PHYTOTHERAPY RESEARCH Phytother. Res. 29: 969–977 (2015) Published online 24 April 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ptr.5348

REVIEW

A Review: The Pharmacology of Isoliquiritigenin Fu Peng,1,2,3 Qiaohui Du,2,3 Cheng Peng,2,3 Neng Wang,1 Hailin Tang,1,4 Xiaoming Xie,4 Jiangang Shen1 and Jianping Chen1,2,3* 1

School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Sichuan Province and Ministry of Science and Technology, Chengdu, 610075, China 4 Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China 2 3

Isoliquiritigenin (ISL) is one of the bioactive ingredients isolated from the roots of plants belonging to licorice, including Glycyrrhiza uralensis, Mongolian glycyrrhiza, Glycyrrhiza glabra, and so forth. Liquiritigenin is available in common foods and alternative medicine, and its derivative-ISL is applied into food additives and disease treatment like cancer therapy, antibiotic therapy, and so on. This review aims at providing a comprehensive summary of the pharmacological activities of ISL. The information published between 1972 and 2014 from a number of reliable sources including PubMed, ScienceDirect, Springer, and Wiley-Blackwell. The practical application of ISL on the various disease prevention and treatments may stem from its numerous pharmacological properties such as antiinflammatory, anti-microbial, anti-oxidative, anticancer activities, immunoregulatory, hepatoprotective, and cardioprotective effects. However, further studies are needed to verify the target-organ toxicity or side effects investigation. Copyright © 2015 John Wiley & Sons, Ltd. Keywords: natural medicine; pharmacological properties; isoliquiritigenin.

INTRODUCTION

PHARMACOLOGICAL EFFECTS

It was a long time that the roots and rhizomes of licorice (Glycyrrhiza) served as traditional Chinese medicines and natural sweeteners. Isoliquiritigenin (ISL, Fig. 1.) could be isolated from the roots of Glycyrrhiza and was considered to be the main biologically active component for its useful pharmacological properties such as antiinflammatory, anti-viral, anti-microbial, anti-oxidative, anticancer activities, immunomodulatory, hepatoprotective, and cardioprotective effects (Asl and Hosseinzadeh, 2008). Meanwhile, ISL could be isolated from the roots of Glycyrrhiza uralensis (Li et al., 2010b), Dianthus chinensis, Astragalus membranaceus (Fisch.) Bunge, and numerous folklore medicines. Apart from the basic pharmacological effects the same as Glycyrrhiza, ISL exerted more biological activities such as anti-diabetic effect, anti-spasmodic effect, and anti-angiogenic effect. To provide further support and evidence for the clinical use of ISL, a comprehensive review of the modern pharmacological properties of this compound was conducted. The available information on the pharmacology of ISL was collected via libraries and electronic search (PubMed, ScienceDirect, Springer, and WileyBlackwell).

Anti-tumor activity

* Correspondence to: Jianping Chen, School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong. E-mail: [email protected]

Copyright © 2015 John Wiley & Sons, Ltd.

Cancer, also known as malignancy, means the growth of abnormal cells, which may eventually develop into distant metastasis and malignant tumor. With the wide abuse of chemotherapy, tumors fail to respond to the treatment and become resistant to drugs at an alarming speed (Wu et al., 2011). Natural products, without the side effect, are gaining acceptance as anticancer agents for the treatment to drug-resistant cancers (Zhang et al., 2009). Especially, ISL, one of the natural compounds, exhibited the direct inhibitory effect on various cancers including cervical, breast, hepatoma, colon, prostate, and other types of cancers. Isoliquiritigenin could inhibit multistage carcinogenesis processes such as formation, progression, and migration, through the induction of cell cycle arrest, apoptosis, autophagy, anti-angiogenesis, and so on.

Effect on human cervical cancer Isoliquiritigenin was considered to be non-hormonal alternatives in botanical supplements. Exposure of ISL to HeLa cells-induced apoptosis. The oxidative stresses, mitochondrion-dependent and the estrogen receptor stress-triggered signaling pathways, were considered to be the reasons of apoptosis in HeLa cells (Yuan et al., 2013b). Isoliquiritigenin treatment inhibited cell proliferation of HeLa cells with increased apoptotic rate and Received 18 August 2014 Revised 06 January 2015 Accepted 13 March 2015

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cancer U14 cells. In vivo test demonstrated that the treatment of combination of CP and ISL had showed a more significant inhibitory effect on KM (Kun Ming) mice-bearing U14 mouse cervical cancer cells than the groups treated with ISL or CP alone. The genotoxic effects of ISL decreased the micronucleus formation in polychromatic erythrocytes, and DNA strand breaks in white blood cells in a dose-dependent way (Zhao et al., 2013), which suggested that ISL could be an attractive candidate as an anticancer therapy for cervical cancer prevention and treatment. Effect on breast cancer

Figure 1. The chemical structure of isoliquiritigenin (ISL) and ISL derivatives.

reactive oxygen species (ROS) production. Meanwhile, co-treatment of ISL and ROS scavengers (N-acetyl-cysteine, catalase, and Tiron) would inhibit the amount of ROS, which could be detected by the degradation of poly-ADP-ribose polymerase (PARP) protein. Additionally, adding pro-oxidant (buthionine sulfoximine) to the treatment of ISL enhanced the PARP degradation. Those results more precisely suggested that the apoptosis induced by ISL treatment could be resulted from the increasing intracellular ROS (iROS) levels in HeLa cells (Yuan et al., 2012). The mechanism of ISL treatment causing cell cycle arrest and cytotoxicity in HeLa human cervical cancer cells was that ISL inhibited topoisomerase II activity and induced DNA damage and arrest in mitotic metaphase-like stage, with DNA damage markers including the formation of c-H2AX foci and the phosphorylation of ataxia-telangiectasia mutated and Chk2 (Park et al., 2009a). For human uterine leiomyoma cells, ISL treatment dose dependently reduced the cell viability and proliferation and induced subG1 or G2/M arrest as well. In principle, the treatment of ISL increased p21(Cip1/) Waf1 expression in a p53-dependent manner, activated caspase-3, and downregulated Bcl-2, cdk 2/4, as well as E2F, with increases in dephosphorylation of Rb PARP cleavage (Kim et al., 2008). Also, ISL could decrease cell viability and induce cell accumulation in G2/M and morphological and biochemical features of apoptosis in human cervical cancer cells. Isoliquiritigenin led to a downregulation of HPV16 E6 expression, enhanced the expression of Bax, and decreased the expression of Bcl-2 and Bid proform, triggering dissipation of the mitochondrial membrane potential, released cytochrome c to the cytosol followed by the activation of caspase cascades with the cleavage of caspase-9, caspase-8, caspase-3, and PARP (Hirchaud et al., 2013). When combined with cyclophosphamide (CP), ISL enhanced antitumor activities of CP and suppressed the growth of cervical Copyright © 2015 John Wiley & Sons, Ltd.

Isoliquiritigenin could be served as a novel natural inhibitor for cancer angiogenesis via the vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR-2) pathway in breast tumor. The mechanism was that ISL could significantly inhibit VEGF expression in breast cancer cells via promoting hypoxia inducible factor-1α (HIF-1α) proteasome degradation and directly interacted with VEGFR-2 to block its kinase activity. In vivo studies, ISL therapy could inhibit breast cancer growth and neoangiogenesis accompanying with suppressed VEGF/VEGFR-2 signaling elevated apoptosis ratio and little toxic effects. The reason for this could be that ISL significantly inhibited VEGF expression in breast cancer cells via promoting HIF-1α proteasome degradation and directly interacted with VEGFR2 to block its kinase activity (Wang et al., 2013). Concerning the inhibition of tumorigenesis and metastasis of breast cancer, recently, a study showed that ISL inhibited phorbol 12-myristate 13-acetate (PMA)-induced cyclooxygenases (COX)-2 expression, an enzyme upregulating during breast tumor, in the non-tumorigenic (spontaneously immortal cell line) MCF-10A cells. In the molecular level, ISL deactivated protein kinase C alpha downstream mitogen-activated protein kinase, extracellular regulated protein kinases (ERK)-1/2, and suppressed DNA binding at the COX-2 promoter region ( 72/ 53), which was the binding location of the transcriptional factor of activator protein (AP)-1 or cyclic AMP response element Lau et al., Additionally, with the strong ability to suppress the expression of HIF-1α, VEGF, matrix metalloproteinase (MMP) 9/ 2, low concentration of ISL was considered to have therapeutic potential in the treatment of aggressive breast carcinoma via the inhibition of p38 expression, PI3K/Akt pathway, and nuclear factor-κ B (NF-κ B) signaling pathway. (Lorusso and Marech, 2013). (Jang et al., 2003) investigated numerous compounds isolated from the seeds of Dipteryx odorata. The result showed that ISL exhibited 76% inhibition in a mouse mammary organ at a dose of 10 μg/mL (Jang et al., 2003). It was also investigated that ISL could induce growth inhibition and apoptosis in human breast cancer cells (MCF-7 and MDAMB-231 (human breast adenocarcinoma cells) cells). In vitro test, ISL inhibited multiple key enzymes such as phospholipase A2, COX-2, and cytochrome P450 4A, in arachidonic acid (AA) metabolic network, with decreasing secretion of prostaglandin E2, 20hydroxyeicosatetraenoic acid, and downregulating the levels of phospho-PI3K, phospho-phosphoinositide-dependent kinase (Ser241), phospho-Akt (Thr308), phospho-Bad (Ser136), and Bcl-xL expression, which Phytother. Res. 29: 969–977 (2015)

A REVIEW: THE PHARMACOLOGY OF ISL

resulted in activating caspase cascades and eventually cleaving PARP. In vivo test, the treatment with ISL led to significant inhibition of tumor growth of MDAMB-231 human breast cancer xenografts in nude mice, which could be attributive to the ability of ISL to downregulate AA-metabolizing enzymes and the deactivation of PI3K/Akt (Li et al., 2013). Meanwhile, it was found that ISL served as the active component with rLE (roasted licorice) treatment to bone destruction in patients with breast cancer, remarkably suppressed receptor activator of nuclear factor kappa-B ligand-induced osteoclast formation murine bone marrowderived macrophages (Lee et al., 2013). Effect on hepatoma cancer As for hepatoma cancer cells, ISL has anti-hepatoma cancer activities as follows. First, Cuendet et al. (2010) (Cuendet et al., 2010) suggested that ISL had chemoprevention activity to murine hepatoma cells through induction of phase II enzymes such as quinone reductase-1, glutathione and glutathione S-transferase in the liver (Cuendet et al., 2010). Second, ISL was shown to be a monofunctional inducer and had quinone reductase inducing ability in wild-type Hepa 1c1c7 cells, leading to the decrease of the risk of developing cancer (Cuendet et al., 2006). Third, ISL could be served as a natural antioxidant abating ROS in human hepatoma cells (HepG2) in a time-dependent manner in the first 6 h, with the decrease of NF erythroid-2-related factor 2 and antioxidant enzymes. After 6 h of ISL treatment, because original redox status was disrupted, ROS was clearly higher than before, which resulted in serious oxidative stress and ultimately enhanced the radio sensitivity of HepG2 cells (Sun et al., 2013). Fourth, ISL showed anti-proliferation effects in HepG2 cells by arresting G2/M-phase and programming cell death. The further mechanism might be ISL upregulating p53, then triggering the p21/WAF1, Fas/apolipoprotein-1 receptor, Fas ligand, Bax, and NOXA (Hsu et al., 2005a). Meanwhile, ISL upregulated Iκα expression in the cytoplasm, decreased NF-κB expression, and suppressed the expression of Bcl-xL and c-IAP1/ 2 protein, as well as the downstream target molecule of NF-κB to inhibit the growth of HepG2 cells (Hsu et al., 2005b). Additionally, according to the study of Zhang et al. (Zhang et al., 2013a), it could be inferred that when combined with nanostructured lipid carriers, ISL showed a more significant anticancer activity than the group only treated with ISL to murine hepatoma 22 (H22)-bearing mice mode and improved the ability of ISL to enhance immunity. In vitro test, ISL-loaded nanostructured lipid carrier (ISL-NLC) significantly inhibited tumor growth, and the ISL concentration of ISL-NLC in tumor is 2.5-fold higher than ISL suspension. Besides, the elimination half-life (t1/2), area under the curve, and the mean residence times of the ISL-NLC were much longer than that of the ISL suspension (Zhang et al., 2013a). Effect on colon cancer Isoliquiritigenin was found to be the most potent antioxidant agent and prevented the incidence of 1,2-dimethylhydrazine-induced colon tumors (Chin et al., 2007). In respect of antineoplastic effects on colon Copyright © 2015 John Wiley & Sons, Ltd.

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tumors, it was the first time to find that ISL could overcome resistance to tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in colon cancer HT29 (Human colon adenocarcinoma cells) cells mainly via increasing the amount of dearth receptor 5 protein among TRAIL receptors and the chemopreventive effects of ISL treatment combined with TRAIL, which markedly induced apoptosis was primarily dependent on TRAIL function (Yoshida et al., 2008). Isoliquiritigenin markedly decreased prostaglandin E2, nitric oxide (NO) production in RAW264.7 mouse macrophage cells, and suppressed cell growth, caused apoptosis in mouse and human colon carcinoma cells. Moreover, the in vivo administration of ISL inhibited the induction of preneoplastic aberrant crypt foci in the male F344 rat colon (Takahashi et al., 2004). However, it was reported that apoptosis induced by ISL in mouse colon adenocarcinoma colon 26 was negatively regulated by the COX2, the enzyme in chronic inflammation, which was the reason of carcinogenesis, especially for colon cancer (Takahashia et al., 2006).

Effect on prostate cancer Recent study investigation showed that ISL markedly inhibited the proliferation of both C4-2 and LNCaP prostate cancer cells in a dose-dependent fashion through significantly decreasing ROS levels and the mitochondrial membrane potential [Psi(m)], without affecting intraepithelial carcinoma-6 normal epithelial cells. The mechanism of selective inhibition to C4-2 cells was partly attributed to defective AMP-dependent/activated protein kinase and ERK signaling pathways (Zhang et al., 2010). Isoliquiritigenin exerted the antitumorigenic activities on DU145 human and MatLyLu rat prostate cancer cells through the alteration of cell cycle progression. Isoliquiritigenin increased the percentage of cells in the G1 phase and promoted cell cycle arrest, with the mechanism of decreasing the protein levels of cyclin D1, cyclin E, and cyclin-dependent kinase-4 (Lee et al., 2009c). In addition, ISL was also reported about the effects on the characteristics of DU145, especially cell invasion and migration. The mechanisms were that ISL could inhibit c-Jun NH2-terminal kinase (JNK (Jun N-terminal kinase))/AP-1 signaling pathway, with the decrease of epidermal growth factor-induced secretion of urokinase-type plasminogen activator, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, VEGF, and AP-1 binding activity (Kwon et al., 2009). Due to enhancing the expression of growth arrest DNA damage (GADD)153 mRNA and protein and stimulating transcriptional activity of (growth arrest- and DNA damage-inducible gene) GADD153 promoter, ISL inhibited the proliferation of prostate cancer cell lines in S and G2/M phase (Kanazawa et al., 2003). Furthermore, ISL had an inhibitory effect on prostate cancer cell growth by inducing apoptosis, which was the result of the increase of cytochrome c and Smac/diablo from the mitochondria into the cytoplasm, the levels of cleaved caspase-9, caspase-7, caspase-3, and poly (ADP-ribose) polymerase (Jung et al., 2006b), and the reduction of protein or mRNA levels of ErbB3 (Jung et al., 2006a). Phytother. Res. 29: 969–977 (2015)

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Effect on human leukemia Antioxidant ISL inhibited the proliferation and induced the monocytic differentiation in human promyelocytic leukemia cells, mainly through decreasing iROS level and increasing nitro blue tetrazolium chloride reductive activity in HL-60 is Human promyelocytic leukemia cells (HL)60 cells (Li et al., 2009b). Chowdhury et al. (2005) (Chowdhury et al., 2005) test some constituents anti-tumor effects in squamous cell carcinoma hepatic stellate cell (HSC)-2, HSC-3, submandibular gland carcinoma human submandibular gland cell line can be abbreviated as HSG, and promyelocytic leukemia HL-60 cell lines. The results demonstrated that ISL exerted higher cytotoxicity against the all tumor cell lines than normal cells, with the ability to induce internucleosomal DNA fragmentation and activate caspase-3, caspase-8, and, caspase-9 dose dependently in HL-60 cells (Chowdhury et al., 2005). The study of Chen et al (2013) (Chen et al., 2013) showed that the exposure of ISL could facilitate differentiation in HL-60 cells, which resulted in ameliorating morphology changes. Isoliquiritigenin also decreased iROS-reduced nitro blue tetrazolium chloride activities and expression levels of surface antigens CD11b/CD14 through modulation of the nuclear erythroid-related factor 2/antioxidant responsive element [NF-E2-related factor 2 (Nrf2)/ARE (antioxidant responsive element)] pathway. Moreover, intercellular redox homeostasis in HL-60 changed toward oxidation with the ISL treatment, while the unique expression levels of Nrf2/ARE downstream target genes showed significant and dose-dependent increase (Chen et al., 2013). The mechanism demonstration conducted by their group showed that ISL-induced monocytic differentiation was associated with the increase of both translation and transcription of the nicotinamide adenine dinucleotide phosphate oxidase subunits gp91phox and p47phox (Chen et al., 2012a). Meanwhile, assayed by the microfluidic approach, ISL was found to stimulate sustained cellular [Ca2+] elevations and cytotoxicity on leukemia cell, leading to its damage and death (Li et al., 2009b). As for the cytotoxic activity to CCRF-CEM human T-cell leukemia cells, ISL could arrest the cell cycle in the G2/M phase, disrupt mitochondrial membrane potential (delta psim), and damage plasmid DNA (Zu et al., 2009). Effect on oral carcinoma Assayed with human oral carcinoma, ISL showed high cytotoxicity against tumor cells, with the molecular basis of bulky and a mass of phenolic OH groups (Ohno et al., 2013). One of the derivatives, ISL 20-methyl ether (ILME) inhibited the growth of the oral cancer cells in a time and dose-dependent manner. The molecular mechanism was that ILME could time dependently activate NF-ĸB transcription factors and phosphorated the Mitogen-activated protein kinases JNK and ERK. Likewise, ILME treatment upregulated heme oxygenase 1 (HO-1) expression though activation of Nrf2 pathway and induced the expression (Lee et al., 2010b). Effect on other types of cancer It was found that ISL showed concentration-dependent inhibition on the growth, viability, migration, and ability Copyright © 2015 John Wiley & Sons, Ltd.

to induce tube formation of human endothelial hybridoma cells of adenoid cystic carcinoma (ACC) cells in vitro test. In vivo test, ISL also significantly decreased microvessel density within xenograft tumors, associating with the reduction of VEGF production and suppression of the mammalian target of rapamycin (mTOR) pathway coregulated by JNK and ERK. The study revealed that the mechanism was that ISL downregulated mTOR pathway-dependent VEGF production on ACC cells, correlating with concurrent activation of JNK and inhibition of ERK (Sun et al., 2010). Isoliquiritigenin also possessed antitumor activity to U87 glioma cells in a time and dose-dependent manner. In the molecular level, it had been demonstrated that ISL induced the apoptosis of the U87 cells and blocked cell cycle progression at the S and G2/M phases with upregulating p21/WAF1 and p27 (Zhou et al., 2013). In the present study, in vitro, ISL showed its anti-melanoma activities via limiting tumorigenicity of mouse melanoma B16F0 cells, inducing dendrite morphological changes in B16F0 cells, stimulating melanin biosynthesis, and increasing TYR (tyrosinase) activity. As for in vivo assay, ISL pretreatment inhibited the tumor of B16F0 cells. The mechanism was involving the increase of iROS formation and accumulation facilitating melanogenesis (Chen et al., 2012c). Additionally, ISL significantly inhibited A549 human lung cancer cell line proliferation by restraining the cell cycle progression at G1 and G2/M phase, meanwhile, enhancing the expression of p53 and p21CIP1/WAF1, improving Fas and its two ligands (Hsu et al., 2004) (Ii et al., 2004). Moreover, a study investigated the mechanisms of ISL-induced apoptosis in ovarian carcinoma SKOV-3 cells and found that ISL intensified iROS levels and induced SKOV-3 cell apoptosis, which was the result of the enhancement of estrogen receptor stress-related molecules α-subunit of eukaryotic initiation factor 2 phosphorylation, DNA damageinducible gene (GADD153/CHOP), 78 kDa glucoseregulated protein, X-box binding protein 1, and cleavage of activating transcription factor 6α (Yuan et al., 2013a). In addition, another finding suggested that the treatment with ISL, in vitro test, could inhibit the growth of multiple myeloma (MM) cells and induce the apoptosis in a time and dose-dependent manner. In vivo, the effect of ISL on MM xenograft model was significant, with enhancing the anti-myeloma activity of adriamycin. This action might relate to ISL’s ability to downregulate both IL-6 expression and levels of phosphorylated ERK as well as signal transducers and activators of transcription 3 (Chen et al., 2012b). Antiinflammation activity Isoliquiritigenin suppressed the expression of (vascular cell adhesion molecule) VCAM-1 and E-selectin on activated human umbilical vein endothelial cells (HUVEC), markedly interfered with THP monocyte adhesion to TNF-α-activated endothelial cells and attenuated platelet endothelial cell adhesion molecule-1 expression induced by TNF-α. In the molecular basis, ISL abolished TNF-α-induced mRNA accumulation of VCAM-1 and E-selectin and downregulated cell adhesion molecule proteins in TNF-α-activated HUVEC at the transcriptional levels by blocking degradation of Phytother. Res. 29: 969–977 (2015)

A REVIEW: THE PHARMACOLOGY OF ISL

IĸBα and nuclear translocation of NF-κB (Kwon et al., 2007). Isoliquiritigenin also exerted antiinflammatory effects through antinephritic effects on high serum IgA mice because of a specific inhibitory effect on plateletderived growth factor receptor tyrosine kinase (Hattori et al., 2007). Moreover, ISL abated the inflammatory response of macrophages, which were induced by aggregatibacter actinomycetemcomitans lipopolysaccharide (LPS), via inhibiting the activation of NF-κB p65 and AP-1 (Feldman et al., 2011). The mechanism was that ISL could induce HO-1 expression through the ERK 1/2 pathway in RAW264.7 macrophages, with the inhibition of LPS-induced NO, IL-1β, and TNF-α production, and HO-1 could mediate the antiinflammatory effects of ISL through LPS-induced NO and TNF-α production reversedly (Lee et al., 2009b). Meanwhile, due to the ability to affect Th2-mediated inflammation, ISL could be served as anti-asthma herbal medicine with inhibitory effects on memory Th2 responses in vitro and antigen-induced Th2 inflammation in vivo via significant suppressing IL-4 and IL-5 production in a dose-dependent manner (Yang et al., 2013). As for the effect on LPS-stimulated bone marrow-derived dendritic cells, ISL exhibited significant inhibitory effects on LPS-induced IL-6 and IL-12 p40 production and showed a moderate inhibitory effect on LPSstimulated production of TNF-α (Li et al., 2014).

Hepatoprotective effects Gaur et al. (Gaur et al., 2010) revealed that ISL had hepatoprotective activity against D-galactosaminelipopolysaccharide (GalN/LPS)-induced toxicity, because in the ISL treatment groups, there was a significant increase in liver toxicity biomarkers, serum glutamic-pyruvic transaminase, serum glutamicoxaloacetic transaminase, ALKP, triglyceride, lipid peroxidation, NO, and lactate dehydrogenase (Gaur et al., 2010). Isoliquiritigenin could stimulate the proliferation of hepatocytes but did not affect liverspecific functions (De Bartolo et al., 2005). While in the Abdollahi et al. (2003) (Abdollahi et al., 2003) study, ISL showed a weak effect on increasing cAMP (Cyclic adenosine monophosphate) and glucose formation after preincubation of isolated hepatocytes with phosphodiesterase 3 and 4 inhibitors (Abdollahi et al., 2003). Besides, against toxicity, ISL inhibited liver X receptor-α (LXRα)-mediated hepatic lipogenesis and steatosis and protected hepatocytes from oxidative injury inflicted. The molecular basis was that the treatment with ISL antagonized the ability of an LXRα agonist (T0901317) through the inhibitory effect on activating phosphorylation of JNK1 elicited by palmitate or TNF-α, then, leading to promoting LXRα activation and activating the sterol regulatory element-binding protein-1c (Kim et al., 2010). Additionally, ISL exhibited the inhibitory ability to HSCs, and relevant findings indicated that the antiproliferative effect of ISL on rat HSCs was associated with the mitogen-activated protein kinase and phosphatidylinositol 3-kinase-Akt-p70 (S6K) pathways as well as HO-1, which could mediate the inhibitory action of ISL on platelet-derived growth factor-induced proliferation (Woo et al., 2008). Copyright © 2015 John Wiley & Sons, Ltd.

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Cardioprotective effects Zhang et al. (2013b) (Zhang et al., 2013b) indicated that ISL could protect the heart against ischemic injury, via ameliorating cardiomyocytes contractile dysfunction and reducing the mitochondrial potential of isolated mouse cardiomyocytes, which may attribute to the activation of activated protein kinase and ERK signaling pathways and balance of cellular redox status (Zhang et al., 2013b). Isoliquiritigenin could also attenuate myocardial ischemia reperfusion injury in rats by inducing metallothionein (MT). Isoliquiritigenin treatment decreased the severity of reperfusion-induced arrhythmias and myocardial infarct size, through ameliorating the activation of janus kinase 2/signal transducers and activators of transcription 3 pathway, accompanied by increased synthesis of MT (Wei et al., 2006). Additionally, ISL concentration dependently inhibited ultrarapidly activating delayed-rectifier K+ current (IKur) in H9c2 cells, a cell-line derived from rat cardiac myoblasts. Therefore, ISL was a potent inhibitor of K+ channels and involved in pharmacological effects on protection of heart diseases like ischemic injury (Noguchi et al., 2008). Effect on diabetes Isoliquiritigenin offered the potential for being natural sources for therapeutic and preventive agents for diabetic complications, because of its inhibitory effects on aldose reductase (AR), human recombinant AR, and sorbitol formation in rat lenses with high levels of glucose. The molecular mechanism counted on the presence of a γ, γ-dimethylchromene ring in the structure of ISL, and the special molecular constitution was partly responsible for the AR inhibitory activity so as to prevent osmotic stress in hyperglycemia (Lee et al., 2010a). In the meantime, ISL could abate the symptoms induced by high glucose (HG). More precisely, ISLinhibited HG-induced mesangial fibrosis, boosted HGplummeted type MMP-1 expression, and dampened HG-elevated TIMP-2 expression facilitated the degradation of mesangial matrix. The mechanism of the ISL inhibition of HG-upregulated connective tissue growth factor and TIMP-2 expression was that ISL disturbed transforming growth factor (TGF)-β1 signaling in HRMC, as evidenced by TGF-β receptor I kinase (TGF-βRI) inhibitor. Isoliquiritigenin suppressed induction of TGF-β RII and TGF-β RI with blunting their downstream SMAD signaling and repealed HGinduced SMAD4 expression of HRMC (human mesangial cells) (Li et al., 2010a). Meanwhile, as for ISL derivatives, it is manifested that ISL derivatives 2, 3, 4, and 6 (Fig. 1.) displayed significant blood glucose lowering effect, and compounds 3 (Fig. 1.) demonstrated the antidiabetic activity on in vivo level. Hence, natural products owing similar structures are potential candidates for treatment of diabetes (Gaur et al., 2014). Antiangiogenic activity The antiangiogenic property of ISL was mainly relied on its ability to inhibit VEGF-induced vessel growth in a dose-dependent manner and induce pigment epithelium-derived factor expression in cultured Phytother. Res. 29: 969–977 (2015)

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endothelial cells. In vivo experiments, topical ISL alleviated corneal neovascularisation and intravitreal ISLreduced vessel leakage as well as Griffonia simplicifolia isolectin- B4 (GSA I-B4)-positive vascular area in choroidal and retinal neovascularisation (Jhanji et al., 2011). Isoliquiritigenin significantly inhibited the VEGF-induced proliferation of HUVEC at non-toxic concentration. In vitro assay, ISL interrupted tube formation, invasion, and migration abilities of HUVEC, a series of angiogenesis processes as well. In an ex vivo model, ISL suppressed sprout formation from VEGFtreated aortic rings (Wang et al., 2013). Additionally, ISL dose dependently restrained PMA-induced MMP production, whose aberrant expression in matrix degradation would lead to angiogenesis, increased TIMP production in endothelial cells. At length, ISL inhibited PMA-triggered migration, tube formation in a dosedependent manner, and blocked cJNK-responsive or p38 mitogen-activated protein kinase-responsive pathways, which was responsible for the MMP production (Kang et al., 2010). Immunoregulatory effects The therapeutic potential of ISL was on (toll-interleukin-1 receptor domain-containing adapter inducing interferon-beta) TRIF-dependent signaling pathways of toll-like receptors (TLRs), which played an important role in host defense by sensing invading microbial pathogens and initiating innate immune responses. Mechanically, ISL inhibited NF-κB and interferon regulatory factor 3 activation induced by LPS or polyinosinicpolycytidylic acid and had inhibitory effect on the LPSinduced phosphorylation of interferon regulatory factor 3 as well as interferon-inducible genes such as interferon inducible protein-10, with regulating activation of normal T-cell expressed and secreted (Park et al., 2009b). Likewise, ISL inhibited LPS-induced TLR4 dimerization at the receptor level, resulting in the inhibition of NF-κB and interferon regulatory factor 3 activation, and COX-2 and nducible nitric oxide synthase (iNOS) expression (Park and Youn, 2010a). In addition, TANK-binding kinase 1 kinase was one of the molecular targets of ISL, resulting in the downregulation of the TRIF-dependent signaling pathway (Park and Youn, 2010b).

As for cerebral ischemia injury, ISL showed the protective potential activity via increasing the brain ATP (Adenosine triphosphate) content, energy charge, and total adenine nucleotides in a dose-dependent manner, inhibiting brain malondialdehyde content and preventing the activities of brain superoxide dismutase, catalase, and glutathione peroxidase from declines caused by cerebral ischemia–reperfusion, which could be concluded as the amelioration of cerebral energy metabolism and its antioxidant property (Zhan and Yang, 2006). Besides that, because ISL had furan rings of the polyphenols and apioside group, ISL had a strong inhibitory activity on neuraminidase activation (Ryu et al., 2010). Anti-microbial activity Compared with liquiritigenin, it was reported that ISL showed a more essential antibacterial activity against three major periodontopathogens, that is, Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia, and a stronger inhibitory activity to P. gingivalis collagenase and human MMP-9 (Feldman et al., 2011). Recently, Zhao et al. (2011) (Zhao et al., 2011) found that ISL showed a strong inhibitory activity against Ralstonia solanacearum with an inhibition zone diameter of 14.15 mm (Zhao et al., 2011). Similarly, ISL inhibited the growth of Mycobacterium bovis targeting Rv0636 and decreased putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II (Brown et al., 2007). Anti-anorexia activity A recent study found that ISL, an ingredient of rikkunshito (RKT), had inhibitory effects on phosphodiesterase 3 that could be the reason why RKT had the ability to ameliorate aging-associated anorexia (Takeda et al., 2010). The study of the mechanism revealed that ISL suppressed 5-HT-induced Ca2+ increases, which would help RKT action to attenuate anorexia induced by excessive 5-HT release, and ISL could antagonize 5-HT action in arcuate nucleus pro-opiomelanocortin neurons (Arai et al., 2013). Other effects

Neuroprotective activity Isoliquiritigenin abated glutamate-induced mitochondrial damage and hippocampal neuronal cell death caused by glutamate, with the molecular mechanisms that ISL inhibited the release of apoptosis-inducing factor, Bcl-2 and Bax, from mitochondria into the cytosol, and suppressed glutamate-induced ROS production (Yang et al., 2012). In addition, ISL had the ability to prevent Aβ (25–35)-induced neuronal apoptotic death through elevation of Ca2+, ROS generation, and the change of apoptosis-associated proteins in cultured cortical neurons (Lee et al., 2012). The inhibitory effect of ISL on methamphetamine-induced reduction of striatal dopamine transporter and tyrosine hydroxylase could protect cells from methamphetamine-induced neurotoxicity through impeding the expression of NO synthase and the activation of NF-κB (Lee et al., 2009b). Copyright © 2015 John Wiley & Sons, Ltd.

Isoliquiritigenin was found to reduce gastric acid secretion and protect gastric mucosal lesion formation in pylorus-ligated rat model in the study of Kim et al. (2006) (Kim et al., 2006). The decrease of gastric acid secretion counted on the selective H2 histamine receptor (H2R) antagonistic effect of ISL. Isoliquiritigenin could serve as an effective H2R antagonist via inhibiting H2R agonist-induced cAMP response in a concentrationdependent manner and blocking the binding affinity of [(3)H] tiotidine to membrane receptors. In molecular docking studies, ISL prominently inhibited H2Rselective agonist dimaprit-induced cAMP generation in an MKN-45 gastric cancer cell (Kim et al., 2006). With the ability to block mainly the cystic fibrosis transmembrane conductance regulator (CFTR) Cl channels, ISL dose dependently abolished the cholera toxin-induced transepithelial Cl secretion in human Phytother. Res. 29: 969–977 (2015)

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intestinal epithelial (T84) cells, reduced the cholera toxin-induced intestinal fluid secretion in mouse-closed loop models, inhibited the cAMP-activated apical Cl current in monolayers of Madin–Darby canine kidney (MDCK) cells, and retarded cyst growth in MDCK cyst models. The results suggested that ISL had the therapeutic potential for treatment of cholera and polycystic kidney disease as a potent CFTR inhibitor (Muanprasat et al., 2012). Also, ISL significantly inhibited the mono and diphenolase tyrosinase activities with (half maximal inhibitory concentration) IC 50 value of 8.1 μM and inhibited melanin formation in melanocytes, respectively (Nerya et al., 2003). In addition, ISL promoted human retinal pigment epithelial (ARPE19) cells growth at noncytotoxic 10 μM while suppressing HUVEC growth and migration. In protein level, ISL mildly increased total focal adhesion kinase (FAK) expression and the proportion of phospho-FAK in total FAK and maintained PEDF (pigment epithelium-derived factor) at a slightly higher level (Cao et al., 2010). Additionally, ISL dose dependently inhibited cocaine-induced extracellular dopamine level in the nucleus accumbens, resulting in attenuation of the expression of c-Fos, via modulating GABAB receptor (Jang et al., 2008). Isoliquiritigenin had a spasmolytic effect on uterine contraction in a concentration-dependent fashion in vitro and reduced the acetic acid-induced writhing response and hot-plate test in vivo, of which the mechanism involved Ca2+ channels, NOS, and COX (Shi et al.,

2012). Likewise, it suggested that ISL, isolated from RKT, could improve the decrease in food intake after exposure to novelty stress by antagonizing 5-HT2B receptor (Yamada et al., 2013).

CONCLUSION Overall, the various researches exhibited significant pharmacological properties of ISL in vitro and in vivo, especially about anticancer activity, which could be beneficial for both the prevention and the treatment of tumor. However, further studies are required for investigation in molecular basis underlying certain pharmacological actions, antibacterial effects for an example. Although various bioactivities of ISL are confirmed in laboratory animals, organs, or cells, few molecular mechanisms of action are known, and the definitive target proteins bound by ISL still remain undetermined, which will make against further clinical applications of ISL. When a drug is used in clinical practice, its safety is especially important. Unfortunately, there are also few toxicological evaluations reported on ISL.

Conflict of Interest The authors have declared that there is no conflict of interest.

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Phytother. Res. 29: 969–977 (2015)

A Review: The Pharmacology of Isoliquiritigenin.

Isoliquiritigenin (ISL) is one of the bioactive ingredients isolated from the roots of plants belonging to licorice, including Glycyrrhiza uralensis, ...
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