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Lung cancer (LC) represents the leading cause of global cancer deaths, with cigarette smoking being considered a major risk factor. Nicotine is a major hazardous compound in cigarette smoke (CS), which stimulates LC progression and non-small cell lung cancer (NSCLC) specifically through activation of the nicotinic acetylcholine receptor (α7nAChR)-mediated cell-signaling pathways and molecular genes involved in proliferation, angiogenesis, and metastasis. Chalcones (CHs) and their derivatives are intermediate plant metabolites involved in flavonol biosynthesis. Isoliquiritigenin (ILTG), licochalcone A–E (LicoA–E), and echinatin (ECH) are the most common natural CHs isolated from the root of Glycyrrhiza (also known as licorice). In vitro and/or vivo experiments have shown that licorice CHs treatment exhibits a range of pharmacological effects, including antioxidant, anti-inflammatory, and anticancer effects. Despite advances in NSCLC treatment, the mechanisms of licorice CHs in nicotine-induced NSCLC treatment remain unknown. Therefore, the aim of this paper is to review experimental studies through the PubMed/Medline database that reveal the effects of licorice CHs and their potential mechanisms in nicotine-induced NSCLC treatment.

Isoliquiritigenin (ISL) has excellent neuroprotective effects. However, its limitations, including poor solubility, low bioavailability, and low accumulation in the brain, restrict its clinical promotion. In this study, a novel type of ISL-loaded liposome (ISL-LP) modified with the brain-targeting polypeptide angiopep-2 was prepared to improve these properties. The zeta potential, morphology, particle size, encapsulation efficiency, drug loading, and in vitro release of ISL-LP were evaluated. The pharmacokinetics and tissue distribution of ISL and ISL-LP were also investigated. The results demonstrated that ISL-LP had an average particle size of 89.36 ± 5.04 nm, a polymer dispersity index of 0.17 ± 0.03, a zeta potential of −20.27 ± 2.18 mV, and an encapsulation efficiency of 75.04 ± 3.28%. The in vitro release experiments indicate that ISL-LP is a desirable sustained-release system. After intravenous administration, LPC-LP prolonged the circulation time of ISL in vivo and enhanced its relative brain uptake. In conclusion, ISL-LP could serve as a promising brain-targeting system for the treatment and prevention of central nervous system (CNS) disorders.

Colorectal cancer (CRC) is one of the most common malignancies. Isoliquiritigenin (ISL), a flavonoid phytoestrogen, has shown anti-tumour activities against various cancers. However, its anti-CRC mechanism has not been clarified. In this study, the potential molecular mechanism of ISL against CRC was investigated through network pharmacological prediction and experimental validation. The results of the network prediction indicate that ESR2, PIK3CG and GSK3β might be the key targets of ISL against CRC, which was verified by molecular docking, and that its anti-tumour mechanisms might be related to the oestrogen and PI3K/AKT signalling pathway. The experimental results show that ISL reduced the viability of SW480 and HCT116 cells, induced apoptosis, blocked the cell cycle in the G2 phase in vitro, and suppressed xenograft tumour growth in vivo. In addition, ISL significantly down-regulated the protein expression of PIK3CG, AKT, p-AKT, p-GSK3β, CDK1, NF-κB and Bcl-2; up-regulated ESR2 and Bax; decreased the ratio of p-AKT/AKT and p-GSK3β/GSK3β; and increased the Bax/Bcl-2 ratio. This study indicates that ISL can inhibit the growth of CRC cells and induce apoptosis, which may be related to the up-regulation of ESR2 and inhibition of the PI3K/Akt signalling pathway.

Identifying cancer biomarkers is imperative, as upregulated genes offer a better microenvironment for the tumor; hence, targeted inhibition is preferred. The theme of our study is to predict molecular interactions between cancer biomarker proteins and selected natural compounds. We identified an overexpressed potential molecular target (AKT1) and computationally evaluated its inhibition by four dietary ligands (isoliquiritigenin, shogaol, tehranolide, and theophylline). The three-dimensional structures of protein and phytochemicals were retrieved from the RCSB PDB database (4EKL) and NCBI’s PubChem, respectively. Rational structure-based docking studies were performed using AutoDock. Results were analyzed based primarily on the estimated free binding energy (kcal/mol), hydrogen bonds, and inhibition constant, Ki, to identify the most effective anti-cancer phytomolecule. Toxicity and drug-likeliness prediction were performed using OSIRIS and SwissADME. Amongst the four phytocompounds, tehranolide has better potential to suppress the expression of AKT1 and could be used for anti-cancer drug development, as inhibition of AKT1 is directly associated with the inhibition of growth, progression, and metastasis of the tumor. Docking analyses reveal that tehranolide has the most efficiency in inhibiting AKT1 and has the potential to be used for the therapeutic management of cancer. Natural compounds targeting cancer biomarkers offer less rejection, minimal toxicity, and fewer side effects.

Isoliquiritigenin (ISL) is a flavonoid with a chalcone structure extracted from the natural herb Glycyrrhiza glabra. Its anti-inflammatory, antibacterial, antioxidant, and anticancer activities have been extensively studied. Moreover, ISL also possess hypolipidemic and atherosclerosis-reducing effects. However, its cholesterol-lowering mechanisms have not been reported yet. Niemann Pick C1 Like 1 (NPC1L1) is a specific transporter of cholesterol uptake. In this study, we found for the first time that ISL downregulates NPC1L1 expression and competitively inhibits cellular cholesterol uptake by binding to NPC1L1 in a concentration-dependent manner in vitro. This study provides a theoretical basis for further investigation of the molecular mechanisms of its cholesterol-lowering effect in vivo and inspired emerging drug research for cholesterol-lowering purposes through NPC1L1 inhibition.

It is considered that glutamate excitotoxicity may be a major factor in the pathological death of neurons and mediate the development of neurodegenerative diseases in humans. Here, we show that isoliquiritigenin (ILG) at a concentration of 0.5–5 µM protects primary neuroglial cell culture from glutamate-induced death (glutamate 100 µM). ILG (1 µM) prevented a sharp increase in [Ca2+]i and a decrease in mitochondrial potential (ΔΨm). With the background action of ILG (1–5 µM), there was an increase in oxygen consumption rate (OCR) in response to glutamate, as well as in reserve respiration. The neuroprotective effect of ILG (5 µM) was accompanied by an increase in non-mitochondrial respiration. The results show that ILG can protect cortical neurons from death by preventing the development of calcium deregulation and limiting mitochondrial dysfunction caused by a high dose of glutamate. We hypothesize that ILG will be useful in drug development for the prevention or treatment of neurodegenerative diseases accompanied by glutamate excitotoxicity.

Isoliquiritigenin (ILQ) has a number of biological activities such as antitumor and anti-inflammatory effects. However, biomedical applications of ILQ are impeded by its poor aqueous solubility. Therefore, in this research, we prepared a novel ILQ-loaded nanoemulsion, i.e., ILQ-NE, which consisted of Labrafil® M 1944 CS (oil), Cremophor® EL (surfactant), ILQ, and phosphate-buffered saline, by employing a combined sonication (high-energy) and phase-inversion composition (low-energy) method (denoted as the SPIC method). The ILQ-NE increased the ILQ solubility ~1000 times more than its intrinsic solubility. It contained spherical droplets with a mean diameter of 44.10 ± 0.28 nm and a narrow size distribution. The ILQ loading capacity was 4%. The droplet size of ILQ-NE remained unchanged during storage at 4 °C for 56 days. Nanoemulsion encapsulation effectively prevented ILQ from degradation under ultraviolet light irradiation, and enhanced the ILQ in vitro release rate. In addition, ILQ-NE showed higher cellular uptake and superior cytotoxicity to 4T1 cancer cells compared with free ILQ formulations. In conclusion, ILQ-NE may facilitate the biomedical application of ILQ, and the SPIC method presents an attractive avenue for bridging the merits and eliminating the shortcomings of traditional high-energy methods and low-energy methods.

Oxidative stress could lead to a variety of body dysfunctions, including neurodegeneration and cancer, which are closely associated with intracellular signal transducers such as reactive oxygen species (ROS). It has been suggested that ROS is the upstream regulator of autophagy, and that it provides a negative feedback regulation to remove oxidative damage. Defects in the ROS-autophagic redox homeostasis could lead to the increased production of ROS and the accumulation of damaged organelles that in turn promote metabolic reprogramming and induce tumorigenesis. One significant characteristic of pancreatic cancer is the reprogramming of cellular energy metabolism, which facilitates the rapid growth, invasiveness, and the survival of cancer cells. Thus, the rectification of metabolic dysfunction is essential in therapeutic cancer targeting. Isoliquiritigenin (ISL) is a chalcone obtained from the plant Glycyrrhiza glabra, which is a powdered root licorice that has been consumed for centuries in different regions of the world. ISL is known to be a natural antioxidant that possesses diversified functions, including redox regulation in cells. This review contains discussions on the herbal source, biological properties, and anticancer potential of ISL. This is the first time that the anticancer activities of ISL in pancreatic cancer has been elucidated, with a coverage of the involvement of antioxidation, metabolic redox regulation, and autophagy in pancreatic cancer development. Furthermore, some remarks on related compounds of the isoflavonoid biosynthetic pathway of ISL will also be discussed.

Chemotherapy is the treatment of choice for gastric cancer; however, the currently available therapeutic drugs for treatment have limited efficacy. Cancer stemness and the tumor microenvironment may play crucial roles in tumor growth and chemoresistance. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum chaperone facilitating protein folding and cell homeostasis during stress and may participate in chemoresistance. Isoliquiritigenin (ISL) is a bioactive flavonoid found in licorice. In this study, we demonstrated the role of GRP78 in gastric cancer stemness and evaluated GRP78-mediated stemness inhibition, tumor microenvironment regulation, and chemosensitivity promotion by ISL. ISL not only suppressed GRP78-mediated gastric cancer stem cell–like characteristics, stemness-related protein expression, and cancer-associated fibroblast activation but also gastric tumor growth in xenograft animal studies. The findings indicated that ISL is a promising candidate for clinical use in combination chemotherapy.

Reduction in glutamate release is a key mechanism for neuroprotection and we investigated the effect of isoliquiritigenin (ISL), an active ingredient of Glycyrrhiza with neuroprotective activities, on glutamate release in rat cerebrocortical nerve terminals (synaptosomes). ISL produced a concentration-dependent inhibition of glutamate release and reduced the intraterminal [Ca2+] increase. The inhibition of glutamate release by ISL was prevented after removing extracellular Ca2+ or blocking P/Q-type Ca2+ channels. This inhibition was mediated through the γ-aminobutyric acid type B (GABAB) receptors because ISL was unable to inhibit glutamate release in the presence of baclofen (an GABAB agonist) or CGP3548 (an GABAB antagonist) and docking data revealed that ISL interacted with GABAB receptors. Furthermore, the ISL inhibition of glutamate release was abolished through the inhibition of Gi/o-mediated responses or Gβγ subunits, but not by 8-bromoadenosine 3′,5′-cyclic monophosphate or adenylate cyclase inhibition. The ISL inhibition of glutamate release was also abolished through the inhibition of protein kinase C (PKC), and ISL decreased the phosphorylation of PKC. Thus, we inferred that ISL, through GABAB receptor activation and Gβγ-coupled inhibition of P/Q-type Ca2+ channels, suppressed the PKC phosphorylation to cause a decrease in evoked glutamate release at rat cerebrocortical nerve terminals.

Human adipose-derived stem cells (hASCs) can be isolated from fat tissue and have attracted interest for their potential therapeutic applications in metabolic disease. hASCs can be induced to undergo adipogenic differentiation in vitro by exposure to chemical agents or inductive growth factors. We investigated the effects and mechanism of differentiating hASC-derived white adipocytes into functional beige and brown adipocytes with isoliquiritigenin (ILG) treatment. Here, we showed that hASC-derived white adipocytes could promote brown adipogenesis by expressing both uncoupling protein 1 (UCP1) and PR/SET Domain 16 (PRDM16) following low-dose ILG treatments. ILG treatment of white adipocytes enhanced the expression of brown fat-specific markers, while the expression levels of c-Jun N-terminal kinase (JNK) signaling pathway proteins were downregulated. Furthermore, we showed that the inhibition of JNK phosphorylation contributed to white adipocyte differentiation into beige adipocytes, which was validated by the use of SP600125. We identified distinct regulatory effects of ILG dose responses and suggested that low-dose ILG induced the beige adipocyte potential of hASCs via JNK inhibition.

Isoliquiritigenin (IsoLQ) is a flavonoid with antioxidant properties and inducer of endoplasmic reticulum (ER) stress. In vitro and in vivo studies show that ER stress-mediated hormesis is cytoprotective; therefore, natural antioxidants and ER stress inducers have been used to prevent renal injury. Oxidative stress and ER stress are some of the mechanisms of damage involved in cisplatin (CP)-induced nephrotoxicity. This study aims to explore whether IsoLQ pretreatment induces ER stress and produces hormesis to protect against CP-induced nephrotoxicity in Lilly Laboratories Cell-Porcine Kidney 1 (LLC-PK1) cells. During the first stage of this study, both IsoLQ protective concentration and pretreatment time against CP-induced toxicity were determined by cell viability. At the second stage, the effect of IsoLQ pretreatment on cell viability, ER stress, and oxidative stress were evaluated. IsoLQ pretreatment in CP-treated cells induces expression of glucose-related proteins 78 and 94 kDa (GRP78 and GRP94, respectively), attenuates CP-induced cell death, decreases reactive oxygen species (ROS) production, and prevents the decrease in glutathione/glutathione disulfide (GSH/GSSG) ratio, free thiols levels, and glutathione reductase (GR) activity. These data suggest that IsoLQ pretreatment has a moderately protective effect on CP-induced toxicity in LLC-PK1 cells, through ER stress-mediated hormesis, as well as by the antioxidant properties of IsoLQ.

Isoliquiritigenin, a natural chalcone-type flavonoid, has been recognized as an allelochemical with phytotoxicity to lettuce; however, not enough attention has been paid to the mechanisms of this secondary metabolite. In this work, we investigated the physiological and biochemical mechanisms of isoliquiritigenin on lettuce seedlings. The results show that isoliquiritigenin has a concentration-dependent inhibitory effect on radicle elongation of lettuce seedlings, but no significant impact on lettuce germination. Microscopy analyses suggest that the surface morphology of lettuce radicle tips was atrophied and the intracellular tissue structure deformed at high concentrations. Isoliquiritigenin induced the overproduction of reactive oxygen species (ROS), which led to loss of cell viability in the radicle cells. In addition, malondialdehyde (a product of lipid peroxidation) and free proline levels were found to have increased, while chlorophyll content in lettuce seedlings decreased. All these changes suggest that the primary allelopathic mechanism of isoliquiritigenin by which it inhibits radicle elongation in lettuce seedlings might be due to the overproduction of ROS, which causes oxidative damage to membrane lipids and cell death.

The epithelial-to-mesenchymal transition (EMT) plays a prominent role in cancer metastasis. Isoliquiritigenin (ISL), one of the flavonoids in licorice, has been shown to exhibit anticancer activities in many cancer types through various mechanisms. However, it is unknown whether ISL impacts the EMT process. Here, we show that ISL is able to suppress mesenchymal features of ovarian cancer SKOV3 and OVCAR5 cells, evidenced by an apparent morphological change from a mesenchymal to an epithelial phenotype and reduced levels of mesenchymal markers accompanied by the gain of E-cadherin expression. The suppression of EMT is also supported by the observed decrease in cell migration and in vitro invasion upon ISL treatment. Moreover, we show that ISL effectively blocks the intraperitoneal xenograft development of the SKOV3 cell line and prolonged the survival of tumor-bearing mice. These data suggest that ISL inhibits intraperitoneal ovary tumor development through the suppression of EMT, indicating that ISL may be an effective therapeutic agent against ovarian cancer.

Glycyrrhizae Radix is widely used as herbal medicine and is effective against inflammation, various cancers, and digestive disorders. We aimed to develop a sensitive and simultaneous analytical method for detecting glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin, the four marker components of Glycyrrhizae Radix extract (GRE), in rat plasma using liquid chromatography-tandem mass spectrometry and to apply this analytical method to pharmacokinetic studies. Retention times for glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin were 7.8 min, 4.1 min, 3.1 min, and 2.0 min, respectively, suggesting that the four analytes were well separated without any interfering peaks around the peak elution time. The lower limit of quantitation was 2 ng/mL for glycyrrhizin and 0.2 ng/mL for isoliquiritigenin, liquiritigenin, and liquiritin; the inter- and intra-day accuracy, precision, and stability were less than 15%. Plasma concentrations of glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin were quantified for 24 h after a single oral administration of 1 g/kg GRE to four rats. Among the four components, plasma concentration of glycyrrhizin was the highest and exhibited a long half-life (23.1 ± 15.5 h). Interestingly, plasma concentrations of isoliquiritigenin and liquiritigenin were restored to the initial concentration at 4–10 h after the GRE administration, as evidenced by liquiritin biotransformation into isoliquiritigenin and liquiritigenin, catalyzed by fecal lysate and gut wall enzymes. In conclusion, our analytical method developed for detecting glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin could be successfully applied to investigate their pharmacokinetic properties in rats and would be useful for conducting further studies on the efficacy, toxicity, and biopharmaceutics of GREs and their marker components.

The aim of this study was to evaluate the antitumour activities and genotoxic effects of isoliquiritigenin (ISL) combined with cyclophosphamide (CP) in vitro and in vivo. U14 cells were treated with either of ISL (5–25 μg/mL) or CP (0.25–1.25 mg/mL) alone or with combination of ISL (5–25 μg/mL) and CP (1.0 mg/mL) for 48 h. The proliferation inhibitory effect in vitro was evaluated by MTT and colony formation assays. KM mice bearing U14 mouse cervical cancer cells were used to estimate the antitumour activity in vivo. The genotoxic activity in bone marrow polychromatic erythrocytes was assayed by frequency of micronuclei. The DNA damage in peripheral white blood cells was assayed by single cell gel electrophoresis. The results showed that ISL enhanced antitumour activity of CP in vitro and in vivo, and decreased the micronucleus formation in polychromatic erythrocytes and DNA strand breaks in white blood cells in a dose-dependent way.

The present study was undertaken to test the hypothesis that NADPH oxidase-derived reactive oxygen species (ROS) are involved in isoliquiritigenin (ISL)-induced monocytic differentiation in human acute promyelocytic leukemia HL-60 cells. Morphological changes, cell surface markers CD11b/CD14 and NBT-reducing ability were used to determine the differentiation of HL-60 cells, and 2,7-dichlorofluorescein (DCFH-DA) was used to detect the level of intracellular ROS. ISL-induced HL-60 cell differentiation was accompanied by an increase in the intracellular ROS levels. l-Buthionine-(S,R)-sulfoximine (BSO), N-acetyl-l-cysteine (NAC), superoxide dismutase (SOD) and 4-hydroxy-2,2,6,6-tetramethylpiperidinoxyl (Tempol) were used to interfere with ROS production. NADPH oxidase inhibitors, apocynin (APO) and diphenyleneiodonium (DPI) were used to study the role of NADPH oxidase in ISL-induced HL-60 cell differentiation. The ISL-induced HL-60 cell differentiation and intracellular ROS generation were enhanced by the oxidant BSO and inhibited by the antioxidants NAC, SOD, and tempol, and were also inhibited by the NADPH oxidase inhibitors APO and DPI. The protein and mRNA expression of the NADPH oxidase subunits gp91phox and p47phox were determined by Western blotting and RT-PCR, respectively. The levels of translation and transcription of the NADPH oxidase subunits gp91phox and p47phox increased markedly in a concentration-dependent manner. These findings suggest that NADPH oxidase plays a critical role in HL-60 cell differentiation induced by ISL and that NADPH oxidase-derived ROS is involved in the differentiation mechanism.

Isoliquiritigenin (ILQ) has a number of biological activities such as antitumor and anti-inflammatory effects. However, biomedical applications of ILQ are impeded by its poor aqueous solubility. Therefore, in this research, we prepared a novel ILQ-loaded nanoemulsion, i.e., ILQ-NE, which consisted of Labrafil ® M 1944 CS (oil), Cremophor ® EL (surfactant), ILQ, and phosphate-buffered saline, by employing a combined sonication (high-energy) and phase-inversion composition (low-energy) method (denoted as the SPIC method). The ILQ-NE increased the ILQ solubility ~1000 times more than its intrinsic solubility. It contained spherical droplets with a mean diameter of 44.10 ± 0.28 nm and a narrow size distribution. The ILQ loading capacity was 4%. The droplet size of ILQ-NE remained unchanged during storage at 4 °C for 56 days. Nanoemulsion encapsulation effectively prevented ILQ from degradation under ultraviolet light irradiation, and enhanced the ILQ in vitro release rate. In addition, ILQ-NE showed higher cellular uptake and superior cytotoxicity to 4T1 cancer cells compared with free ILQ formulations. In conclusion, ILQ-NE may facilitate the biomedical application of ILQ, and the SPIC method presents an attractive avenue for bridging the merits and eliminating the shortcomings of traditional high-energy methods and low-energy methods.

Oxidative stress could lead to a variety of body dysfunctions, including neurodegeneration and cancer, which are closely associated with intracellular signal transducers such as reactive oxygen species (ROS). It has been suggested that ROS is the upstream regulator of autophagy, and that it provides a negative feedback regulation to remove oxidative damage. Defects in the ROS-autophagic redox homeostasis could lead to the increased production of ROS and the accumulation of damaged organelles that in turn promote metabolic reprogramming and induce tumorigenesis. One significant characteristic of pancreatic cancer is the reprogramming of cellular energy metabolism, which facilitates the rapid growth, invasiveness, and the survival of cancer cells. Thus, the rectification of metabolic dysfunction is essential in therapeutic cancer targeting. Isoliquiritigenin (ISL) is a chalcone obtained from the plant Glycyrrhiza glabra , which is a powdered root licorice that has been consumed for centuries in different regions of the world. ISL is known to be a natural antioxidant that possesses diversified functions, including redox regulation in cells. This review contains discussions on the herbal source, biological properties, and anticancer potential of ISL. This is the first time that the anticancer activities of ISL in pancreatic cancer has been elucidated, with a coverage of the involvement of antioxidation, metabolic redox regulation, and autophagy in pancreatic cancer development. Furthermore, some remarks on related compounds of the isoflavonoid biosynthetic pathway of ISL will also be discussed.

Chemotherapy is the treatment of choice for gastric cancer; however, the currently available therapeutic drugs for treatment have limited efficacy. Cancer stemness and the tumor microenvironment may play crucial roles in tumor growth and chemoresistance. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum chaperone facilitating protein folding and cell homeostasis during stress and may participate in chemoresistance. Isoliquiritigenin (ISL) is a bioactive flavonoid found in licorice. In this study, we demonstrated the role of GRP78 in gastric cancer stemness and evaluated GRP78-mediated stemness inhibition, tumor microenvironment regulation, and chemosensitivity promotion by ISL. ISL not only suppressed GRP78-mediated gastric cancer stem cell-like characteristics, stemness-related protein expression, and cancer-associated fibroblast activation but also gastric tumor growth in xenograft animal studies. The findings indicated that ISL is a promising candidate for clinical use in combination chemotherapy.

Isoliquiritigenin, a natural chalcone-type flavonoid, has been recognized as an allelochemical with phytotoxicity to lettuce; however, not enough attention has been paid to the mechanisms of this secondary metabolite. In this work, we investigated the physiological and biochemical mechanisms of isoliquiritigenin on lettuce seedlings. The results show that isoliquiritigenin has a concentration-dependent inhibitory effect on radicle elongation of lettuce seedlings, but no significant impact on lettuce germination. Microscopy analyses suggest that the surface morphology of lettuce radicle tips was atrophied and the intracellular tissue structure deformed at high concentrations. Isoliquiritigenin induced the overproduction of reactive oxygen species (ROS), which led to loss of cell viability in the radicle cells. In addition, malondialdehyde (a product of lipid peroxidation) and free proline levels were found to have increased, while chlorophyll content in lettuce seedlings decreased. All these changes suggest that the primary allelopathic mechanism of isoliquiritigenin by which it inhibits radicle elongation in lettuce seedlings might be due to the overproduction of ROS, which causes oxidative damage to membrane lipids and cell death., Competing Interests: The authors declare no conflict of interest.