with considerable efficacy in the prevention and treatment of malignant tumors; however, further research is required. Although astragalin has demonstrated promising antitumor effects, its pharmacokinetic profile is incompletely defined, and its low oral bioavailability limits its potential clinical application. Future studies should investigate the bioavailability of astragalin through systematic in vitro and animal experiments, and the optimization of formulation processes for novel drug delivery systems. With further research, astragalin has the potential to become an alternative drug for cancer treatment in the future.

Acknowledgements

Not applicable.

Funding

The present study was supported by the National Natural Science Foundation of China (grant no. 82274566).

Availability of data and materials

Not applicable.

Authors' contributions

YFZ retrieved the data and participated in the conceptualization and design of the article as well as the data analysis; YQF wrote the original manuscript and made several revisions with the assistance and editing of CL, DND and FYL. FJH was involved in the design of the manuscript and the interpretation of the data. Data authentication is not applicable. All authors contributed to the article and read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

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References