The antitumor mechanisms of glabridin and drug delivery strategies for enhancing its bioavailability

Abstract

Glabridin, a flavonoid derived from the plant Glycyrrhiza glabra, has garnered significant attention due to its diverse pharmacological effects, including antioxidant, antibacterial, anti-inflammatory, hypolipidemic, and hypoglycemic activities. Studies have shown that glabridin exhibits substantial antitumor activity by modulating the proliferation, apoptosis, metastasis, and invasion of cancer cells through the targeting of various signaling pathways, thus indicating its potential as a therapeutic agent for malignant tumors. To enhance its solubility, stability, and bioavailability, several drug delivery systems have been developed, including liposomes, cyclodextrin inclusion complexes, nanoparticles, and polymeric micelles. These de.livery systems have shown promise in preclinical studies but face challenges in clinical translation, such as issues with biocompatibility, delivery efficiency, and long-term stability. A comprehensive analysis of the antitumor mechanism of glabridin and its novel drug delivery system is still lacking. Therefore, the authors performed a comprehensive review of recent literature on the antitumor effects of glabridin and its novel drug delivery systems, covering the antitumor mechanism, action targets, and novel drug delivery systems, offering new theoretical insights and development directions for its further advancement and clinical application.

1 Introduction

The incidence of malignant tumors is increasing worldwide due to aging populations, environmental degradation, and lifestyle changes. There were close to 20 million new cases of cancer in the year 2022 alongside 9.7 million deaths from cancer. The estimates suggest that approximately one in five men or women develop cancer in a lifetime, whereas around one in nine men and one in 12 women die from it (1). Malignant tumors pose a severe threat to physical and mental health, as well as life safety, and are a leading cause of death (2). Surgery, radiotherapy, chemotherapy, immunotherapy, and gene-targeted therapies are commonly used to treat malignant tumors (3). Despite improvements in survival rates with these treatments, challenges such as recurrence, radiotherapy-related toxicity, and drug resistance remain. Therefore, identifying new, effective antitumor drugs and exploring their mechanisms is crucial for progress.

In recent years, Traditional Chinese Medicine (TCM) has gained recognition for its role in cancer treatment, with several anti-tumor compounds identified in traditional remedies (4–6). This underscores the substantial potential of TCM for anti-cancer development, warranting further investigation. Glabridin, a flavonoid extracted from the medicinal plant Glycyrrhiza glabra, pharmacological studies have demonstrated that, beyond its antioxidant (7), anti-inflammatory (8), osteoprotective (9), hypoglycemic (10), and neuroprotective effects (11, 12), glabridin also exhibits notable antitumor activity (13).

Compared with other anti-tumor compounds derived from Chinese herbal medicine, glabridin shows significant advantages. First, glabridin has a broad spectrum of pharmacological effects and is widely used in the food (14) and cosmetics (15) industries, in addition to the medical field, demonstrating considerable development potential. Second, from a pharmacokinetic perspective, some common anti-tumor compounds derived from traditional Chinese medicine, such as curcumin (16), baicalin (17), and quercetin (18), have poor water solubility, low absorption, low bioavailability, rapid metabolism, and high systemic clearance, which limits their therapeutic efficacy. Research has shown that glabridin undergoes primary metabolism via glucuronidation (19), with intestinal microsomes exhibiting only 1/15 to 1/20 of the metabolic capacity of liver microsomes, and circulates in the bloodstream primarily as glycoside conjugates, indicating a higher bioavailability compared to other flavonoids, such as quercetin (20). In addition, glabridin is broadly distributed across various tissues and is detectable in all tissues except the brain (21), suggesting its potential for therapeutic effects across multiple tissues. Studies have shown that glabridin’s binding affinity for the human estrogen receptor is comparable to genistein’s (the best-known phytoestrogen) (22) and that abnormally high estrogen levels are associated with an increased incidence of certain cancers (23), particularly breast cancer (24) and endometrial cancer (25). This suggests that glabridin has significant potential as a therapeutic agent for breast and endometrial cancer. In summary, the distinct characteristics and therapeutic advantages of glabridin suggest promising applications in anti-tumor therapies.

In recent years, several reviews have examined the pharmacological effects of glabridin and its derivatives (22, 26), with a primary focus on the common pharmacological mechanisms of glabridin’s action. However, reviews specifically addressing the unique molecular targets of glabridin in various cancer types and its integration with novel drug delivery systems are still lacking. Therefore, this review aims to examine the anticancer mechanisms, molecular targets, and novel drug delivery systems of glabridin, providing the latest advancements and comprehensive insights in the field of anti-malignant tumors and drug delivery, with the goal of offering a scientific basis for its further development and clinical application. For information on the types of cancers treated by glabridin, please refer to Figure 1.

Figure 1

2 Chemical properties of glabridin

Glabridin is a flavonoid primarily extracted from the root of Glycyrrhiza glabra, commonly known as licorice. It has a molecular formula of C₂₀H₂₀O₄ and a molecular weight of 324.37 g/mol. Glabridin appears as a pale yellow powder, insoluble in water but soluble in organic solvents such as ethanol, methanol, and acetone (27). Its structure features a flavone backbone with hydroxyl groups at the 7 and 4’ positions. The chemical structure of glabridin underpins its biological activities, including antioxidant and antitumor properties. Light exposure is the primary factor affecting the stability of glabridin. Additionally, interactions between temperature and pH, temperature and humidity, and light exposure and pH can further accelerate the degradation of glabridin (28). The chemical formula of glabridin is shown in Figure 2.

Figure 2

3 Pharmacokinetics of glabridin

Glabridin has poor water solubility, and low bioavailability, and is prone to isomerization under light, temperature, and humidity. Its pharmacological mechanism is not yet fully understood. Pharmacokinetic analysis of human oral metabolism experiments indicated that glabridin reached a maximum concentration of approximately 4 hours post-administration in blood, with a half-life (T1/2) of about 10 hours (29). In vivo studies show glabridin peaks at 87 nmol/L 1-hour post-administration, with a half-life (T1/2) of 8.2 hours and bioavailability (AUCinf) of 0.825 μM·h (20). Animal experiments have shown that glabridin has an oral bioavailability of 6.63% and a first-pass effect in the liver of 62.12% (21). Additionally, studies have identified several metabolic pathways for glabridin, including glucuronidation, demethylation, hydroxylation, and sulfation. Glabridin metabolites have been detected in various biological fluids and tissues, including plasma from the abdominal aorta and hepatic portal vein, as well as in the brain, liver, heart, lung, spleen, kidney, bile, urine, and feces (30). The high first-pass effect in the liver and extensive metabolism may account for the low oral bioavailability of glabridin. Therefore, enhancing the bioavailability of glabridin remains a pressing challenge.

4 Safety evaluation of glabridin

As research progresses, the safety of glabridin has increasingly become a focal point of investigation. There are no in vivo toxicity data on glabridin, but safety assessments exist for Licorice flavonoid oil (LFO), where glabridin is a major marker compound. LFO is marketed as Glavonoid and approved by the European Food Safety Authority as a novel food ingredient (13).

Fumiki Aoki et al. evaluated the clinical safety of LFO. Hematological and related biochemical indicators showed that LFO doses up to 1200 mg/day were safe and well tolerated over a 4-week period. Subsequent pharmacokinetic studies showed that LFO exhibited linear pharmacokinetics across doses ranging from 300 to 1200 mg per person (29).

Animal studies also demonstrate that LFO is highly safe. In an 8-week study involving LFO intervention in obese mice, there were no significant differences in the liver, kidney, and spleen weights between the treated and control groups, suggesting that glabridin is non-toxic (31).

Nakagawa et al. (32) conducted a 90-day oral toxicity study in rats using an LFO concentrate containing 2.9% glabridin. The results showed that the no-observed-adverse-effect level (NOAEL) was 800 mg/kg/day for female rats and 400 mg/kg/day for male rats. In addition, Nakagawa et al. (33) used three different methods to study the genotoxicity of LFO in another experiment. In the bacterial reverse mutation assay, using four strains of Salmonella typhimurium and Escherichia coli, LFO did not increase the number of colonies in any of the test strains. In the Chinese hamster lung (CHL/IU) cell chromosome aberration assay, only LFO at concentrations exceeding 0.6 mg/mL induced structural chromosomal aberrations in the short-term test, while LFO at lower concentrations did not cause chromosomal aberrations in mice. In the bone marrow micronucleus assay conducted on male F344 rats, doses up to 5000 mg/kg/day did not significantly increase the frequency of micronucleated polychromatic erythrocytes (MNPCE). Therefore, LFO demonstrates good tolerance and safety, with a low incidence of adverse reactions, making it suitable for long-term disease treatment.

It is important to note that, while glabridin is the primary marker compound of LFO, the current safety evaluation studies of LFO do not fully establish the safety of glabridin. Therefore, further animal studies are needed to clarify the metabolic pathway of glabridin and evaluate its safety in vivo. In preclinical studies, glabridin demonstrated good tolerability within a specific dose range, with no significant weight loss or organ toxicity. In a mouse model, doses of 10-20 mg/kg did not produce significant toxic effects and remained unchanged in liver and kidney function or hematological indicators (34–38). However, the potential chronic toxicity of glabridin with long-term use has not been fully assessed. In vitro experiments have shown that glabridin has significant inhibitory effects on cancer cells at concentrations of 10-100 μM and effectively induces apoptosis. Additionally, the IC50 values of glabridin vary across different cancer cell lines, indicating that its inhibitory effect is dose- and cell-type dependent. Future studies should further assess the long-term toxicity of glabridin, determine its maximum tolerated dose, and establish its safety margin through additional in vitro and in vivo experiments. Furthermore, potential interactions between glabridin and other drugs need to be thoroughly evaluated at the preclinical stage to prevent increased toxicity from drug interactions in combination therapies.

5 Glabridin anti-tumor mechanisms

5.1 Inhibition of tumor cell invasion and metastasis

Invasion and metastasis refer to the spread of tumor cells from the primary site to distant tissues or organs via lymph or blood circulation and are the leading causes of cancer-related deaths (39). The first-line treatment for metastatic tumors is systemic chemotherapy, which often causes severe side effects, such as organ failure and high infection rates (40). Therefore, discovering new methods to inhibit the invasion and metastasis of malignant tumor cells is of paramount importance in the fight against cancer. The mechanism of glabridin inhibition of tumor cell metastasis and invasion is shown in Figure 3.

Figure 3

5.1.1 Promotion of microRNA-148a signaling pathway

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and serve as cancer biomarkers. Studies show that miR-148a suppression is linked to metastasis in various tumors and upregulation of metastasis-related genes (41). Transforming growth factor-β (TGF-β) plays an important role in tissue and organ development, as well as cell proliferation, differentiation, and apoptosis. It can affect epithelial and endothelial cell differentiation, increase immune cell recruitment, and is an important cytokine involved in the activation of cancerous mesenchyme (42). Small mothers against decapentaplegic (SMAD) proteins are key proteins that conduct TGF-β signaling from cell surface receptors to the nucleus (43).

Jiang et al. found that glabridin significantly inhibited the adhesion-dependent growth and sphere formation of HepG2 and MHCC97H hepatocellular carcinoma cells (44). It increased miR-148a expression in a dose- and time-dependent manner, targeting TGF-β and SMAD protein activation, and reducing tumor cell invasion and metastasis. Another study showed that glabridin reduced miR-148a methylation and upregulated its expression in breast cancer cells, inhibiting the TGF-β/SMAD pathway and suppressing metastasis (34).

miR-148a significantly inhibits tumor cell invasion and metastasis by targeting the TGF-β/SMAD signaling pathway. However, the mechanisms of action of miR-148a across different cancer types have not been fully elucidated. miR-148a not only exerts its effects within cancer cells, but may also influence immune escape mechanisms by modulating immune responses in the tumor microenvironment (45). Whether glabridin can alter the tumor microenvironment by regulating miR-148a and thereby provide a new target for immunotherapy requires further investigation.

5.1.2 Blocking the epithelial-mesenchymal transition process

EMT is a crucial process involving the transformation of epithelial cells, which alters intercellular adhesion patterns and affects cell proliferation and differentiation. EMT is closely associated with embryonic development, tissue repair, and cancer progression (46). Aberrant activation of EMT is linked to malignant properties of tumor cells during cancer progression and metastasis, such as increased tumor cell migration and invasiveness, enhanced tumor stemness, and greater resistance to chemotherapy and immunotherapy (47). Therefore, targeting and blocking the EMT process is crucial for controlling tumor invasion and metastasis.

Glabridin inhibited the proliferation, migration, and invasion of lung adenocarcinoma cells A549 (35). Further studies revealed that glabridin decreased the expression of neural cadherin (N-cadherin) and vimentin, and upregulated the expression of epithelial cadherin (E-cadherin) in tumor cells. N-cadherin and vimentin are positively correlated with EMT and are considered its markers (48, 49), whereas E-cadherin acts as a tumor suppressor protein (50). Another study found that glabridin inhibited EMT in breast cancer cells by upregulating E-cadherin and occludin, while downregulating vimentin, E-box-binding zinc finger protein 1 (Zeb1), and other critical EMT markers, thereby exerting a controlling effect on tumor invasion and metastasis (36).

5.1.3 Inhibition of focal adhesion kinase/sarcoma receptor coactivator signaling pathway

FAK is a key signaling molecule involved in cell adhesion, migration, proliferation, and survival. Its overactivation in various cancers makes it an important target for developing new anti-cancer therapies (51). Src is a non-receptor tyrosine kinase that phosphorylates tyrosine residues on proteins. Unlike receptor tyrosine kinases, Src is not membrane-bound and acts at various intracellular sites, affecting many cellular processes. Src is often overactive in cancers, leading to uncontrolled cell proliferation, increased invasion and metastasis, and resistance to apoptosis (52). FAK typically forms a complex with Src, jointly regulating cell growth, survival, and motility. Aberrant activation of FAK/Src signaling is frequently observed in aggressive tumors (53).

Glabridin was found to inhibit the invasion and metastasis of human non-small cell lung cancer A549 cells (54). Studies have shown that glabridin inhibits lung cancer cell invasion and metastasis by reducing FAK and Src activities, leading to FAK/Src complex inactivation. Additionally, glabridin can suppress the invasion, metastasis, and angiogenesis of breast cancer cells through the FAK/Src pathway (55), the specific mechanism is that glabridin inhibits the migration and invasion of cancer cells by reducing the phosphorylation of key proteins. It also regulates cytoskeleton reorganization to prevent cell movement by inhibiting the Ras homolog family member A(RhoA)/Rho-associated coiled-coil containing protein kinase (ROCK) signaling pathway and reducing the phosphorylation of myosin light chain (MLC). In addition, glabridin directly inhibits the migration and tube formation of vascular endothelial cells, thereby effectively inhibiting angiogenesis. These multi-pathway effects suggest that glabridin has a strong potential to inhibit breast cancer invasion and metastasis.

The FAK/Src signaling pathway plays a crucial role in tumor cell migration, invasion, and metastasis. Glabridin exerts anti-metastatic effects in various tumors by inhibiting the activation of the FAK/Src complex. Since FAK/Src also plays a key role in tumor angiogenesis (56), future research should focus on the inhibition of tumor angiogenesis by glabridin through its effect on FAK/Src, to assess its novel potential as a therapeutic strategy.

5.1.4 Inhibition of matrix metalloproteinases family proteases

MMPs have been shown to play an important role in the abnormal proliferation, local invasion, and metastasis of tumor cells (57). They can degrade almost all protein components in the extracellular matrix (ECM), destroy the histological barrier to tumor cell invasion, and act as proteases that remodel the extracellular matrix, driving the cell invasion process (58).

Jie et al. (59) found that glabridin inhibits the invasion and migration of osteosarcoma cells. The specific mechanism involves down-regulating p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation, which affects the binding of cyclic adenosine monophosphate response element-binding protein-associated protein 1 (CREB-AP1) to the promoters of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), thereby inhibiting tumor cell migration and invasion. Another study found that glabridin inhibits melanoma cell proliferation and migration by reducing MMP-2 activity and expression (60). In a study involving glabridin intervention in liver cancer cells Huh7 and Sk-Hep-1, the relationship between glabridin’s regulation of MMPs and the inhibition of tumor cell invasion and migration was further verified (61). The results showed that glabridin downregulated MMP-9 by interfering with nuclear factor-κB (NF-κB) and AP-1 binding activity, ultimately inhibiting tumor cell invasion and metastasis. For detailed information, please refer to Table 1.

5.2 Induction of tumor cell apoptosis

Apoptosis is a mechanism that maintains tissue homeostasis by removing damaged cells through programmed cell death (62). Dysregulation of the apoptosis mechanism is a significant hallmark of cancer. Apoptosis affects tumor initiation, progression, and the development of drug resistance during cancer treatment. Therefore, inducing apoptosis is a crucial component in anti-tumor strategies (63). The mechanism of glabridin-induced tumor cell apoptosis is shown in Figure 4.

Figure 4

5.2.1 Inhibition of glycolysis

Energy metabolism disorders are regarded as one of the hallmarks of cancer (64). In tumor tissues, glycolysis is the main metabolic pathway for adenosine triphosphate (ATP) production. Cancer cells depend on metabolic reprogramming and transition to a “glycolytic” metabolic phenotype to sustain the energy necessary for proliferation (65, 66). Hexokinase-2 (HK-2) is the primary rate-limiting enzyme in glycolysis and a key regulator in the glucose metabolic pathway. HK-2 catalyzes the phosphorylation of glucose to produce glucose-6-phosphate (G-6-P) (67). Lactate dehydrogenase (LDH) is a crucial enzyme in glycolysis. LDH exists in three isoforms: Lactate dehydrogenase A (LDHA), Lactate dehydrogenase B (LDHB), and Lactate dehydrogenase C (LDHC). Among these, LDHA is the predominant isoform in various malignant tumors, including colon cancer, ovarian cancer, gastric cancer, and lung cancer (68). LDH catalyzes the conversion of pyruvate (PA) to lactic acid (LA), and elevated levels of lactic acid can lead to extracellular acidosis, which in turn promotes tumor cell invasion, angiogenesis, and metastasis (69).

Glabridin significantly inhibited the expression of glycolysis-related genes HK-2 and LDHA in melanoma cells, and reduced levels of lactate (LD) and ATP in the cell culture medium. Furthermore, animal studies demonstrated that glabridin intervention significantly slowed tumor tissue growth in mice, resulting in up-regulation of cellular Bax expression and down-regulation of B-cell lymphoma-2 (Bcl-2), HK-2, and LDHA expression in tumor tissues (37). During glycolysis, glucose transporter protein-1 (GLUT-1) is a key protein responsible for transporting glucose into the cell and maintaining the intracellular glucose concentration (70). Li et al. (71) found that glabridin significantly downregulated GLUT-1 expression and inhibited the glycolytic pathway in MDA-MB-231 breast cancer cells, regulating their energy metabolism. Therefore, the mechanism of apoptosis induced by glabridin may be related to its regulation of the expression of glycolysis-related genes.

Inhibition of the glycolytic pathway as a novel cancer therapeutic strategy has shown initial success in tumor models such as melanoma and breast cancer. Glabridin exhibits anti-tumor potential by modulating the glycolytic pathway and has demonstrated remarkable effects in several cell lines and animal models. However, the inhibition of glycolysis may be accompanied by metabolic adaptation and the development of drug resistance. Therefore, precisely regulating the glycolytic pathway to enhance therapeutic effects and prevent the development of drug resistance remains a key focus for future research.

5.2.2 Promotion of mitochondrial apoptosis pathway

Mitochondria play a crucial role in regulating energy metabolism and apoptosis. In cancer cells, mitochondria overproduce reactive oxygen species (ROS), which contribute to cancer progression by inducing genomic instability, modifying gene expression, and participating in signaling pathways (72).

Yang et al. found that glabridin significantly inhibits the proliferation of bladder urothelial carcinoma cells and induces apoptosis (38). In a nude mouse model, glabridin significantly inhibits tumor growth and prolongs the survival time of tumor-bearing mice. The mechanism may involve glabridin-induced permeabilization of the outer mitochondrial membrane, which leads to the release of mitochondrial cytochrome c (CYCS) and subsequently triggers apoptosis. In addition, glabridin promotes vacuole formation in the cytoplasm of MDA-MB-231 breast cancer cells, causing loss of mitochondrial membrane potential and ROS production, leading to mitochondrial dysfunction and cancer cell apoptosis (73).

The role of glabridin in bladder and breast cancer cells reveals its potential to induce apoptosis through ROS production and loss of mitochondrial membrane potential. This mechanism may have broad applications in cancer therapy, as inducing cancer cell death through targeting the mitochondrial pathway is a promising strategy to overcome drug resistance. However, precisely regulating this process to avoid damage to normal cells remains a key focus for future research.

5.2.3 Inhibition of the epidermal growth factor receptor signaling pathway

EGFR is a receptor tyrosine kinase commonly associated with cancer progression and poor prognosis. Inhibition of EGFR tyrosine kinase activity is considered a promising strategy for cancer treatment (74). Studies have shown that EGFR signaling is closely linked to breast cancer development and resistance to cytotoxic drugs (75).

Through molecular docking, ADMET profiling, and pharmacophore modeling, it was found that glabridin is an effective EGFR inhibitor, with an optimal binding affinity of -7.63 kcal/mol, comparable to the highly effective anti-cancer drug afatinib, and has demonstrated good efficacy in the treatment of breast cancer (76). Zhu et al. (77) found that glabridin can reduce the viability of breast cancer SK-BR-3 cells and induce apoptosis. Further studies showed that glabridin down-regulated the levels of phosphorylated epidermal growth factor receptor (P-EGFR) and phosphorylated protein kinase B (P-AKT) and promoted the expression of cysteine-aspartic acid protease 3 (caspase-3), cysteine-aspartic acid protease 8 (caspase-8), and cysteine-aspartic acid protease 9 (caspase-9), indicating that glabridin exerts its anti-cancer effects by regulating the activation of the EGFR signaling cascade. For detailed information, please refer to Table 2.

5.3 Inhibition of tumor cell proliferation

Cell proliferation is a crucial factor in cell growth and differentiation. Inhibiting tumor cell proliferation can effectively hinder cancer progression and is a critical aspect of cancer treatment (64, 78). The mechanism of glabridin inhibiting tumor cell proliferation is shown in Figure 5.

Figure 5

5.3.1 Inhibition of P13K/Akt signaling pathway

The phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway is a critical signaling pathway in various cancers, exerting extensive regulatory effects on cell survival, growth, migration, metabolism, and angiogenesis (79).

Tan et al. (80) found that glabridin significantly inhibits the proliferation of prostate cancer cells. Network pharmacology and molecular docking results showed that the PI3K/Akt pathway is key to this process. In vitro experiments showed that glabridin significantly inhibits Akt phosphorylation, suggesting it inhibits prostate cancer cell proliferation by regulating the PI3K/Akt pathway. Zhang et al. (81) also confirmed this view in their study, finding that glabridin promoted ROS signaling in prostate cancer cells in a dose-dependent manner. The excessive production of ROS is an important marker of cancer and can regulate a variety of tumor-related signaling pathways (82). Glabridin can promote apoptosis by inhibiting PI3K/Akt signaling via ROS, enhancing caspase-3 activity, and increasing the Bcl-2-associated X protein (Bax)/Bcl-2 expression ratio.

The mammalian target of rapamycin (mTOR) is a protein kinase that regulates cell proliferation, survival, metabolism, and immunity. It plays an important role in many human cancers and can promote tumor cell growth and metastasis through multiple mechanisms (83). Li et al. (84) investigated the effect and molecular mechanism of glabridin on inhibiting the proliferation of colon cancer cells. After glabridin intervention, the expression of PI3K, Akt, and mTOR proteins, as well as downstream molecules MMP-9, MMP-2, and Bcl-2, was significantly reduced, while the expression of Bax, caspase-3, and caspase-9 proteins was significantly increased. The mechanism of action may be related to the inhibition of the PI3K-Akt-mTOR signaling pathway.

5.3.2 Inhibition of JNK/P38 signaling pathway

JNK is a member of the mitogen-activated protein kinase (MAPK) family (85) and plays a role in regulating signaling pathways involved in tumor cell proliferation, migration, and apoptosis. It is regarded as a potential target for cancer therapy (86). p38 MAPK is also a member of the MAPK family and can be activated by inflammatory factors and various environmental stresses. These kinases are key components of signal transduction cascades used by cancer cells to sense and adapt to their environment (87).

Studies have found that glabridin regulates JNK1/2 and P38 MAPK phosphorylation, downregulates the anti-apoptotic protein Bcl-2 and procaspase-9, and upregulates Bax and caspase-3, inhibiting colorectal cancer cell proliferation (88). Huang et al. investigated the molecular mechanism of glabridin’s anti-cancer effects in human promyelocytic leukemia and found (89) that glabridin upregulates the phosphorylation of P38 MAPK and JNK1/2 in a time- and dose-dependent manner, promoting the activation of caspase-3, caspase-8, and caspase-9, thereby inhibiting the proliferation of acute myeloid leukemia (AML) cell lines (HL-60, MV4-11, U937, and THP-1). For detailed information, please refer to Table 3.

5.4 Induction of tumor cell cycle arrest

The disruption of normal cell cycle progression is a fundamental mechanism underlying tumorigenesis. Interfering with and blocking various stages of the cell cycle can effectively inhibit the division and proliferation of tumor cells (90). Cyclins regulate the cell cycle by binding to and activating cyclin-dependent kinases (CDKs) (91). Wang et al. found that glabridin can significantly inhibit the expression of cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and G1/S-specific cyclin D3(cyclin D3), blocking the cell cycle at the G1 phase, thereby inhibiting the proliferation of liver cancer cells (92).

The Wnt/β-catenin signaling pathway and its downstream target proteins are crucial regulators of cell proliferation (93). Abnormal Wnt/β-catenin signaling leads to the proliferation and differentiation of cancer cells, playing a significant role in tumorigenesis and progression (94, 95). Huang et al. found that glabridin exhibits high cytotoxicity against cervical cancer cells (Hela), promoting cell cycle arrest in the S and G2/M phases and inducing apoptosis in the G0/G1 phase (96). Experimental results showed a significant reduction in the expression levels of Wnt1, β-catenin, G1/S-specific cyclin D3(cyclin D1), and MMP-2 proteins. This mechanism may be associated with the inhibition of the Wnt/β-catenin signaling pathway.

5.5 Induction of autophagy in tumor cells

Autophagy is an intracellular catabolic process that involves the delivery of misfolded proteins, damaged or aged organelles, and excess cytoplasmic components to lysosomes for degradation via autophagosomes. This process is crucial for maintaining cellular homeostasis and vitality (97). Microtubule-associated protein light chain 3-II (LC3-II) and Beclin 1, a key molecule in autophagy, are autophagy-related markers that play crucial roles in the autophagic process (98, 99).

Hsieh et al. investigated the role of glabridin in inducing autophagy and related signaling pathways in liver cancer cells. They found that glabridin upregulated the expression of LC3-II and Beclin1 and induced autophagy by modulating the phosphorylation of p38MAPK and JNK1/2, which subsequently led to cell death (100).

5.6 Inhibition of tumor angiogenesis

Angiogenesis is a critical marker of cancer development and progression (101). The rapid proliferation of malignant tumors leads to insufficient oxygen and nutrient supply, driving tumor cells to promote angiogenesis by increasing angiogenic factors like vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and angiopoietin. This process supports the survival, growth, and proliferation of tumor cells and facilitates tumor invasion and metastasis to other tissues via the bloodstream (102). Consequently, inhibiting tumor angiogenesis has emerged as a significant strategy in cancer treatment.

Mu et al. (103) found that the molecular mechanism of glabridin in treating breast cancer involves upregulating miR-148a and inhibiting the Wnt/β-catenin pathway. Specifically, glabridin upregulates miR-148a expression in a dose-dependent manner. miR-148a targets Wnt1, leading to the accumulation of β-catenin in the cell membrane and nucleus. This results in reduced VEGF secretion, decreased angiogenesis, and ultimately inhibits tumor growth and development. The mechanism by which glabridin induces cellular autophagy, causes cell cycle arrest, and inhibits tumor angiogenesis is shown in Figure 6.

Figure 6

5.7 Enhancing chemotherapy drug sensitivity

The conventional method for treating malignant tumors is chemotherapy; however, cancer cells are prone to developing resistance to these drugs, which often leads to reduced efficacy or even treatment failure (104). Combination chemotherapy is a treatment method that involves the simultaneous use of two or more chemotherapy drugs. Compared with monotherapy, combination therapy not only reduces drug resistance but also more effectively controls and cures cancer (105).

5-fluorouracil is one of the most commonly used chemotherapeutic agents and is widely employed in the treatment of colon cancer, breast cancer, and liver cancer (106). However, its low bioavailability, short half-life, rapid metabolism, and the development of resistance following chemotherapy limit its therapeutic efficacy (107). Zhang’s research indicates that glabridin, in combination with 5-fluorouracil, can effectively inhibit the malignant proliferation and invasion of the MKN-45 gastric cancer cell line (108). This effect may be associated with the downregulation of MMP-9 and MMP-2 expression.

Tamoxifen is an anti-estrogen drug that has become the primary treatment option for postmenopausal women with metastatic breast cancer (109). Paclitaxel is a naturally occurring compound found in yew trees and is widely used for cancer treatment (110). The current drug resistance of cancer cells has become a major obstacle to the effective treatment of these two drugs (111, 112). Lin et al. (113) found that glabridin significantly enhanced the anti-proliferative and pro-apoptotic effects of tamoxifen on breast cancer cells, as well as the anti-proliferative and pro-apoptotic effects of paclitaxel on prostate cancer cells. The mechanism may be related to a reduction in mitochondrial transmembrane potential and an increase in intracellular ROS, which in turn induces the activation of the caspase cascade.

Doxorubicin (DOX) is a topoisomerase inhibitor and an anthracycline-class anticancer drug (114). Qian et al. (115) found that glabridin reduces the IC50 values of paclitaxel and DOX in MDA-MB-231 breast cancer cells and enhances DOX-induced apoptosis. The mechanism involves glabridin downregulating the expression of P-glycoprotein (P-gp) and competitively inhibiting P-gp efflux pumps, thereby increasing the accumulation of DOX and paclitaxel in breast cancer cells. In another study, researchers assessed the cytotoxicity of glabridin on three cancer cell lines: A2780 (human ovarian carcinoma), SKNMC (human neuroblastoma), and H1299 (human non-small cell lung carcinoma). The results indicated that glabridin can kill up to 90% of cancer cells in these lines, with IC50 values of 10, 12, and 38 μM for A2780, SKNMC, and H1299, respectively. Additionally, glabridin enhances the cytotoxicity of DOX against these cancer cells and significantly reduces cell viability. The synergistic inhibitory effect of glabridin and DOX on H1299 cells was most pronounced, with glabridin significantly increasing DOX accumulation in a dose-dependent manner. At DOX concentrations of 15 µM and 30 µM, intracellular accumulation of doxorubicin increased by 2.8-fold and 2.5-fold, respectively (116).

Glabridin not only enhances the anti-tumor effects of DOX but also reduces DOX-induced cardiotoxicity. Huang et al. (117) found that glabridin can reduce DOX-induced myocardial enzyme leakage, including aminotransferase, creatine kinase, lactate dehydrogenase, and creatine kinase-MB, downregulate pro-apoptotic proteins (Bax, caspase 9, and caspase 3), and upregulate anti-apoptotic proteins (Bcl-2) in cardiac tissues. In addition, glabridin can regulate the DOX-induced imbalance of intestinal flora, thereby reducing the ratio of M1/M2 macrophages in the colon. This is accompanied by the downregulation of lipopolysaccharide (LPS) in feces and peripheral blood, and the upregulation of butyrate, indicating that glabridin can effectively prevent DOX-induced cardiotoxicity by modulating the intestinal flora and polarization of colonic macrophages. For detailed information, please refer to Table 4.

5.8 Glabridin prevents skin and endometrial cancer

5.8.1 Prevention of skin cancer

Ultraviolet B (UVB) is considered a major environmental factor detrimental to human health. It can activate various signal transduction pathways and induce the expression of multiple specific genes, which are the main mechanisms behind skin aging and cancer development (118). Therefore, it is important to prevent and reverse UVB damage to reduce the incidence of skin cancer. A study on the anti-photoaging properties of glabridin found that glabridin effectively attenuated the levels of pro-inflammatory factors, including IL-1β, tumor necrosis factor-α (TNF-α), IL-22, and IFN-γ, thereby preventing UVB-induced photoaging in mice and reducing skin inflammation (119). Another study found that glabridin possesses antioxidant activity, can prevent DNA oxidative damage caused by UVB irradiation, and reduces the production of ROS and the activation of apoptosis pathway proteins (120), thereby preventing skin cancer.

5.8.2 Prevention of endometrial cancer

It has been reported that the affinity of glabridin for the human estrogen receptor is comparable to that of genistein, the best-known phytoestrogen (22). Abnormally high estrogen levels are associated with an increased incidence of certain cancers, especially breast and endometrial cancer. The International Agency for Research on Cancer (IARC) has classified estrogen and combined estrogen-progestin postmenopausal therapy as known human carcinogens (23). Glabridin exhibits an estrogenic effect in the endometrial cell line Ishikawa, increasing in a dose-dependent manner and potentially reducing the risk of endometrial cancer (121). Another study found that glabridin, in combination with tamoxifen, exhibited estrogenic activity and inhibited cell proliferation (122). Compared to tamoxifen alone, glabridin in combination with tamoxifen reduced the proliferation of MCF-7 cells twofold. This suggests that combining glabridin with tamoxifen may serve as an estrogen replacement therapy to reduce the risk of tamoxifen-associated endometrial cancer.

6 Glabridin drug delivery systems

Glabridin exhibits inhibitory effects on the growth of various tumors; however, its poor water solubility, low bioavailability, and lack of specific targeting limit its clinical application. Numerous studies have demonstrated that novel drug delivery systems can significantly enhance the solubility, stability, targeting, and bioavailability of poorly soluble drugs (123). Currently, several glabridin drug delivery systems have been developed, such as liposomes, cyclodextrin inclusion complexes, nanoparticles, and polymer micelles. These advancements offer promising solutions for improving the clinical application of glabridin. Glabridin drug delivery systems can be classified based on the physical state of the delivery system and the mechanisms of drug release as follows: The glabridin drug delivery system is shown in Figure 7.

Figure 7

6.1 Liquid carrier system

6.1.1 Liposomes

Liposomes are vesicular structures formed by encapsulating drugs within a lipid bilayer (124). They can significantly enhance the permeability and solubility of drugs and possess high biocompatibility, non-immunogenicity, low toxicity, and biodegradability (125, 126). Thus, they serve as an excellent drug delivery system.

Huang et al. prepared glabridin liposomes using the complex coacervation method and investigated their particle size distribution, in vitro drug release characteristics, and stability. The results showed that glabridin liposomes had superior in vitro drug release compared to pure glabridin in the first 120 minutes. After three months, the mass fraction of glabridin in the liposomes remained at 38.5%, with a retention rate of 96.25% (127). Zhang et al. prepared glabridin liposomes using the thin film dispersion method and evaluated their effects on skin aging. The results demonstrated that glabridin liposomes exhibited lower cytotoxicity compared to pure glabridin and were more effective in inhibiting melanin production (128). Another study employed the ultrasonic emulsification method to prepare glabridin nanoliposomes. The results indicated that glabridin nanoliposomes exhibited excellent sustained release, transdermal absorption, and photostability, thereby enhancing the utilization of glabridin (129).

Wang et al. utilized Confocal Raman Spectroscopy (CRS) to assess the epidermal permeability of glabridin liposomes compared to pure glabridin. The study showed that glabridin liposomes had 3.8 times greater skin permeability than pure glabridin, and liposome encapsulation significantly enhanced its transdermal absorption and bioavailability (130).

Currently, liposomes are regarded as one of the most advanced drug delivery vehicles. Given their excellent biocompatibility and low toxicity, they have been successfully utilized in various small-molecule drugs and large-molecule biologics (131). For glabridin, liposomes significantly enhance its skin penetration and antioxidant activity. However, the significant efficacy of glabridin liposomes in skin cancer requires further experimental verification. Additionally, the production processes of liposomes (e.g., thin-film dispersion and ultrasonic emulsification) have matured (132) and received multiple approvals from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) (133), particularly for cancer treatment drugs (134). Therefore, glabridin liposomes are regarded as one of the most promising delivery systems for rapid advancement to clinical applications. However, their high material cost and the necessity of refrigeration post-preparation, owing to the susceptibility of phospholipids to oxidation, limit their long-term stability (135).

6.1.2 Nanosuspension

Nanosuspension is the dispersions of drug nanoparticles within a liquid medium, typically water, and consists mainly of nanoparticles with sizes ranging from 100 to 1000 nm. To maintain stability, nanosuspensions are generally stabilized with a small amount of surfactant (136, 137).

Wang et al. prepared a glabridin nanosuspension using the anti-solvent precipitation-homogenization method and optimized particle size by evaluating formulation parameters with the Box-Behnken design (138). The optimal formulation consisted of 0.25% glabridin, 0.47% poloxamer 188, and 0.11% polyvinylpyrrolidone K30. The average particle size of the resulting nanosuspension was 149.2 nm with a polydispersity index of 0.254. The results showed that the nanosuspension significantly enhanced the transdermal penetration flux of glabridin both in vitro and in vivo, without any lag phase. After 3 months of storage at room temperature, no significant particle aggregation was observed, and the drug loss was minimal at 5.46%.

Due to the large specific surface area of nanoparticles, nanosuspensions can enhance the stability of drugs in solvents and extend their shelf life (139, 140); they are suitable for topical administration (e.g., eyes, lungs, and skin) (141). Nanosuspensions are relatively inexpensive to produce and simple to scale up. Several nanosuspension formulations have been approved worldwide (142). However, particle aggregation and changes in particle size need to be controlled during long-term storage.

6.1.3 Nanoemulsion

Nanoemulsion is a thermodynamically unstable yet kinetically stable colloidal solution, formed by dispersing droplets with a particle size of less than 100 nm in a different liquid medium. Its composition typically includes water, oil, surfactants, and co-surfactants (143). Nanoemulsions are characterized by low surface tension, good physical stability, high solubility, and ease of preparation (144).

Liu et al. prepared nanoemulsions using various oil phases and compared their physicochemical properties, including apparent solubility, droplet size, and zeta potential, as well as in vitro and in vivo skin permeability and stability (145). Their study identified the eutectic mixture of menthol and camphor as the optimal solvent for glabridin. The solubility of glabridin in the prepared nanoemulsion was 76.6 mg/g, and both its in vitro and in vivo skin permeability were significantly enhanced compared to pure glabridin. Additionally, the nanoemulsion exhibited excellent chemical stability.

Nanoemulsions are highly efficient transdermal absorption systems suitable for local drug delivery (146). For glabridin, Nanoemulsion can enhance its skin absorption rate and stability; however, whether they can improve glabridin’s efficacy against skin cancer requires further experimental verification. The production processes of Nanoemulsion are relatively simple and easy to scale up (147). Currently, many approved products in cosmetics and pharmaceuticals utilize Nanoemulsion (141). However, the chemical stability of Nanoemulsion requires improvement, as they may undergo phase separation at extreme temperatures (high or low) (148).

6.2 Solid carrier system

6.2.1 Nanoparticles

Nanoparticles are solid particles sized between 10 and 1000 nm, created using nanotechnology to dissolve or encapsulate drugs within a polymer carrier material (149). These nanoparticles can target drug delivery to tumors or diseased tissues (150), exhibiting high drug loading, high encapsulation efficiency, and controlled drug release (151).

Li et al. discovered that glabridin-loaded nanoparticles not only possess antioxidant activity but also specifically accumulate in the spleen to inhibit inflammatory responses (12). Chen et al. employed an ionic-gelation method to prepare glabridin nanoparticles by blending glabridin with chitosan (CS) and poly-γ-glutamic acid (γ-PGA). The results indicated that the appearance and particle size of the nanoparticles remained stable after 90 days, with an encapsulation rate of 88.30 ± 0.54% and a drug loading rate of 26.47 ± 0.73% (152).

The preparation processes of nanoparticles are well-established, with methods such as solvent evaporation and ultrasound widely applied in industrial production (153). Currently, various nanoparticle drugs have been approved for cancer treatment (154), and their high targeting and controlled release properties demonstrate significant potential in clinical trials for cancer therapies. However, different types of nanomaterials exhibit significant variability in toxicity and metabolic pathways, which may lead to potential immune responses and cumulative toxicity; therefore, rigorous safety evaluations are still required for clinical applications (155).

6.2.2 Nanocomplex

Nanocomplexes are nano-aggregates formed by non-covalent interactions between carrier molecules, such as proteins or oligosaccharides, and drugs (156), which can improve the physicochemical properties of drugs, increasing solubility, encapsulation rate, and bioavailability (157).

Chitosan is a natural polysaccharide widely utilized in drug delivery applications owing to its excellent biocompatibility and biodegradability (158). Su et al. studied the stability of glabridin in the chitosan-glabridin nanocomplex, finding that the encapsulation rate of glabridin in the nanocomplex could reach up to 84%, significantly enhancing stability in aqueous solution and under ultraviolet light (159). Beta-lactoglobulin (β-Ig) is an essential milk protein widely utilized in food and drug delivery systems owing to its excellent biocompatibility and biodegradability (160). Based on the fact that β-lg readily solubilizes in water and binds many small hydrophobic molecules, Wei et al. developed a novel nanocomplexed glabridin with β-lg using an antisolvent precipitation method (161). Molecular docking modeling showed that glabridin binds to β-lg through hydrophobic and hydrogen bond interactions, increasing its solubility in aqueous solution by 21 times. At the same concentration, nanocomplexed glabridin with β-lg shows better 2,2-diphenyl-1-pyridinium hydrazone and 2,2’-azino-3-ethylbenzothiazoline-6-sulfonic acid radical scavenging capacities compared to pure glabridin. Therefore, the nanocomplexation of β-lg with glabridin, which enhances the solubility of glabridin in aqueous systems, offers a promising opportunity for β-lg to serve as an effective carrier molecule.

Nanocomplexes enhance drug stability and solubility, effectively preventing rapid metabolism or degradation within the biological environment (162). They perform excellently in localized and targeted drug delivery, demonstrating significant potential for cancer treatment (163). However, the long-term stability of nanocomplexes in vivo and their potential immune response risks require further investigation.

6.2.3 Metal-organic frameworks

Metal-organic frameworks (MOFs) are porous materials formed by the coordination of metal ions or metal clusters with organic ligands. Compared to other nanomaterials, MOF nanoparticles have several advantages, including adjustable pore size, low density, and high surface area (164, 165). These characteristics have led to the increasing use of MOFs as carriers in drug delivery systems in biomedical research, particularly for the delivery of anticancer drugs (166).

ZIF-8 is a special metal-organic framework formed by the self-assembly of zinc ions (Zn²⁺ >) and 2-methylimidazole (2-MIM). In addition to the advantages of other MOFs, ZIF-8 shows high stability in aqueous solutions due to the strong interaction between Zn²⁺ and 2-MIM. Chen et al. prepared a ZIF-8 metal-organic framework (MOF) encapsulating glabridin using the anti-solvent precipitation method (167). The drug encapsulation efficiency was 98.67%, and pH-controlled release of glabridin was achieved. Additionally, cell experiments demonstrated that the MOF significantly enhanced the antioxidant activity, melanin-inhibiting activity, and bioavailability of glabridin.

MOFs can respond to external stimuli (e.g., temperature, light, pH) by adjusting their pore structures to enable controlled drug release (168), demonstrating significant potential in targeted drug delivery, gene therapy, and related fields. However, the incorporation of metal components raises concerns about the potential biotoxicity and biodegradability of MOFs, which remain insufficiently verified (169), posing challenges for safety assessments in biomedical applications.

6.3 Inclusion and polymer systems

6.3.1 Cyclodextrin inclusion complex

An inclusion complex is a special complex formed when a drug is partially or completely encapsulated within the cavity structure of a host molecule (170). Cyclodextrin is a cyclic oligosaccharide synthesized by cyclodextrin glucosyltransferase (CGRase) using starch as a substrate (171). Its hydrophilic outer surface and relatively hydrophobic central cavity can form complexes with drugs, thereby enhancing their solubility and stability (172, 187).

Wei et al. employed a co-evaporation method to prepare a complex of glabridin and hydroxypropyl-β-cyclodextrin (HP-β-CD). The results demonstrated that at 25°C, the solubility of the complex in pure water was 40.74 ± 0.44 mM, which was 1852 times higher than that of glabridin. In vitro experiments revealed that the DPPH free radical scavenging capacity and the tyrosinase inhibitory activity of the complex were enhanced by approximately 9 and 20 times, respectively (173).

Li et al. demonstrated that the encapsulation efficiency and drug loading capacity of the glabridin/HP-β-CD inclusion complex were 90.03% and 14.51%, respectively. The saturation solubility of the inclusion complex was 109.36 mg/mL. The cumulative dissolution rates in gastric and intestinal juices after 1 hour were 15.75 and 12.4 times higher than those of glabridin, respectively, while the cumulative release rate over 24 hours was 53 times that of glabridin. The uptake of Caco-2 cells was 0.349 mg/g, significantly higher than that of glabridin (0.039 mg/g). These results indicate that the glabridin/HP-β-CD inclusion complex significantly enhances the dissolution and release of glabridin, thereby increasing its bioavailability (174). Thus, the glabridin/HP-β-CD inclusion complex is expected to be an ideal form of glabridin for drug delivery.

Wang et al. developed a novel inclusion complex, sulfobutylether-β-cyclodextrin/glabridin, using the freeze-drying method. The solubility of this inclusion complex was 1889 times higher than that of glabridin. Moreover, this inclusion complex exhibited excellent biocompatibility, along with significant antibacterial, anti-inflammatory, and antioxidant activities, and effectively accelerated the healing of skin damage (175).

Yao et al. prepared 2-sulfobutyl-β-cyclodextrin/glabridin inclusion complexes using freeze-drying, spray-drying, and kneading methods. The saturation solubility of these complexes was greater than 83 mg/mL. The encapsulation efficiency and drug loading capacity of the inclusion complex prepared by freeze-drying were 86.09% and 22.39%, respectively. The cumulative dissolution rates in gastric and intestinal fluids, as well as the antiproliferative activity against the human liver cancer cell line (HepG-2), were significantly higher than those of glabridin (176).

Cyclodextrin inclusion complex significantly enhances the solubility of glabridin and effectively improves the bioavailability of drugs, making them suitable for oral and topical administration (177). However, the production costs of cyclodextrin complexes remain relatively high (178). Studies indicate that cyclodextrin complexes are valuable not only for cancer and inflammation treatment but also for delivering novel small molecule and peptide drugs (133). Nonetheless, further toxicological and biocompatibility studies are required to ensure their safety across various administration routes (179, 180).

6.3.2 Polymeric micelles

Polymeric micelles are thermodynamically stable colloidal solutions that form through the self-assembly of synthetic amphiphilic block copolymers in aqueous environments. Their hydrophilic shell and nanoscale particle size facilitate drug release within the body and enhance drug concentration at the target site (181).

Partially myristoylated chitosan pyrrolidone carboxylate (PMCP) is a cationic, amphiphilic derivative of chitosan. Senio et al. employed PMCP emulsification to develop novel, nanoparticle-sized cationic polymeric micelles encapsulating glabridin (182). The skin permeability and melanin inhibition efficacy of the polymeric micelles were evaluated using a human skin model. The results showed that the glabridin dose absorbed 24 hours after applying polymeric micelles was approximately four times higher than that of conventional oil-in-water micelles with Tween 60 (control), significantly inhibiting melanin production. These polymeric micelles hold significant promise as a transdermal drug delivery system for treating skin pigmentation.

Polymer micelles represent a novel delivery system that has emerged in recent years. For glabridin, polymer micelles enhance drug transdermal absorption and stability, making them suitable for intravenous injection and targeted drug delivery (183, 184). However, the preparation process is complex, with stringent requirements for storage and transportation conditions. Large-scale production requires further optimization (185). Currently, the regulatory pathway for polymer micelles remains unclear, and their large-scale clinical application continues to face challenges (186).

In summary, new drug delivery systems for glabridin, including liposomes, cyclodextrin complexes, polymer micelles, nanoparticles, nanoemulsions, nanosuspensions, and nanocomposites, have been extensively researched. These systems have made significant strides in improving the solubility, stability, and bioavailability of glabridin. Notably, glabridin is widely utilized in the cosmetics industry for its whitening effects. Current drug delivery systems for glabridin primarily focus on enhancing skin permeability and anti-melanin effects. However, there is a notable lack of research on its release rate, stability, accumulation, and targeting within the body. Furthermore, existing studies have mainly addressed issues related to drug distribution and release, with insufficient consideration of disease pathology and innovative treatment strategies. Future research should prioritize understanding disease pathogenesis and utilize functionalized materials sensitive to pH, redox conditions, temperature, light, sound, and magnetism. This approach aims to create synergistic effects between drugs and carriers, as well as between different drugs, while integrating diverse treatment methods to further explore the potential of glabridin in disease treatment. For detailed information, please refer to Table 5.

7 Conclusion and outlook

In recent years, plant extracts have been increasingly utilized in the clinical treatment of various diseases. Compared to synthetic drugs, plant extracts exhibit greater biodegradability, enhanced biocompatibility, and fewer side effects, making them considered safer alternatives (188). Malignant tumors pose a significant threat to human health and social development. Increasing evidence suggests that monomeric compounds derived from Chinese herbal medicine play a crucial role in anti-tumor therapy.

Glabridin demonstrates considerable promise in the realm of anti-tumor research. Its anti-tumor effects include inhibition of tumor cell proliferation, metastasis, and invasion; induction of apoptosis and cell cycle arrest; promotion of autophagy; suppression of angiogenesis; enhancement of chemotherapy sensitivity; and prevention of cancer. Compared to commonly used anti-tumor drugs, glabridin exhibits lower toxicity and side effects, along with good tolerance and safety. When combined with other anti-tumor drugs, glabridin can enhance therapeutic efficacy. Given its broad anti-tumor effects and its capacity to improve resistance to traditional chemotherapeutic drugs, glabridin can serve as an effective adjunct in small molecule targeted anti-tumor therapy, gene therapy, anti-angiogenesis therapy, and radiotherapy.

Although preclinical data indicate that glabridin has significant anti-cancer potential, significant challenges remain in translating preclinical findings to clinical applications. Current research on glabridin’s anti-tumor effects primarily focuses on in vitro cell studies. Future preclinical trials should include more animal models, particularly xenograft mouse models of various cancers, to evaluate glabridin’s anti-tumor efficacy and safety. Additionally, dose-optimization studies are necessary to establish the optimal dose range and assess long-term safety, especially regarding potential toxicity to target organs like the liver and kidneys. As a natural anti-tumor compound, glabridin holds promise for combination use with existing anti-cancer therapies, such as chemotherapy, radiotherapy, and immune checkpoint inhibitors. Future studies should explore combining it with standard anti-cancer drugs to evaluate the potential of combination therapy in overcoming drug resistance and enhancing efficacy.

Current drug delivery systems primarily focus on enhancing skin penetration and transdermal absorption, while research on dosage forms targeting tumors within the body remains limited. Future studies should aim to optimize drug delivery systems, particularly by enhancing the delivery efficiency, targeting, and therapeutic effects of glabridin through nano-carrier systems. For instance, polymeric nanoparticles (PNPs), lipid nanoparticles (LNPs), and nanogels can encapsulate glabridin effectively, enhancing its water solubility and controlling drug release. Adjusting particle size, surface modification, and drug loading can modify these nanocarriers to promote drug accumulation in tumor tissue, thereby enhancing therapeutic effects and minimizing side effects on normal tissues. Additionally, to further enhance glabridin’s therapeutic efficacy, developing tumor-targeted delivery systems is essential. Nanocarrier surfaces can be functionalized with specific antibodies, small-molecule peptides, or carbohydrate molecules to precisely target tumor cells. For example, glabridin can be combined with small peptides targeting EGFR or human epidermal growth factor receptor 2 (HER2) to achieve selective delivery to tumor sites.

In summary, glabridin exhibits substantial anti-tumor potential and holds considerable promise for future development and application. It is anticipated that further in-depth research will elucidate its potential and offer robust references and support for anti-tumor therapies.

References

• 1

  BrayFLaversanneMSungHFerlayJSiegelRLSoerjomataramIet al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. (2024) 74:229–63. doi: 10.3322/caac.21834

  • CrossRef
  • Google Scholar

• 2

  WuCLiMMengHLiuYNiuWZhouYet al. Analysis of status and countermeasures of cancer incidence and mortality in China. Sci China Life Sci. (2019) 62:640–7. doi: 10.1007/s11427-018-9461-5

  • CrossRef
  • Google Scholar

• 3

  HuangZLiGLangYAnQChenHZhangW. Research progress on the mechanisms of apoptosis induced by traditional Chinese medicine in lung cancer cells. Chin J Exp Tradit Med Formulae. (2021) 27:226–36. doi: 10.13422/j.cnki.syfjx.20212326

  • CrossRef
  • Google Scholar

• 4

  ChenYFanWZhaoYLiuMHuLZhangW. Progress in the regulation of immune cells in the tumor microenvironment by bioactive compounds of traditional chinese medicine. Molecules. (2024) 29:2374. doi: 10.3390/molecules29102374

  • CrossRef
  • Google Scholar

• 5

  XieJHuangHLiXOuyangLWangLLiuDet al. The role of traditional chinese medicine in cancer immunotherapy: current status and future directions. Am J Chin Med. (2023) 51:1627–51. doi: 10.1142/S0192415X2350074X

  • CrossRef
  • Google Scholar

• 6

  XieYXuSChenZSongCYanW. Unveiling the therapeutic potential of airpotato yam rhizome against colorectal cancer: a network pharmacology approach. Front Oncol. (2024) 14:1414766. doi: 10.3389/fonc.2024.1414766

  • CrossRef
  • Google Scholar

• 7

  WangMZhangFZhouJGongKChenSZhuXet al. Glabridin Ameliorates Alcohol-Caused Liver Damage by Reducing Oxidative Stress and Inflammation via p38 MAPK/Nrf2/NF-κB Pathway. Nutrients. (2023) 15:2157. doi: 10.3390/nu15092157

  • CrossRef
  • Google Scholar

• 8

  MuhammadHSalahuddinZAkhtarTAftabURafiAHussainSet al. Immunomodulatory effect of glabridin in ovalbumin induced allergic asthma and its comparison with methylprednisolone in a preclinical rodent model. J Cell Biochem. (2023) 124:1503–15. doi: 10.1002/jcb.30459

  • CrossRef
  • Google Scholar

• 9

  LongJLiuHQiuZXiaoZLuZ. Glabridin therapy reduces chronic allodynia, spinal microgliosis, and dendritic spine generation by inhibiting fractalkine-CX3CR1 signaling in a mouse model of tibial fractures. Brain Sci. (2023) 13:739. doi: 10.3390/brainsci13050739

  • CrossRef
  • Google Scholar

• 10

  TanHChenJLiYLiYZhongYLiGet al. Glabridin, a bioactive component of licorice, ameliorates diabetic nephropathy by regulating ferroptosis and the VEGF/Akt/ERK pathways. Mol Med. (2022) 28:58. doi: 10.1186/s10020-022-00481-w

  • CrossRef
  • Google Scholar

• 11

  KaurKNarangRKSinghS. Glabridin mitigates TiO2NP induced cognitive deficit in adult zebrafish. Neurochem Int. (2023) 169:105585. doi: 10.1016/j.neuint.2023.105585

  • CrossRef
  • Google Scholar

• 12

  LiSWangYWuMYounisMHOlsonAPBarnhartTEet al. Spleen-targeted glabridin-loaded nanoparticles regulate polarization of monocyte/macrophage (Mo/Mφ) for the treatment of cerebral ischemia-reperfusion injury. Adv Mater. (2022) 34:e2204976. doi: 10.1002/adma.202204976

  • CrossRef
  • Google Scholar

• 13

  ZhangJWuXZhongBLiaoQWangXXieYet al. Review on the diverse biological effects of glabridin. Drug Des Devel Ther. (2023) 17:15–37. doi: 10.2147/DDDT.S385981

  • CrossRef
  • Google Scholar

• 14

  BombelliAAraya-CloutierCVinckenJ-PAbeeTden BestenHMW. Impact of food-relevant conditions and food matrix on the efficacy of prenylated isoflavonoids glabridin and 6,8-diprenylgenistein as potential natural preservatives against Listeria monocytogenes. Int J Food Microbiol. (2023) 390:110109. doi: 10.1016/j.ijfoodmicro.2023.110109

  • CrossRef
  • Google Scholar

• 15

  CiganovićPJakimiukKTomczykMZovko KončićM. Glycerolic licorice extracts as active cosmeceutical ingredients: extraction optimization, chemical characterization, and biological activity. Antioxidants (Basel). (2019) 8:445. doi: 10.3390/antiox8100445

  • CrossRef
  • Google Scholar

• 16

  FengTWeiYLeeRJZhaoL. Liposomal curcumin and its application in cancer. Int J Nanomedicine. (2017) 12:6027–44. doi: 10.2147/IJN.S132434

  • CrossRef
  • Google Scholar

• 17

  HuangTLiuYZhangC. Pharmacokinetics and bioavailability enhancement of baicalin: A review. Eur J Drug Metab Pharmacokinet. (2019) 44:159–68. doi: 10.1007/s13318-018-0509-3

  • CrossRef
  • Google Scholar

• 18

  AlizadehSREbrahimzadehMA. Quercetin derivatives: Drug design, development, and biological activities, a review. Eur J Med Chem. (2022) 229:114068. doi: 10.1016/j.ejmech.2021.114068

  • CrossRef
  • Google Scholar

• 19

  CaoJChenXLiangJYuX-QXuA-LChanEet al. Role of P-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of Glycyrrhiza glabra. Drug Metab Dispos. (2007) 35:539–53. doi: 10.1124/dmd.106.010801

  • CrossRef
  • Google Scholar

• 20

  ItoCOiNHashimotoTNakabayashiHAokiFTominagaYet al. Absorption of dietary licorice isoflavan glabridin to blood circulation in rats. J Nutr Sci Vitaminol (Tokyo). (2007) 53:358–65. doi: 10.3177/jnsv.53.358

  • CrossRef
  • Google Scholar

• 21

  XieLDiaoZXiaJZhangJXuYWuYet al. Comprehensive evaluation of metabolism and the contribution of the hepatic first-pass effect in the bioavailability of glabridin in rats. J Agric Food Chem. (2023) 71:1944–56. doi: 10.1021/acs.jafc.2c06460

  • CrossRef
  • Google Scholar

• 22

  SimmlerCPauliGFChenS-N. Phytochemistry and biological properties of glabridin. Fitoterapia. (2013) 90:160–84. doi: 10.1016/j.fitote.2013.07.003

  • CrossRef
  • Google Scholar

• 23

  LiangJShangY. Estrogen and cancer. Annu Rev Physiol. (2013) 75:225–40. doi: 10.1146/annurev-physiol-030212-183708

  • CrossRef
  • Google Scholar

• 24

  MaximovPYFanPAbderrahmanBCurpanRJordanVC. Estrogen receptor complex to trigger or delay estrogen-induced apoptosis in long-term estrogen deprived breast cancer. Front Endocrinol (Lausanne). (2022) 13:869562. doi: 10.3389/fendo.2022.869562

  • CrossRef
  • Google Scholar

• 25

  BukatoKKostrzewaTGammazzaAMGorska-PonikowskaMSawickiS. Endogenous estrogen metabolites as oxidative stress mediators and endometrial cancer biomarkers. Cell Commun Signal. (2024) 22:205. doi: 10.1186/s12964-024-01583-0

  • CrossRef
  • Google Scholar

• 26

  ShinJChoiLSJeonHJLeeHMKimSHKimK-Wet al. Synthetic glabridin derivatives inhibit LPS-induced inflammation via MAPKs and NF-κB pathways in RAW264.7 macrophages. Molecules. (2023) 28:2135. doi: 10.3390/molecules28052135

  • CrossRef
  • Google Scholar

• 27

  FengQYeLLiuYGongYLiHWangY. Determination of equilibrium solubility and oil-water partition coefficient of glabridin. J Tianjin Univ Tradit Chin Med. (2017) 36:54–6. doi: 10.11656/j.issn.1673-9043.2017.01.13

  • CrossRef
  • Google Scholar

• 28

  AoMShiYCuiYGuoWWangJYuL. Factors influencing glabridin stability. Nat Prod Commun. (2010) 5:1907–12. doi: 10.1177/1934578X1000501214

  • CrossRef
  • Google Scholar

• 29

  AokiFNakagawaKKitanoMIkematsuHNakamuraKYokotaSet al. Clinical safety of licorice flavonoid oil (LFO) and pharmacokinetics of glabridin in healthy humans. J Am Coll Nutr. (2007) 26:209–18. doi: 10.1080/07315724.2007.10719603

  • CrossRef
  • Google Scholar

• 30

  LiuSLinHChenYWangYZhangXXiangZet al. Metabolic profiling of glabridin in rat plasma, urine, bile, and feces after intragastric and intravenous administration. Eur J Drug Metab Pharmacokinet. (2022) 47:879–87. doi: 10.1007/s13318-022-00797-2

  • CrossRef
  • Google Scholar

• 31

  AokiFHondaSKishidaHKitanoMAraiNTanakaHet al. Suppression by licorice flavonoids of abdominal fat accumulation and body weight gain in high-fat diet-induced obese C57BL/6J mice. Biosci Biotechnol Biochem. (2007) 71:206–14. doi: 10.1271/bbb.60463

  • CrossRef
  • Google Scholar

• 32

  NakagawaKKitanoMKishidaHHidakaTNabaeKKawabeMet al. 90-Day repeated-dose toxicity study of licorice flavonoid oil (LFO) in rats. Food Chem Toxicol. (2008) 46:2349–57. doi: 10.1016/j.fct.2008.03.015

  • CrossRef
  • Google Scholar

• 33

  NakagawaKHidakaTKitanoMAsakuraMKamigaitoTNoguchiTet al. Genotoxicity studies on licorice flavonoid oil (LFO). Food Chem Toxicol. (2008) 46:2525–32. doi: 10.1016/j.fct.2008.04.008

  • CrossRef
  • Google Scholar

• 34

  JiangFLiYMuJHuCZhouMWangXet al. Glabridin inhibits cancer stem cell-like properties of human breast cancer cells: An epigenetic regulation of miR-148a/SMAd2 signaling. Mol Carcinog. (2016) 55:929–40. doi: 10.1002/mc.22333

  • CrossRef
  • Google Scholar

• 35

  HeBLiSLiYHanJLiXFangJet al. Effects of glabridin on the Malignant biological behavior of lung adenocarcinoma A549 cells and its molecular mechanisms. Chin J Cancer Biother. (2023) 30:672–80. doi: 10.3872/j.issn.1007-385x.2023.08.004

  • CrossRef
  • Google Scholar

• 36

  JamwalAChandJDashABhattSDhimanSWazirPet al. Glabridin plays dual action to intensify anti-metastatic potential of paclitaxel via impeding CYP2C8 in liver and CYP2J2/EETs in tumor of an orthotopic mouse model of breast cancer. Chem Biol Interact. (2023) 382:110605. doi: 10.1016/j.cbi.2023.110605

  • CrossRef
  • Google Scholar

• 37

  GaoCWangYLiDTangXZhengQ. Mechanistic study on glabridin-induced apoptosis in mouse melanoma B16F10 cells. Nat Prod Res Dev. (2017) 29:836–42. doi: 10.16333/j.1001-6880.2017.5.021

  • CrossRef
  • Google Scholar

• 38

  YangZBiYXuWGuoRHaoMLiangYet al. Glabridin inhibits urothelial bladder carcinoma cell growth in vitro and in vivo by inducing cell apoptosis and cell cycle arrest. Chem Biol Drug Des. (2023) 101:581–92. doi: 10.1111/cbdd.14147

  • CrossRef
  • Google Scholar

• 39

  LinYXuJLanH. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol. (2019) 12:76. doi: 10.1186/s13045-019-0760-3

  • CrossRef
  • Google Scholar

• 40

  CastanedaMden HollanderPKuburichNARosenJMManiSA. Mechanisms of cancer metastasis. Semin Cancer Biol. (2022) 87:17–31. doi: 10.1016/j.semcancer.2022.10.006

  • CrossRef
  • Google Scholar

• 41

  BudhuAJiaH-LForguesMLiuC-GGoldsteinDLamAet al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology. (2008) 47:897–907. doi: 10.1002/hep.22160

  • CrossRef
  • Google Scholar

• 42

  PickupMWOwensPMosesHL. TGF-β, bone morphogenetic protein, and activin signaling and the tumor microenvironment. Cold Spring Harb Perspect Biol. (2017) 9:a022285. doi: 10.1101/cshperspect.a022285

  • CrossRef
  • Google Scholar

• 43

  ChandrasinghePCereserBMoorghenMAl BakirITabassumNHartAet al. Role of SMAD proteins in colitis-associated cancer: from known to the unknown. Oncogene. (2018) 37:1–7. doi: 10.1038/onc.2017.300

  • CrossRef
  • Google Scholar

• 44

  JiangFMuJWangXYeXSiLNingSet al. The repressive effect of miR-148a on TGF beta-SMADs signal pathway is involved in the glabridin-induced inhibition of the cancer stem cells-like properties in hepatocellular carcinoma cells. PloS One. (2014) 9:e96698. doi: 10.1371/journal.pone.0096698

  • CrossRef
  • Google Scholar

• 45

  AprelikovaOPallaJHiblerBYuXGreerYEYiMet al. Silencing of miR-148a in cancer-associated fibroblasts results in WNT10B-mediated stimulation of tumor cell motility. Oncogene. (2013) 32:3246–53. doi: 10.1038/onc.2012.351

  • CrossRef
  • Google Scholar

• 46

  RoySSunkaraRRParmarMYShaikhSWaghmareSK. EMT imparts cancer stemness and plasticity: new perspectives and therapeutic potential. Front Biosci (Landmark Ed). (2021) 26:238–65. doi: 10.2741/4893

  • CrossRef
  • Google Scholar

• 47

  HuangYHongWWeiX. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol. (2022) 15:129. doi: 10.1186/s13045-022-01347-8

  • CrossRef
  • Google Scholar

• 48

  LohC-YChaiJYTangTFWongWFSethiGShanmugamMKet al. The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition: signaling, therapeutic implications, and challenges. Cells. (2019) 8:1118. doi: 10.3390/cells8101118

  • CrossRef
  • Google Scholar

• 49

  SatelliALiS. Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci. (2011) 68:3033–46. doi: 10.1007/s00018-011-0735-1

  • CrossRef
  • Google Scholar

• 50

  NaT-YSchectersonLMendonsaAMGumbinerBM. The functional activity of E-cadherin controls tumor cell metastasis at multiple steps. Proc Natl Acad Sci U.S.A. (2020) 117:5931–7. doi: 10.1073/pnas.1918167117

  • CrossRef
  • Google Scholar

• 51

  Gabarra-NieckoVSchallerMDDuntyJM. FAK regulates biological processes important for the pathogenesis of cancer. Cancer Metastasis Rev. (2003) 22:359–74. doi: 10.1023/a:1023725029589

  • CrossRef
  • Google Scholar

• 52

  HiscoxSNicholsonRI. Src inhibitors in breast cancer therapy. Expert Opin Ther Targets. (2008) 12:757–67. doi: 10.1517/14728222.12.6.757

  • CrossRef
  • Google Scholar

• 53

  LeungEL-HTamIY-STinVP-CChuaDT-TSihoeAD-LChengL-Cet al. SRC promotes survival and invasion of lung cancers with epidermal growth factor receptor abnormalities and is a potential candidate for molecular-targeted therapy. Mol Cancer Res. (2009) 7:923–32. doi: 10.1158/1541-7786.MCR-09-0003

  • CrossRef
  • Google Scholar

• 54

  TsaiY-MYangC-JHsuY-LWuL-YTsaiY-CHungJ-Yet al. Glabridin inhibits migration, invasion, and angiogenesis of human non-small cell lung cancer A549 cells by inhibiting the FAK/rho signaling pathway. Integr Cancer Ther. (2011) 10:341–9. doi: 10.1177/1534735410384860

  • CrossRef
  • Google Scholar

• 55

  HsuY-LWuL-YHouM-FTsaiE-MLeeJ-NLiangH-Let al. Glabridin, an isoflavan from licorice root, inhibits migration, invasion and angiogenesis of MDA-MB-231 human breast adenocarcinoma cells by inhibiting focal adhesion kinase/Rho signaling pathway. Mol Nutr Food Res. (2011) 55:318–27. doi: 10.1002/mnfr.201000148

  • CrossRef
  • Google Scholar

• 56

  MitraSKSchlaepferDD. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. (2006) 18:516–23. doi: 10.1016/j.ceb.2006.08.011

  • CrossRef
  • Google Scholar

• 57

  NilandSRiscanevoAXEbleJA. Matrix metalloproteinases shape the tumor microenvironment in cancer progression. Int J Mol Sci. (2021) 23:146. doi: 10.3390/ijms23010146

  • CrossRef
  • Google Scholar

• 58

  de AlmeidaLGNThodeHEslambolchiYChopraSYoungDGillSet al. Matrix metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacol Rev. (2022) 74:712–68. doi: 10.1124/pharmrev.121.000349

  • CrossRef
  • Google Scholar

• 59

  JieZXieZZhaoXSunXYuHPanXet al. Glabridin inhibits osteosarcoma migration and invasion via blocking the p38- and JNK-mediated CREB-AP1 complexes formation. J Cell Physiol. (2019) 234:4167–78. doi: 10.1002/jcp.27171

  • CrossRef
  • Google Scholar

• 60

  LiuLChenJZhangBZhengQ. Comparative study on the anti-tumor metastasis effects of isoliquiritigenin and glabridin. Chin J Exp Tradit Med Formulae. (2013) 19:245–50. doi: 10.11653/syfj2013180245

  • CrossRef
  • Google Scholar

• 61

  HsiehM-JLinC-WYangS-FChenM-KChiouH-L. Glabridin inhibits migration and invasion by transcriptional inhibition of matrix metalloproteinase 9 through modulation of NF-κB and AP-1 activity in human liver cancer cells. Br J Pharmacol. (2014) 171:3037–50. doi: 10.1111/bph.12626

  • CrossRef
  • Google Scholar

• 62

  ElmoreS. Apoptosis: a review of programmed cell death. Toxicol Pathol. (2007) 35:495–516. doi: 10.1080/01926230701320337

  • CrossRef
  • Google Scholar

• 63

  PistrittoGTrisciuoglioDCeciCGarufiAD’OraziG. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY). (2016) 8:603–19. doi: 10.18632/aging.100934

  • CrossRef
  • Google Scholar

• 64

  HanahanDWeinbergRA. Hallmarks of cancer: the next generation. Cell. (2011) 144:646–74. doi: 10.1016/j.cell.2011.02.013

  • CrossRef
  • Google Scholar

• 65

  ChelakkotCChelakkotVSShinYSongK. Modulating glycolysis to improve cancer therapy. Int J Mol Sci. (2023) 24:2606. doi: 10.3390/ijms24032606

  • CrossRef
  • Google Scholar

• 66

  AkinsNSNielsonTCLeHV. Inhibition of glycolysis and glutaminolysis: an emerging drug discovery approach to combat cancer. Curr Top Med Chem. (2018) 18:494–504. doi: 10.2174/1568026618666180523111351

  • CrossRef
  • Google Scholar

• 67

  XuSHerschmanHR. A tumor agnostic therapeutic strategy for hexokinase 1-null/hexokinase 2-positive cancers. Cancer Res. (2019) 79:5907–14. doi: 10.1158/0008-5472.CAN-19-1789

  • CrossRef
  • Google Scholar

• 68

  ForkasiewiczADorociakMStachKSzelachowskiPTabolaRAugoffK. The usefulness of lactate dehydrogenase measurements in current oncological practice. Cell Mol Biol Lett. (2020) 25:35. doi: 10.1186/s11658-020-00228-7

  • CrossRef
  • Google Scholar

• 69

  SharmaDSinghMRaniR. Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics. Semin Cancer Biol. (2022) 87:184–95. doi: 10.1016/j.semcancer.2022.11.007

  • CrossRef
  • Google Scholar

• 70

  AnceyP-BContatCMeylanE. Glucose transporters in cancer - from tumor cells to the tumor microenvironment. FEBS J. (2018) 285:2926–43. doi: 10.1111/febs.14577

  • CrossRef
  • Google Scholar

• 71

  LiLLiGXieY. Regulatory effects of glabridin and quercetin on energy metabolism in breast cancer cells. Chin J Chin Mater Med. (2019) 44:3786–91. doi: 10.19540/j.cnki.cjcmm.20190505.401

  • CrossRef
  • Google Scholar

• 72

  YangYKarakhanovaSHartwigWD’HaeseJGPhilippovPPWernerJet al. Mitochondria and mitochondrial ROS in cancer: novel targets for anticancer therapy. J Cell Physiol. (2016) 231:2570–81. doi: 10.1002/jcp.25349

  • CrossRef
  • Google Scholar

• 73

  CuiXCuiM. Glabridin induces paraptosis-like cell death via ER stress in breast cancer cells. Heliyon. (2022) 8:e10607. doi: 10.1016/j.heliyon.2022.e10607

  • CrossRef
  • Google Scholar

• 74

  TalukdarSEmdadLDasSKFisherPB. EGFR: An essential receptor tyrosine kinase-regulator of cancer stem cells. Adv Cancer Res. (2020) 147:161–88. doi: 10.1016/bs.acr.2020.04.003

  • CrossRef
  • Google Scholar

• 75

  LiXZhaoLChenCNieJJiaoB. Can EGFR be a therapeutic target in breast cancer? Biochim Biophys Acta Rev Cancer. (2022) 1877:188789. doi: 10.1016/j.bbcan.2022.188789

  • CrossRef
  • Google Scholar

• 76

  GhoshAGhoshDMukerjeeNMaitraSDasPDeyAet al. The efficient activity of glabridin and its derivatives against EGFRmediated inhibition of breast cancer. Curr Med Chem. (2024) 31:573–94. doi: 10.2174/0929867330666230303120942

  • CrossRef
  • Google Scholar

• 77

  ZhuKLiKWangHKangLDangCZhangY. Discovery of glabridin as potent inhibitor of epidermal growth factor receptor in SK-BR-3 cell. Pharmacology. (2019) 104:113–25. doi: 10.1159/000496798

  • CrossRef
  • Google Scholar

• 78

  CardanoMTribioliCProsperiE. Targeting proliferating cell nuclear antigen (PCNA) as an effective strategy to inhibit tumor cell proliferation. Curr Cancer Drug Targets. (2020) 20:240–52. doi: 10.2174/1568009620666200115162814

  • CrossRef
  • Google Scholar

• 79

  HeYSunMMZhangGGYangJChenKSXuWWet al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. (2021) 6:425. doi: 10.1038/s41392-021-00828-5

  • CrossRef
  • Google Scholar

• 80

  TanWZhouSKangHJiangXMaoZYangKet al. Mechanism of glabridin in the treatment of castration-resistant prostate cancer based on network pharmacology and experimental validation. Nat Prod Res Dev. (2023) 35:310–318, 259. doi: 10.16333/j.1001-6880.2023.2.015

  • CrossRef
  • Google Scholar

• 81

  ZhangFWangFLiWLiangLSangX. The toxicity mechanism of glabridin in prostate cancer cells is involved in reactive oxygen species-dependent PI3K/Akt pathway: Integrated utilization of bioinformatic analysis and in vitro test validation. Environ Toxicol. (2022) 37:2937–46. doi: 10.1002/tox.23649

  • CrossRef
  • Google Scholar

• 82

  MoloneyJNCotterTG. ROS signalling in the biology of cancer. Semin Cell Dev Biol. (2018) 80:50–64. doi: 10.1016/j.semcdb.2017.05.023

  • CrossRef
  • Google Scholar

• 83

  HuaHKongQZhangHWangJLuoTJiangY. Targeting mTOR for cancer therapy. J Hematol Oncol. (2019) 12:71. doi: 10.1186/s13045-019-0754-1

  • CrossRef
  • Google Scholar

• 84

  LiTLiHXiaWLiMNiuYFuX. Investigation of the effects of glabridin on the proliferation, apoptosis, and migration of the human colon cancer cell lines SW480 and SW620 and its mechanism based on reverse virtual screening and proteomics. Oxid Med Cell Longev. (2023) 2023:1117431. doi: 10.1155/2023/1117431

  • CrossRef
  • Google Scholar

• 85

  AbdelrahmanKSHassanHAAbdel-AzizSAMarzoukAANarumiAKonnoHet al. JNK signaling as a target for anticancer therapy. Pharmacol Rep. (2021) 73:405–34. doi: 10.1007/s43440-021-00238-y

  • CrossRef
  • Google Scholar

• 86

  WuQWuWJacevicVFrancaTCCWangXKucaK. Selective inhibitors for JNK signalling: a potential targeted therapy in cancer. J Enzyme Inhib Med Chem. (2020) 35:574–83. doi: 10.1080/14756366.2020.1720013

  • CrossRef
  • Google Scholar

• 87

  ZouXBlankM. Targeting p38 MAP kinase signaling in cancer through post-translational modifications. Cancer Lett. (2017) 384:19–26. doi: 10.1016/j.canlet.2016.10.008

  • CrossRef
  • Google Scholar

• 88

  YangXZouDDingYZuoLZhouQWangY. Effects of glabridin on proliferation and apoptosis of colorectal cancer RKO cells. J Anhui Med Univ. (2017) 52:42–6. doi: 10.19405/j.cnki.issn1000-1492.2017.01.009

  • CrossRef
  • Google Scholar

• 89

  HuangH-LHsiehM-JChienM-HChenH-YYangS-FHsiaoP-C. Glabridin mediate caspases activation and induces apoptosis through JNK1/2 and p38 MAPK pathway in human promyelocytic leukemia cells. PloS One. (2014) 9:e98943. doi: 10.1371/journal.pone.0098943

  • CrossRef
  • Google Scholar

• 90

  LiuJPengYWeiW. Cell cycle on the crossroad of tumorigenesis and cancer therapy. Trends Cell Biol. (2022) 32:30–44. doi: 10.1016/j.tcb.2021.07.001

  • CrossRef
  • Google Scholar

• 91

  TchakarskaGSolaB. The double dealing of cyclin D1. Cell Cycle. (2020) 19:163–78. doi: 10.1080/15384101.2019.1706903

  • CrossRef
  • Google Scholar

• 92

  WangZLuoSWanZChenCZhangXLiBet al. Glabridin arrests cell cycle and inhibits proliferation of hepatocellular carcinoma by suppressing braf/MEK signaling pathway. Tumour Biol. (2016) 37:5837–46. doi: 10.1007/s13277-015-4177-5

  • CrossRef
  • Google Scholar

• 93

  JinTGeorge FantusISunJ. Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of beta-catenin. Cell Signal. (2008) 20:1697–704. doi: 10.1016/j.cellsig.2008.04.014

  • CrossRef
  • Google Scholar

• 94

  YuFYuCLiFZuoYWangYYaoLet al. Wnt/β-catenin signaling in cancers and targeted therapies. Signal Transduct Target Ther. (2021) 6:307. doi: 10.1038/s41392-021-00701-5

  • CrossRef
  • Google Scholar

• 95

  ZhangYWangX. Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol. (2020) 13:165. doi: 10.1186/s13045-020-00990-3

  • CrossRef
  • Google Scholar

• 96

  HuangSLiCHuangJMoDLuoPWangH. Effects and mechanisms of glabridin on proliferation, invasion, and apoptosis of cervical cancer HeLa cells. Mod Oncol. (2020) 28:3289–93. doi: 10.3969/j.issn.1672-4992.2020.19.003

  • CrossRef
  • Google Scholar

• 97

  LevyJMMTowersCGThorburnA. Targeting autophagy in cancer. Nat Rev Cancer. (2017) 17:528–42. doi: 10.1038/nrc.2017.53

  • CrossRef
  • Google Scholar

• 98

  TanidaIUenoTKominamiE. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol. (2004) 36:2503–18. doi: 10.1016/j.biocel.2004.05.009

  • CrossRef
  • Google Scholar

• 99

  KlickaKGrzywaTMMielniczukAKlinkeAWłodarskiPK. The role of miR-200 family in the regulation of hallmarks of cancer. Front Oncol. (2022) 12:965231. doi: 10.3389/fonc.2022.965231

  • CrossRef
  • Google Scholar

• 100

  HsiehM-JChenM-KChenC-JHsiehM-CLoY-SChuangY-Cet al. Glabridin induces apoptosis and autophagy through JNK1/2 pathway in human hepatoma cells. Phytomedicine. (2016) 23:359–66. doi: 10.1016/j.phymed.2016.01.005

  • CrossRef
  • Google Scholar

• 101

  LuganoRRamachandranMDimbergA. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci. (2020) 77:1745–70. doi: 10.1007/s00018-019-03351-7

  • CrossRef
  • Google Scholar

• 102

  LiuZ-LChenH-HZhengL-LSunL-PShiL. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther. (2023) 8:198. doi: 10.1038/s41392-023-01460-1

  • CrossRef
  • Google Scholar

• 103

  MuJZhuDShenZNingSLiuYChenJet al. The repressive effect of miR-148a on Wnt/β-catenin signaling involved in Glabridin-induced anti-angiogenesis in human breast cancer cells. BMC Cancer. (2017) 17:307. doi: 10.1186/s12885-017-3298-1

  • CrossRef
  • Google Scholar

• 104

  ZraikIMHeß-BuschY. Management of chemotherapy side effects and their long-term sequelae. Urologe A. (2021) 60:862–71. doi: 10.1007/s00120-021-01569-7

  • CrossRef
  • Google Scholar

• 105

  PomeroyAESchmidtEVSorgerPKPalmerAC. Drug independence and the curability of cancer by combination chemotherapy. Trends Cancer. (2022) 8:915–29. doi: 10.1016/j.trecan.2022.06.009

  • CrossRef
  • Google Scholar

• 106

  WeiYYangPCaoSZhaoL. The combination of curcumin and 5-fluorouracil in cancer therapy. Arch Pharm Res. (2018) 41:1–13. doi: 10.1007/s12272-017-0979-x

  • CrossRef
  • Google Scholar

• 107

  Valencia-LazcanoAAHassanDPourmadadiMShamsabadipourABehzadmehrRRahdarAet al. 5-Fluorouracil nano-delivery systems as a cutting-edge for cancer therapy. Eur J Med Chem. (2023) 246:114995. doi: 10.1016/j.ejmech.2022.114995

  • CrossRef
  • Google Scholar

• 108

  ZhangLChenHWangMSongXDingFZhuJet al. Effects of glabridin combined with 5-fluorouracil on the proliferation and apoptosis of gastric cancer cells. Oncol Lett. (2018) 15:7037–45. doi: 10.3892/ol.2018.8260

  • CrossRef
  • Google Scholar

• 109

  LeghaSS. Tamoxifen in the treatment of breast cancer. Ann Intern Med. (1988) 109:219–28. doi: 10.7326/0003-4819-109-3-219

  • CrossRef
  • Google Scholar

• 110

  Gallego-JaraJLozano-TerolGSola-MartínezRACánovas-DíazMde Diego PuenteT. A compressive review about taxol^®: history and future challenges. Molecules. (2020) 25:5986. doi: 10.3390/molecules25245986

  • CrossRef
  • Google Scholar

• 111

  ŠkubníkJSvobodová PavlíčkováVRumlTRimpelováS. Autophagy in cancer resistance to paclitaxel: Development of combination strategies. BioMed Pharmacother. (2023) 161:114458. doi: 10.1016/j.biopha.2023.114458

  • CrossRef
  • Google Scholar

• 112

  ChenCLuLYanSYiHYaoHWuDet al. Autophagy and doxorubicin resistance in cancer. Anticancer Drugs. (2018) 29:1–9. doi: 10.1097/CAD.0000000000000572

  • CrossRef
  • Google Scholar

• 113

  LinHAiDLiuQWangXChenQHongZet al. Natural isoflavone glabridin targets PI3Kγ as an adjuvant to increase the sensitivity of MDA-MB-231 to tamoxifen and DU145 to paclitaxel. J Steroid Biochem Mol Biol. (2024) 236:106426. doi: 10.1016/j.jsbmb.2023.106426

  • CrossRef
  • Google Scholar

• 114

  CarvalhoCSantosRXCardosoSCorreiaSOliveiraPJSantosMSet al. Doxorubicin: the good, the bad and the ugly effect. Curr Med Chem. (2009) 16:3267–85. doi: 10.2174/092986709788803312

  • CrossRef
  • Google Scholar

• 115

  QianJXiaMLiuWLiLYangJMeiYet al. Glabridin resensitizes p-glycoprotein-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic agents. Eur J Pharmacol. (2019) 852:231–43. doi: 10.1016/j.ejphar.2019.04.002

  • CrossRef
  • Google Scholar

• 116

  ModarresiMHajialyaniMMoasefiNAhmadiFHosseinzadehL. Evaluation of the cytotoxic and apoptogenic effects of glabridin and its effect on cytotoxicity and apoptosis induced by doxorubicin toward cancerous cells. Adv Pharm Bull. (2019) 19:481–9. doi: 10.15171/apb.2019.057

  • CrossRef
  • Google Scholar

• 117

  HuangKLiuYTangHQiuMLiCDuanCet al. Glabridin prevents doxorubicin-induced cardiotoxicity through gut microbiota modulation and colonic macrophage polarization in mice. Front Pharmacol. (2019) 10:107. doi: 10.3389/fphar.2019.00107

  • CrossRef
  • Google Scholar

• 118

  Van LaethemAGarmynMAgostinisP. Starting and propagating apoptotic signals in UVB irradiated keratinocytes. Photochem Photobiol Sci. (2009) 8:299–308. doi: 10.1039/b813346h

  • CrossRef
  • Google Scholar

• 119

  PengGLiYZengYSunBZhangLLiuQ. Effect of glabridin combined with bakuchiol on UVB-induced skin damage and its underlying mechanism: An experimental study. J Cosmet Dermatol. (2024) 23:2256–69. doi: 10.1111/jocd.16259

  • CrossRef
  • Google Scholar

• 120

  VerattiERossiTGiudiceSBenassiLBertazzoniGMoriniDet al. 18beta-glycyrrhetinic acid and glabridin prevent oxidative DNA fragmentation in UVB-irradiated human keratinocyte cultures. Anticancer Res. (2011) 31:2209–15.

  • Google Scholar

• 121

  Su Wei PohMVoon Chen YongPViseswaranNChiaYY. Estrogenicity of glabridin in Ishikawa cells. PloS One. (2015) 10:e0121382. doi: 10.1371/journal.pone.0121382

  • CrossRef
  • Google Scholar

• 122

  JenSHWeiMPSYinACY. The combinatory effects of glabridin and tamoxifen on ishikawa and MCF-7 cell lines. Nat Prod Commun. (2015) 10:1573–6. doi: 10.1177/1934578X1501000922

  • CrossRef
  • Google Scholar

• 123

  HassanSPrakashGOzturkASaghazadehSSohailMFSeoJet al. Evolution and clinical translation of drug delivery nanomaterials. Nano Today. (2017) 15:91–106. doi: 10.1016/j.nantod.2017.06.008

  • CrossRef
  • Google Scholar

• 124

  GuimarãesDCavaco-PauloANogueiraE. Design of liposomes as drug delivery system for therapeutic applications. Int J Pharm. (2021) 601:120571. doi: 10.1016/j.ijpharm.2021.120571

  • CrossRef
  • Google Scholar

• 125

  LargeDEAbdelmessihRGFinkEAAugusteDT. Liposome composition in drug delivery design, synthesis, characterization, and clinical application. Adv Drug Delivery Rev. (2021) 176:113851. doi: 10.1016/j.addr.2021.113851

  • CrossRef
  • Google Scholar

• 126

  Zununi VahedSSalehiRDavaranSSharifiS. Liposome-based drug co-delivery systems in cancer cells. Mater Sci Eng C Mater Biol Appl. (2017) 71:1327–41. doi: 10.1016/j.msec.2016.11.073

  • CrossRef
  • Google Scholar

• 127

  HuangJHeX. Preparation and quality evaluation of glabridin liposomes. Biomass Chem Eng. (2016) 50:8–12. doi: 10.3969/j.issn.1673-5854.2016.03.002

  • CrossRef
  • Google Scholar

• 128

  ZhangCLuYAiYXuXZhuSZhangBet al. Glabridin liposome ameliorating UVB-induced erythema and lethery skin by suppressing inflammatory cytokine production. J Microbiol Biotechnol. (2021) 31:630–6. doi: 10.4014/jmb.2011.11006

  • CrossRef
  • Google Scholar

• 129

  ZhangCLuoSZhangZNiuYZhangW. Evaluation of Glabridin loaded nanostructure lipid carriers. J Taiwan Inst Chem Eng. (2017) 71:338–43. doi: 10.1016/j.jtice.2016.11.010

  • CrossRef
  • Google Scholar

• 130

  WangYWuKLiSLiXHeY. In vivo confocal Raman spectroscopy investigation of glabridin liposomes dermal penetration process in human skin. Vib Spectrosc. (2023) 129:103610. doi: 10.1016/j.vibspec.2023.103610

  • CrossRef
  • Google Scholar

• 131

  KalaveSChatterjeeBShahPMisraA. Transdermal delivery of macromolecules using nano lipid carriers. Curr Pharm Des. (2021) 27:4330–40. doi: 10.2174/1381612827666210820095330

  • CrossRef
  • Google Scholar

• 132

  kbarzadehARezaei-SadabadyRDavaranSJooSWZarghamiNHanifehpourYet al. Liposome: classification, preparation, and applications. Nanoscale Res Lett. (2013) 8:102. doi: 10.1186/1556-276X-8-102

  • CrossRef
  • Google Scholar

• 133

  LiuPChenGZhangJ. A review of liposomes as a drug delivery system: current status of approved products, regulatory environments, and future perspectives. Molecules. (2022) 27:1372. doi: 10.3390/molecules27041372

  • CrossRef
  • Google Scholar

• 134

  ThotakuraNGuptaMMRajawatJSRazaK. Promises of lipid-based drug delivery systems in the management of breast cancer. Curr Pharm design. (2021) 27: 4568–77. doi: 10.2174/1381612827666210728104318

  • CrossRef
  • Google Scholar

• 135

  ElgartACherniakovIAldoubyYDombAJHoffmanA. Lipospheres and pro-nano lipospheres for delivery of poorly water soluble compounds. Chem Phys Lipids. (2012) 165:438–53. doi: 10.1016/j.chemphyslip.2012.01.007

  • CrossRef
  • Google Scholar

• 136

  AldeebMMEWilarGSuhandiCElaminKMWathoniN. Nanosuspension-based drug delivery systems for topical applications. Int J Nanomedicine. (2024) 19:825–44. doi: 10.2147/IJN.S447429

  • CrossRef
  • Google Scholar

• 137

  JacobSNairABShahJ. Emerging role of nanosuspensions in drug delivery systems. Biomater Res. (2020) 24:3. doi: 10.1186/s40824-020-0184-8

  • CrossRef
  • Google Scholar

• 138

  WangWPHulJSuiHZhaoYSFengJLiuC. Glabridin nanosuspension for enhanced skin penetration: formulation optimization, in vitro and in vivo evaluation. Pharmazie. (2016) 71:252–7.

  • Google Scholar

• 139

  BujňákováZDutkováEBalážMTurianicováEBalážP. Stability studies of As4S4 nanosuspension prepared by wet milling in Poloxamer 407. Int J Pharm. (2015) 478:187–92. doi: 10.1016/j.ijpharm.2014.11.043

  • CrossRef
  • Google Scholar

• 140

  AhireEThakkarSDarshanwadMMisraM. Parenteral nanosuspensions: a brief review from solubility enhancement to more novel and specific applications. Acta Pharm Sin B. (2018) 8:733–55. doi: 10.1016/j.apsb.2018.07.011

  • CrossRef
  • Google Scholar

• 141

  RoyANishchayaKRaiVK. Nanoemulsion-based dosage forms for the transdermal drug delivery applications: A review of recent advances. Expert Opin Drug delivery. (2022) 19:303–19. doi: 10.1080/17425247.2022.2045944

  • CrossRef
  • Google Scholar

• 142

  JetharaSIPatelADPatelMRPatelMSPatelKR. Recent survey on nanosuspension: a patent overview. Recent Pat Drug Delivery Formul. (2015) 9:65–78. doi: 10.2174/1872211308666141028214003

  • CrossRef
  • Google Scholar

• 143

  AntonNVandammeTF. Nano-emulsions and micro-emulsions: clarifications of the critical differences. Pharm Res. (2011) 28:978–85. doi: 10.1007/s11095-010-0309-1

  • CrossRef
  • Google Scholar

• 144

  YangXZhaoKJiangJ. Application of nanoemulsion drug delivery systems. Guangdong Agric Sci. (2011) 38:125–7. doi: 10.16768/j.issn.1004-874x.2011.07.073

  • CrossRef
  • Google Scholar

• 145

  LiuCHuJSuiHZhaoQZhangXWangW. Enhanced skin permeation of glabridin using eutectic mixture-based nanoemulsion. Drug Delivery Transl Res. (2017) 7:325–32. doi: 10.1007/s13346-017-0359-6

  • CrossRef
  • Google Scholar

• 146

  HörmannKZimmerA. Drug delivery and drug targeting with parenteral lipid nanoemulsions - A review. J Control Release. (2016) 223:85–98. doi: 10.1016/j.jconrel.2015.12.016

  • CrossRef
  • Google Scholar

• 147

  MushtaqAMohd WaniSMalikARGullARamniwasSAhmad NayikGet al. Recent insights into Nanoemulsions: Their preparation, properties and applications. Food Chem X. (2023) 18:100684. doi: 10.1016/j.fochx.2023.100684

  • CrossRef
  • Google Scholar

• 148

  SinghYMeherJGRavalKKhanFAChaurasiaMJainNKet al. Nanoemulsion: Concepts, development and applications in drug delivery. J Control Release. (2017) 252:28–49. doi: 10.1016/j.jconrel.2017.03.008

  • CrossRef
  • Google Scholar

• 149

  Ferreira SoaresDCDominguesSCVianaDBTebaldiML. Polymer-hybrid nanoparticles: Current advances in biomedical applications. BioMed Pharmacother. (2020) 131:110695. doi: 10.1016/j.biopha.2020.110695

  • CrossRef
  • Google Scholar

• 150

  GuoYLiuHLiSHeGChenQMeiQet al. Research progress on stimulus-responsive and targeted mesoporous silica nanoparticles for antitumor drug delivery. Chem Biochem Eng. (2021) 38:9–16. doi: 10.3969/j.issn.1672-5425.2021.08.002

  • CrossRef
  • Google Scholar

• 151

  ChenYPingQ. Research progress on oral drug-loaded nanoparticles. Prog Pharm Sci. (2004) 10:451–5. doi: 10.3969/j.issn.1001-5094.2004.10.005

  • CrossRef
  • Google Scholar

• 152

  ChenHZhuangJWuXShenXZhangQZhangW. Preparation of the chitosan/poly-γ-glutamic acid/glabrid in hybrid nanoparticles and study on its releasing property. Curr Drug Delivery. (2023) 20:1195–205. doi: 10.2174/1567201819666220513122319

  • CrossRef
  • Google Scholar

• 153

  LiuYYangGJinSXuLZhaoC-X. Development of high-drug-loading nanoparticles. Chempluschem. (2020) 85:2143–57. doi: 10.1002/cplu.202000496

  • CrossRef
  • Google Scholar

• 154

  ShiJKantoffPWWoosterRFarokhzadOC. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. (2017) 17:20–37. doi: 10.1038/nrc.2016.108

  • CrossRef
  • Google Scholar

• 155

  ElespuruRPfuhlerSAardemaMJChenTDoakSHDohertyAet al. Genotoxicity assessment of nanomaterials: recommendations on best practices, assays, and methods. Toxicol Sci. (2018) 164:391–416. doi: 10.1093/toxsci/kfy100

  • CrossRef
  • Google Scholar

• 156

  D’AngeloNANoronhaMAKurnikISCâmaraMCCVieiraJMAbrunhosaLet al. Curcumin encapsulation in nanostructures for cancer therapy: A 10-year overview. Int J Pharm. (2021) 604:120534. doi: 10.1016/j.ijpharm.2021.120534

  • CrossRef
  • Google Scholar

• 157

  SruthiPMadhava NaiduMRaoPJ. Valorization of cashew nut testa phenolics through nano-complexes stabilized with whey protein isolate and β-cyclodextrin: Characterization, anti-oxidant activity, stability and in vitro release. Food Res Int. (2024) 181:114110. doi: 10.1016/j.foodres.2024.114110

  • CrossRef
  • Google Scholar

• 158

  JafernikKŁadniakABlicharskaECzarnekKEkiertHWiącekAEet al. Chitosan-based nanoparticles as effective drug delivery systems-A review. Molecules. (2023) 28:1963. doi: 10.3390/molecules28041963

  • CrossRef
  • Google Scholar

• 159

  ParkY-SParkH-JLeeJ. Stabilization of glabridin by chitosan nano-complex. J Korean Soc Appl Biol Chem. (2012) 55:457–62. doi: 10.1007/s13765-012-2001-0

  • CrossRef
  • Google Scholar

• 160

  LiuCLiuZSunXZhangSWangSFengFet al. Fabrication and characterization of β-lactoglobulin-based nanocomplexes composed of chitosan oligosaccharides as vehicles for delivery of astaxanthin. J Agric Food Chem. (2018) 66:6717–26. doi: 10.1021/acs.jafc.8b00834

  • CrossRef
  • Google Scholar

• 161

  WeiYVriesekoopFYuanQLiangH. [amp]]beta;-lactoglobulin as a nanotransporter for glabridin: exploring the binding properties and bioactivity influences. ACS Omega. (2018) 3:12246–52. doi: 10.1021/acsomega.8b01576

  • CrossRef
  • Google Scholar

• 162

  ChoKWangXNieSChenZGShinDM. Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res. (2008) 14:1310–6. doi: 10.1158/1078-0432.CCR-07-1441

  • CrossRef
  • Google Scholar

• 163

  KangMLeeSHKwonMByunJKimDKimCet al. Nanocomplex-mediated in vivo programming to chimeric antigen receptor-M1 macrophages for cancer therapy. Adv Mater. (2021) 33:e2103258. doi: 10.1002/adma.202103258

  • CrossRef
  • Google Scholar

• 164

  XuZZhouZYangXThakurAHanNLiH-Tet al. Determining M2 macrophages content for the anti-tumor effects of metal-organic framework-encapsulated pazopanib nanoparticles in breast cancer. J Nanobiotechnology. (2024) 22:429. doi: 10.1186/s12951-024-02694-z

  • CrossRef
  • Google Scholar

• 165

  Chiñas-RojasLEDomínguezJEHerreraLÁAGonzález-JiménezFEColorado-PeraltaRArenzano AltaifJAet al. Exploring synthesis strategies and interactions between MOFs and drugs for controlled drug loading and release, characterizing interactions through advanced techniques. ChemMedChem. (2024) 19:e202400144. doi: 10.1002/cmdc.202400144

  • CrossRef
  • Google Scholar

• 166

  KeQJiangKLiHZhangLChenB. Hierarchically micro-, meso-, and macro-porous MOF nanosystems for localized cross-scale dual-biomolecule loading and guest-carrier cooperative anticancer therapy. ACS Nano. (2024) 18:21911–24. doi: 10.1021/acsnano.4c02288

  • CrossRef
  • Google Scholar

• 167

  ChenLLiuZZhaoXLiuLXinXLiangH. Self-assembled pH-responsive metal-organic frameworks for enhancing the encapsulation and anti-oxidation and melanogenesis inhibition activities of glabridin. Molecules. (2022) 27:3908. doi: 10.3390/molecules27123908

  • CrossRef
  • Google Scholar

• 168

  MhettarPKaleNPantwalawalkarJNangareSJadhavN. Metal-organic frameworks: Drug delivery applications and future prospects. ADMET DMPK. (2024) 12:27–62. doi: 10.5599/admet.2057

  • CrossRef
  • Google Scholar

• 169

  NguyenNTTNguyenTTTGeSLiewRKNguyenDTCTranTV. Recent progress and challenges of MOF-based nanocomposites in bioimaging, biosensing and biocarriers for drug delivery. Nanoscale Adv. (2024) 6:1800–21. doi: 10.1039/d3na01075a

  • CrossRef
  • Google Scholar

• 170

  LuQSunL. Research progress on new dosage forms of baicalein preparations. J Shenyang Pharm Univ. (2023) 40:1253–64. doi: 10.14066/j.cnki.cn21-1349/r.2022.0060

  • CrossRef
  • Google Scholar

• 171

  van der VeenBAvan AlebeekGJUitdehaagJCDijkstraBWDijkhuizenL. The three transglycosylation reactions catalyzed by cyclodextrin glycosyltransferase from Bacillus circulans (strain 251) proceed via different kinetic mechanisms. Eur J Biochem. (2000) 267:658–65. doi: 10.1046/j.1432-1327.2000.01031.x

  • CrossRef
  • Google Scholar

• 172

  KamarajMSuresh BabuPShyamalagowriSPavithraMKSAravindJKimWet al. β-cyclodextrin polymer composites for the removal of pharmaceutical substances, endocrine disruptor chemicals, and dyes from aqueous solution- A review of recent trends. J Environ Manage. (2024) 351:119830. doi: 10.1016/j.jenvman.2023.119830

  • CrossRef
  • Google Scholar

• 173

  WeiYZhangJZhouYBeiWLiYYuanQet al. Characterization of glabridin/hydroxypropyl-β-cyclodextrin inclusion complex with robust solubility and enhanced bioactivity. Carbohydr Polym. (2017) 159:152–60. doi: 10.1016/j.carbpol.2016.11.093

  • CrossRef
  • Google Scholar

• 174

  LiDFanJYaoPRenGDuLZhangX. Release characteristics, mucosal permeability, and cellular uptake of glabridin/hydroxypropyl-β-cyclodextrin inclusion complex. Food Sci. (2023) 44:16–25. doi: 10.7506/spkx1002-6630-20230120-155

  • CrossRef
  • Google Scholar

• 175

  WangWTangKHuangCLiuA. Fabrication of sulfobutylether-β-cyclodextrin/glabridin inclusion complex for promoting bioactivities. Arch Pharm (Weinheim). (2024) 357:e2400082. doi: 10.1002/ardp.202400082

  • CrossRef
  • Google Scholar

• 176

  YaoPFanJLiDZhangXRenGDuL. Preparation and properties of glabridin/cyclodextrin solid inclusion complex. Food Sci. (2022) 43:9–18. doi: 10.7506/spkx1002-6630-20210901-006

  • CrossRef
  • Google Scholar

• 177

  JansookPOgawaNLoftssonT. Cyclodextrins: structure, physicochemical properties and pharmaceutical applications. Int J Pharm. (2018) 535:272–84. doi: 10.1016/j.ijpharm.2017.11.018

  • CrossRef
  • Google Scholar

• 178

  BenkőB-MTóthGMoldvaiDKádárSSzabóESzabóZ-Iet al. Cyclodextrin encapsulation enabling the anticancer repositioning of disulfiram: Preparation, analytical and in vitro biological characterization of the inclusion complexes. Int J Pharm. (2024) 657:124187. doi: 10.1016/j.ijpharm.2024.124187

  • CrossRef
  • Google Scholar

• 179

  ChaudhariPGhateVMLewisSA. Supramolecular cyclodextrin complex: Diversity, safety, and applications in ocular therapeutics. Exp Eye Res. (2019) 189:107829. doi: 10.1016/j.exer.2019.107829

  • CrossRef
  • Google Scholar

• 180

  Serrano-MartínezAVictoria-MontesinosDGarcía-MuñozAMHernández-SánchezPLucas-AbellánCGonzález-LouzaoR. A systematic review of clinical trials on the efficacy and safety of CRLX101 cyclodextrin-based nanomedicine for cancer treatment. Pharmaceutics. (2023) 15:1824. doi: 10.3390/pharmaceutics15071824

  • CrossRef
  • Google Scholar

• 181

  ManjappaASKumbharPSDisouzaJIPatravaleVB. Polymeric mixed micelles: improving the anticancer efficacy of single-copolymer micelles. Crit Rev Ther Drug Carrier Syst. (2019) 36:1–58. doi: 10.1615/CritRevTherDrugCarrierSyst.2018020481

  • CrossRef
  • Google Scholar

• 182

  SeinoHAraiYNagaoNOzawaNHamadaK. Efficient percutaneous delivery of the antimelanogenic agent glabridin using cationic amphiphilic chitosan micelles. PloS One. (2016) 11:e0164061. doi: 10.1371/journal.pone.0164061

  • CrossRef
  • Google Scholar

• 183

  TanbourRMartinsAMPittWGHusseiniGA. Drug delivery systems based on polymeric micelles and ultrasound: A review. Curr Pharm Des. (2016) 22:2796–807. doi: 10.2174/1381612822666160217125215

  • CrossRef
  • Google Scholar

• 184

  ShaikhRBhattacharyaS. Polymeric micelles in colorectal cancer therapy: A comprehensive review of nano-drug delivery strategies, copolymer types, physicochemical characteristics, and therapeutic applications. Curr Med Chem. (2024). doi: 10.2174/0109298673306752240726104241

  • CrossRef
  • Google Scholar

• 185

  YangYXuSChenBTianYZouSChenB. Preparation of amphiphilic polymeric nanomicelles and research progress on their drug-loading methods. Chem Adhes. (2024) 46:397–401. doi: 10.3969/j.issn.1001-0017.2024.04.018

  • CrossRef
  • Google Scholar

• 186

  JunnuthulaVKolimiPNyavanandiDSampathiSVoraLKDyawanapellyS. Polymeric micelles for breast cancer therapy: recent updates, clinical translation and regulatory considerations. Pharmaceutics. (2022) 14:1860. doi: 10.3390/pharmaceutics14091860

  • CrossRef
  • Google Scholar

• 187

  Sarabia-VallejoÁCajaMDMOlivesAIMartínMAMenéndezJC. Cyclodextrin inclusion complexes for improved drug bioavailability and activity: synthetic and analytical aspects. Pharmaceutics. (2023) 15:2345. doi: 10.3390/pharmaceutics15092345

  • CrossRef
  • Google Scholar

• 188

  HeJZhangH-P. Research progress on the anti-tumor effect of Naringin. Front Pharmacol. (2023) 14:1217001. doi: 10.3389/fphar.2023.1217001

  • CrossRef
  • Google Scholar