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1.  Induction of Apoptosis and Nonsteroidal Antiinflammatory Drug-Activated Gene 1 in Pancreatic Cancer Cells By A Glycyrrhetinic Acid Derivative 
Molecular carcinogenesis  2009;48(8):692-702.
Methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) is a synthetic triterpenoid derived from glycyrrhetinic acid, a bioactive phytochemical in licorice, CDODA-Me inhibits growth of Panc1 and Panc28 pancreatic cancer cell lines and activates peroxisome proliferator-activated receptor γ (PPARγ)-dependent transactivation in these cells. CDODA-Me also induced p21 and p27 protein expression and downregulates cyclin D1; however, these responses were receptor-independent. CDODA-Me induced apoptosis in Panc1 and Panc28 cells, and this was accompanied by receptor-independent induction of the proapoptotic proteins early growth response-1 (Egr-1), nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), and activating transcription factor-3 (ATF3). Induction of NAG-1 and Egr-1 by CDODA-Me was dependent on activation of phosphatidylinositol-3-kinase (PI3-K) and/or p42 and p38 mitogen-activated protein kinase (MAPK) pathways but there were differences between Panc28 and Panc1 cells. Induction of NAG-1 in Panc28 cells was p38-MAPK- and PI3-K-dependent but Egr-1-independent, whereas induction in Panc1 cells was associated with activation of p38-MAPK, PI3-K and p42-MAPK and was only partially Egr-1-dependent. This is the first report of the induction of the proapoptotic protein NAG-1 in pancreatic cancer cells.
PMCID: PMC2746008  PMID: 19125423
CDODA-Me; pancreatic cancer; apoptosis
2.  Unifying Mechanisms of Action of the Anticancer Activities of Triterpenoids and Synthetic Analogs 
Triterpenoids such as betulinic acid (BA) and synthetic analogs of oleanolic acid [2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)] and glycyrrhetinic acid [2-cyano-3,11-dioxo-18β-oleana-1,12-dien-30-oc acid (CDODA)] are potent anticancer agents that exhibit antiproliferative, antiangiogenic, anti-inflammatory and pro-apoptotic activities. Although their effects on multiple pathways have been reported, unifying mechanisms of action have not been reported. Studies in this laboratory have now demonstrated that several triterpenoids including BA and some derivatives, celastrol, methyl ursolatee, β-boswellic acid derivatives, and the synthetic analogs CDDO, CDODA and their esters decreased expression of specificity protein (Sp) transcription factors and several pro-oncogenic Sp-regulated genes in multiple cancer cell lines. The mechanisms of this response are both compound- and cell context-dependent and include activation of both proteasome-dependent and -independent pathways. Triterpenoid-mediated induction of reactive oxygen species (ROS) has now been characterized as an important proteasome-independent pathway for downregulation of Sp transcription factors. ROS decreases expression of microRNA-27a (miR-27a) and miR-20a/miR-17-5p and this results in the induction of the transcriptional “Sp-repressors” ZBTB10 and ZBTB4, respectively, which in turn downregulate Sp and Sp-regulated genes. Triterpenoids also activate or deactive nuclear receptors and G-protein coupled receptors, and these pathways contribute to their antitumorigenic activity and may also play a role in targeting Sp1, Sp3 and Sp4 which are highly overexpressed in multiple cancers and appear to be important for maintaining the cancer phenotype.
PMCID: PMC3532564  PMID: 22583404
Sp transcription factors; downregulation; reactive oxygen species
3.  Structural basis for 18-β-glycyrrhetinic acid as a novel non-GSH analog glyoxalase I inhibitor 
Acta Pharmacologica Sinica  2015;36(9):1145-1150.
Glyoxalase I (GLOI), a glutathione (GSH)-dependent enzyme, is overexpressed in tumor cells and related to multi-drug resistance in chemotherapy, making GLOI inhibitors as potential anti-tumor agents. But the most studied GSH analogs exhibit poor pharmacokinetic properties. The aim of this study was to discover novel non-GSH analog GLOI inhibitors and analyze their binding mechanisms.
Mouse GLOI (mGLOI) was expressed in BL21 (DE3) pLysS after induction with isopropyl-β-D-1-thiogalactopyranoside and purified using AKTA FPLC system. An in vitro mGLOI enzyme assay was used to screen a small pool of compounds containing carboxyl groups. Crystal structure of the mGLOI-inhibitor complex was determined at 2.3 Å resolution. Molecular docking study was performed using Discovery Studio 2.5 software package.
A natural compound 18-β-glycyrrhetinic acid (GA) and its derivative carbenoxolone were identified as potent competitive non-GSH analog mGLOI inhibitors with Ki values of 0.29 μmol/L and 0.93 μmol/L, respectively. Four pentacyclic triterpenes (ursolic acid, oleanolic acid, betulic acid and tripterine) showed weak activities (mGLOI inhibition ratio <25% at 10 μmol/L) and other three (maslinic acid, corosolic acid and madecassic acid) were inactive. The crystal structure of the mGLOI-GA complex showed that the carboxyl group of GA mimicked the γ-glutamyl residue of GSH by hydrogen bonding to the glutamyl sites (residues Arg38B, Asn104B and Arg123A) in the GSH binding site of mGLOI. The extensive van der Waals interactions between GA and the surrounding residues also contributed greatly to the binding of GA and mGLOI.
This work demonstrates a carboxyl group to be an important functional feature of non-GSH analog GLOI inhibitors.
PMCID: PMC4561975  PMID: 26279158
glyoxalase I; 18-β-glycyrrhetinic acid; carbenoxolone; pentacyclic triterpenes; GSH binding site; crystal structure; molecular docking
4.  Synthesis and Pro-Apoptotic Activity of Novel Glycyrrhetinic Acid Derivatives 
Chembiochem  2011;12(5):784-794.
Triterpenoids are used for medicinal purposes in many countries. Some, such as oleanolic and glycyrrhetinic acids, are known to be anti-inflammatory and anticarcinogenic. However, the biological activities of these naturally occurring molecules against their particular targets are weak, so the synthesis of new synthetic analogues with enhanced potency is needed. By combining modifications to both the A and C rings of 18βH-glycyrrhetinic acid, the novel synthetic derivative methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien-30-oate was obtained. This derivative displays high antiproliferative activity in cancer cells, including a cell line with a multidrug-resistance phenotype. It causes cell death by inducing the intrinsic caspase-dependent apoptotic pathway.
PMCID: PMC3085123  PMID: 21328513
antitumor agents; apoptosis; biological activity; glycyrrhetinic acid derivatives; medicinal chemistry
Molecular carcinogenesis  2011;50(9):655-667.
Methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) and the corresponding 2-trifluoromethyl analog (CF3DODA-Me) are derived synthetically from the triterpenoid glycyrrhetinic acid, a major component of licorice. CDODA-Me and CF3DODA-Me inhibited growth of highly invasive ARO, DRO, K-18 and HTh-74 thyroid cancer cells and this was due, in part, to decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 that are overexpressed in these cells. CDODA-Me and CF3DODA-Me also decreased expression of Sp-dependent genes, such as survivin and vascular endothelial growth factor, and induced apoptosis. In addition, pituitary tumor-transforming gene-1 (PTTG-1) protein and mRNA levels were also decreased in thyroid cancer cells treated with CDODA-Me or CF3DODA-Me and this was accompanied by decreased expression of PTTG-1-dependent c-Myc and fibroblast growth factor 2 genes. RNA interference studies against Sp1, Sp3 and Sp4 proteins showed that in thyroid cancer cells, PTTG-1 was an Sp-dependent gene. This study demonstrates for the first time that drugs, such as CDODA-Me and CF3DODA-Me, that decrease Sp protein expression also downregulate PTTG-1 in thyroid cancer cells and therefore have potential for clinical treatment of thyroid cancer and other endocrine neoplasias where PTTG-1 is a major pro-oncogenic factor.
PMCID: PMC3128656  PMID: 21268135
PTTG-1; Sp proteins; thyroid cancer; anticancer agents
6.  Ursolic acid, a natural pentacyclic triterpenoid, inhibits intracellular trafficking of proteins and induces accumulation of intercellular adhesion molecule-1 linked to high-mannose-type glycans in the endoplasmic reticulum 
FEBS Open Bio  2014;4:229-239.
Graphical abstract
•Ursolic acid inhibits cell-surface expression of ICAM-1.•Ursolic acid induces accumulation of high-mannose-type ICAM-1 in ER.•Ursolic acid induces morphological changes of Golgi apparatus.•Ursolic acid inhibits intracellular trafficking of proteins.
Ursolic acid (3β-hydroxy-urs-12-en-28-oic acid) is a natural pentacyclic triterpenoid that is present in many plants, including medicinal herbs, and foods. Ursolic acid was initially identified as an inhibitor of the expression of intercellular adhesion molecule-1 (ICAM-1) in response to interleukin-1α (IL-1α). We report here a novel biological activity: ursolic acid inhibits intracellular trafficking of proteins. Ursolic acid markedly inhibited the IL-1α-induced cell-surface ICAM-1 expression in human cancer cell lines and human umbilical vein endothelial cells. By contrast, ursolic acid exerted weak inhibitory effects on the IL-1α-induced ICAM-1 expression at the protein level. Surprisingly, we found that ursolic acid decreased the apparent molecular weight of ICAM-1 and altered the structures of N-linked oligosaccharides bound to ICAM-1. Ursolic acid induced the accumulation of ICAM-1 in the endoplasmic reticulum, which was linked mainly to high-mannose-type glycans. Moreover, in ursolic-acid-treated cells, the Golgi apparatus was fragmented into pieces and distributed over the cells. Thus, our results reveal that ursolic acid inhibits intracellular trafficking of proteins and induces the accumulation of ICAM-1 linked to high-mannose-type glycans in the endoplasmic reticulum.
PMCID: PMC3958921  PMID: 24649404
BSA, bovine serum albumin; Endo H, endoglycosidase H; ER, endoplasmic reticulum; HRP, horseradish peroxidase; HUVEC, human umbilical vein endothelial cells; ICAM-1, intercellular adhesion molecule-1; IκB, inhibitor of nuclear factor κB; IL-1, interleukin-1; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NF-κB, nuclear factor κB; PBS, phosphate-buffered saline; PNGase F, peptide: N-glycosidase F; Glycosylation; Golgi apparatus; Intercellular adhesion molecule-1; Intracellular trafficking; Ursolic acid
7.  Ursolic acid inhibits the invasive phenotype of SNU-484 human gastric cancer cells 
Oncology Letters  2014;9(2):897-902.
Metastasis is a major cause of cancer-related mortality in patients with gastric cancer. Ursolic acid, a pentacyclic triterpenoid compound derived from medicinal herbs, has been demonstrated to exert anticancer effects in various cancer cell systems. However, to the best of our knowledge, the inhibitory effect of ursolic acid on the invasive phenotype of gastric cancer cells has yet to be reported. Therefore, the aim of the present study was to investigate the effect of ursolic acid on the invasiveness of SNU-484 human gastric cancer cells. Ursolic acid efficiently induced apoptosis, possibly via the downregulation of B-cell lymphoma 2 (Bcl-2), the upregulation of Bcl-2-associated X protein and the proteolytic activation of caspase-3. Furthermore, the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase was increased by the administration of ursolic acid. In addition, ursolic acid significantly suppressed the invasive phenotype of the SNU-484 cells and significantly decreased the expression of matrix metalloproteinase (MMP)-2, indicating that MMP-2 may be responsible for the anti-invasive activity of ursolic acid. Taken together, the results of the present study demonstrate that ursolic acid induces apoptosis and inhibits the invasive phenotype of gastric cancer cells; therefore, ursolic acid may have a potential application as a chemopreventive agent to prevent the metastasis of gastric cancer or to alleviate the process of metastasis.
PMCID: PMC4301486  PMID: 25621065
ursolic acid; cell invasion; matrix metalloproteinase
Biochemical pharmacology  2012;83(10):1445-1455.
NR4A2 (Nurr 1) is an orphan nuclear receptor with no known endogenous ligands and is highly expressed in many cancer cell lines including Panc1 and Panc28 pancreatic cancer cells. Structure-dependent activation of NR4A2 by a series of 1,1-bis(3′-indolyl)-1-(aromatic)methane (C-DIM) analogs was determined in pancreatic cancer cells transfected with yeast GAL4-Nurr1 chimeras and a UASx5-luc reporter gene or constructs containing response elements that bind NR4A2. Among 23 different structural analogs, phenyl groups containing p-substituted trifluoromethyl, t-butyl, cyano, bromo, iodo and trifluoromethoxy groups were the most active compounds in transactivation assay. The p-bromophenyl analog (DIM-C-pPhBr) was used as a model for structure-activity studies among a series of ortho-, meta- and para-bromophenyl isomers and the corresponding indole 2- and N-methyl analogs. Results show that NR4A2 activation was maximal with the p-bromophenyl analog and methylation of the indole NH group abrogated activity. Moreover, using GAL4-Nurr1 (full length) or GAL-Nurr1-A/B and GAL4-Nurr1-(C-F) chimeras expressing N- and C-terminal domains of Nurr1, respectively, DIM-C-pPhBr activated all three constructs and these responses were differentially affected by kinase inhibitors. DIM-C-pPhBr also modulated expression of several Nurr1-regulated genes in pancreatic cancer cells including vasoactive intestinal peptide (VIP), and the immunohistochemical and western blot analyses indicated that DIM-C-pPhBr activates nuclear NR4A2.
PMCID: PMC3408083  PMID: 22405837
DIM analogs; NR4A2/Nurr1; structure-activity
9.  Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway*  
Objective: To investigate the effects of ursolic acid on the proliferation and apoptosis of human HT-29 colon cancer cells. Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays were performed to evaluate the effects of ursolic acid on the growth and apoptosis of HT-29 cells. Western blot analysis was applied to investigate the inhibitory effects of ursolic acid on the phosphorylation of the epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK), and the activity of B cell leukemia-2 (Bcl-2), B cell leukemia-xL (Bcl-xL), caspase-3, and caspase-9. Results: Ursolic acid inhibited the growth of HT-29 cells in dose- and time-dependent manners. The median inhibition concentration (IC50) values for 24, 48, and 72 h treatment were 26, 20, and 18 μmol/L, respectively. The apoptotic rates of 10, 20, and 40 μmol/L ursolic acid treatments for 24 h were 5.74%, 14.49%, and 33.05%, and for 48 h were 9%, 21.39%, and 40.49%, respectively. Ursolic acid suppressed the phosphorylation of EGFR, ERK1/2, p38 MAPK, and JNK, which is well correlated with its growth inhibitory effect. 10, 20, and 40 μmol/L ursolic acid significantly inhibited the proliferation of EGF-stimulated HT-29 cells (P<0.05). Cell proliferation was most significantly inhibited when treated with 10 and 20 μmol/L ursolic acid combined with 200 nmol/L AG 1478 or 10 μmol/L U0126 (P<0.01). Besides, it also down-regulated the expression of Bcl-2 and Bcl-xL and activated caspase-3 and caspase-9. Conclusion: Ursolic acid induces apoptosis in HT-29 cells by suppressing the EGFR/MAPK pathway, suggesting that it may be a potent agent for the treatment of colorectal cancer.
PMCID: PMC2738836  PMID: 19735099
Colon cancer; Ursolic acid; Epidermal growth factor receptor (EGFR); Mitogen-activated protein kinase (MAPK); Apoptosis
10.  Oncogenic MicroRNA-27a Is A Target For Anticancer Agent Methyl 2-Cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate in Colon Cancer Cells 
Methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) is a synthetic derivative of glycyrrhetinic acid, a triterpenoid phytochemical found in licorice extracts. CDODA-Me inhibited growth of RKO and SW480 colon cancer cells and this was accompanied by decreased expression of Sp1, Sp3 and Sp4 protein and mRNA and several Sp-dependent genes including survivin, vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1 or Flt-1). CDODA-Me also induced apoptosis, arrested RKO and SW480 cells at G2/M, and inhibited tumor growth in athymic nude mice bearing RKO cells as xenografts. CDODA-Me decreased expression of microRNA-27a (miR-27a), and this was accompanied by increased expression of two miR-27a-regulated mRNAs, namely ZBTB10 (an Sp repressor) and Myt-1 which catalyzes phosphorylation of cdc2 to inhibit progression of cells through G2/M. Both CDODA-Me and antisense miR-27a induced comparable responses in RKO and SW480 cells, suggesting that the potent anticarcinogenic activity of CDODA-Me is due to repression of oncogenic miR-27a.
PMCID: PMC2766353  PMID: 19582879
CDODA-Me; anticarcinogenicity; miR-27a; colon cancer; cell cycle
11.  CDDO-Me: A Novel Synthetic Triterpenoid for the Treatment of Pancreatic Cancer 
Cancers  2010;2(4):1779-1793.
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancy with dismal prognosis and few effective therapeutic options. Novel agents that are safe and effective are urgently needed. Oleanolic acid-derived synthetic triterpenoids are potent antitumorigenic agents, but their efficacy or the mechanism of action for pancreatic cancer has not been adequately investigated. In this study, we evaluated the antitumor activity and the mechanism of action of methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me), a oleanane-derived synthetic triterpenoid for human pancreatic cancer cell lines. CDDO-Me inhibited the growth of both K-ras mutated (MiaPaca2, Panc1 and Capan2) and wild-type K-ras (BxPC3) pancreatic cancer cells at very low concentrations. The growth inhibitory activity of CDDO-Me was attributed to the induction of apoptosis characterized by increased annexin-V-FITC binding and cleavage of PARP-1 and procaspases-3, -8 and-9. In addition, CDDO-Me induced the loss of mitochondrial membrane potential and release of cytochrome C. The antitumor activity of CDDO-Me was associated with the inhibition of prosurvival p-Akt, NF-κB and mammalian target of rapamycin (mTOR) signaling proteins and the downstream targets of Akt and mTOR, such as p-Foxo3a (Akt) and p-S6K1, p-eIF-4E and p-4E-BP1 (mTOR). Silencing of Akt or mTOR with gene specific-siRNA sensitized the pancreatic cancer cells to CDDO-Me, demonstrating Akt and mTOR as molecular targets of CDDO-Me for its growth inhibitory and apoptosis-inducing activity.
PMCID: PMC3143824  PMID: 21799944
pancreatic cancer; CDDO-Me; apoptosis; Akt/mTOR signaling pathway
12.  CDDO-Me: A Novel Synthetic Triterpenoid for the Treatment of Pancreatic Cancer 
Cancers  2010;2(4):1779-1793.
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancy with dismal prognosis and few effective therapeutic options. Novel agents that are safe and effective are urgently needed. Oleanolic acid-derived synthetic triterpenoids are potent antitumorigenic agents, but their efficacy or the mechanism of action for pancreatic cancer has not been adequately investigated. In this study, we evaluated the antitumor activity and the mechanism of action of methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me), a oleanane-derived synthetic triterpenoid for human pancreatic cancer cell lines. CDDO-Me inhibited the growth of both K-ras mutated (MiaPaca2, Panc1 and Capan2) and wild-type K-ras (BxPC3) pancreatic cancer cells at very low concentrations. The growth inhibitory activity of CDDO-Me was attributed to the induction of apoptosis characterized by increased annexin-V-FITC binding and cleavage of PARP-1 and procaspases-3, -8 and-9. In addition, CDDO-Me induced the loss of mitochondrial membrane potential and release of cytochrome C. The antitumor activity of CDDO-Me was associated with the inhibition of prosurvival p-Akt, NF-κB and mammalian target of rapamycin (mTOR) signaling proteins and the downstream targets of Akt and mTOR, such as p-Foxo3a (Akt) and p-S6K1, p-eIF-4E and p-4E-BP1 (mTOR). Silencing of Akt or mTOR with gene specific-siRNA sensitized the pancreatic cancer cells to CDDO-Me, demonstrating Akt and mTOR as molecular targets of CDDO-Me for its growth inhibitory and apoptosis-inducing activity.
PMCID: PMC3143824  PMID: 21799944
pancreatic cancer; CDDO-Me; apoptosis; Akt/mTOR signaling pathway
13.  Steroid-like compounds in Chinese medicines promote blood circulation via inhibition of Na+/K+-ATPase 
Acta Pharmacologica Sinica  2010;31(6):696-702.
To examine if steroid-like compounds found in many Chinese medicinal products conventionally used for the promotion of blood circulation may act as active components via the same molecular mechanism triggered by cardiac glycosides, such as ouabain.
The inhibitory potency of ouabain and the identified steroid-like compounds on Na+/K+-ATPase activity was examined and compared. Molecular modeling was exhibited for the docking of these compounds to Na+/K+-ATPase.
All the examined steroid-like compounds displayed more or less inhibition on Na+/K+-ATPase, with bufalin (structurally almost equivalent to ouabain) exhibiting significantly higher inhibitory potency than the others. In the pentacyclic triterpenoids examined, ursolic acid and oleanolic acid were moderate inhibitors of Na+/K+-ATPase, and their inhibitory potency was comparable to that of ginsenoside Rh2. The relatively high inhibitory potency of ursolic acid or oleanolic acid was due to the formation of a hydrogen bond between its carboxyl group and the Ile322 residue in the deep cavity close to two K+ binding sites of Na+/K+-ATPase. Moreover, the drastic difference observed in the inhibitory potency of ouabain, bufalin, ginsenoside Rh2, and pentacyclic triterpenoids is ascribed mainly to the number of hydrogen bonds and partially to the strength of hydrophobic interaction between the compounds and residues around the deep cavity of Na+/K+-ATPase.
Steroid-like compounds seem to contribute to therapeutic effects of many cardioactive Chinese medicinal products. Chinese herbs, such as Prunella vulgaris L, rich in ursolic acid, oleanolic acid and their glycoside derivatives may be adequate sources for cardiac therapy via effective inhibition on Na+/K+-ATPase.
PMCID: PMC4002980  PMID: 20523340
cardiac glycoside; molecular modeling; Na+/K+-ATPase; ouabain; steroid-like; Traditional Chinese Medicine
14.  Effects of Ursolic Acid and its Analogues on Soybean 15-Lipoxygenase Activity and the Proliferation Rate of A human Gastric Tumour Cell Line 
Mediators of Inflammation  1994;3(3):181-184.
The authors have previously isolated and purified ursolic acid from heather flowers (Calluna vulgarts). This terpene was found to inhibit HL-60 leukaemic cell proliferation and arachidonic acid oxidative metabolism in various cell species. The effects of ursolic acid and its analogues on soybean 15-lipoxygenase activity and on the proliferation of a human gastric tumour cell line (HGT), have been assessed. These triterpenes inhibited soybean 15-lipoxygenase at its optimal activity (pH 9). The proliferation ofHGT was decreased in a dose-dependent manner. At 20 μM the rank order is: ursolic acid > uvaol > oleanolic acid > methyl ursolate. The carboxylic group at the C28 position of ursolic acid appears to be implicated in the inhibition of both lipoxygenase activity and cell proliferation. Thus methylation of this group decreases these two inhibitory properties. Oleanolic acid, which differs by the position of one methyl group (C20 instead of C19) is less inhibitory than ursolic acid. The lipophilicity of the terpene is also implicated since uvaol appears to be more inhibitory than methyl ursolate.
PMCID: PMC2367043  PMID: 18472939
15.  Antitumor Agents 255. Novel Glycyrrhetinic Acid-Dehydrozingerone Conjugates as Cytotoxic Agents 
Bioorganic & medicinal chemistry  2007;15(18):6193-6199.
Esterification of glycyrrhetinic acid (GA) with dehydrozingerone (DZ) resulted in a novel cytotoxic GA-DZ conjugate. Based on this exciting finding, we conjugated eleven different DZ analogs with GA or other triterpenoids, including oleanoic acid (OA) or ursolic acid (UA). In an in vitro anticancer assay using nine different human tumor cell lines, most of the GA-DZ conjugates showed significant potency. Particularly, compounds 5, 29, and 30 showed significant cytotoxic effects against LN-Cap, 1A9, and KB cells with ED50 values of 0.6, 0.8, and 0.9 μM, respectively. Similar conjugates between DZ and OA or UA were inactive suggesting that the GA component is critical for activity. Notably, although GA-DZ conjugates showed potent cytotoxic activity, the individual components (GA and DZ analogs) were inactive. Thus, GA-DZ conjugates are new chemical entities and represent interesting hits for anticancer drug discovery and development.
PMCID: PMC2034305  PMID: 17591444
Glycyrrhetinic acid; Dehydrozingerone; Conjugation; Cytotoxicity
16.  Interaction of Natural Dietary and Herbal Anionic Compounds and Flavonoids with Human Organic Anion Transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11) 
Active components of complementary/alternative medicines and natural supplements are often anionic compounds and flavonoids. As such, organic anion transporters (OATs) may play a key role in their pharmacokinetic and pharmacological profiles, and represent sites for adverse drug-drug interactions. Therefore, we assessed the inhibitory effects of nine natural products, including flavonoids (catechin and epicatechin), chlorogenic acids (1,3- and 1,5-dicaffeoylquinic acid), phenolic acids (ginkgolic acids (13 : 0), (15 : 1), and (17 : 1)), and the organic acids ursolic acid and 18β-glycyrrhetinic acid, on the transport activity of the human OATs, hOAT1 (SLC22A6), hOAT3 (SLC22A8), and hOAT4 (SLC22A11). Four compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acid (17 : 1), and 18β-glycyrrhetinic acid, significantly inhibited hOAT1-mediated transport (50 μM inhibitor versus 1 μM substrate). Five compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acids (15 : 1) and (17 : 1), and epicatechin, significantly inhibited hOAT3 transport under similar conditions. Only catechin inhibited hOAT4. Dose-dependency studies were conducted for 1,3-dicaffeoylquinic acid and 18β-glycyrrhetinic acid on hOAT1, and IC50 values were estimated as 1.2 ± 0.4 μM and 2.7 ± 0.2 μM, respectively. These data suggest that 1,3-dicaffeoylquinic acid and 18β-glycyrrhetinic acid may cause significant hOAT1-mediated DDIs in vivo; potential should be considered for safety issues during use and in future drug development.
PMCID: PMC3618943  PMID: 23573138
17.  Inhibition of cell proliferation and induction of apoptosis by CDDO-Me in pancreatic cancer cells is ROS-dependent 
Oleanolic acid-derived synthetic triterpenoids are broad spectrum antiproliferative and antitumorigenic agents. In this study, we investigated the role of reactive oxygen species (ROS) in induction of apoptosis and inhibition of prosurvival Akt, NF-κB and mTOR signaling proteins by methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) in pancreatic cancer cells. Micromolar concentrations of CDDO-Me inhibited proliferation and induced apoptosis in MiaPaCa-2 and Panc-1 pancreatic cancer cells. Treatment with CDDO-Me caused the generation of hydrogen peroxide and superoxide anion and pretreatment of cells with NADPH oxidase inhibitor diphylene iodonium (DPI) or respiratory chain complex 1 inhibitor rotenone prevented ROS generation. Pretreatment with N-acetylcysteine (NAC) or overexpression of glutathione peroxidase (GPx) or superoxide dismutase-1 (SOD-1) blocked the antiproliferative effects of CDDO-Me. Likewise, NAC prevented the induction of apoptosis (annexin V-FITC binding and cleavage of PARP-1 and procaspases-3,-8 and -9) and reversed the loss of mitochondrial membrane potential and release of cytochrome c from mitochondria by CDDO-Me. CDDO-Me down-regulated p-Akt, p-mTOR and NF-κB (p65) but increased the activation of Erk1/2 and NAC blocked the modulation of these cell signaling proteins by CDDO-Me. Thus, the results of this study indicate that the antiproliferative and apoptosis inducing effects of CDDO-Me are mediated through a ROS-dependent mechanism and the role of ROS in modulation of signaling proteins by CDDO-Me warrants further investigation.
PMCID: PMC3846287  PMID: 22946344
Pancreatic cancer; CDDO-Me; apoptosis; ROS; Akt; NF-κB; mTOR; Erk1/2
18.  Chemical modifications of natural triterpenes - glycyrrhetinic and boswellic acids: evaluation of their biological activity 
Tetrahedron  2008;64(51):11541-11548.
Synthetic analogues of naturally occurring triterpenoids; glycyrrhetinic acid, arjunolic acid and boswellic acids, by modification of A-ring with a cyano- and enone- functionalities, have been reported. A novel method of synthesis of α-cyanoenones from isoxazoles is reported. Bio-assays using primary mouse macrophages and tumor cell lines indicate potent anti-inflammatory and cytotoxic activities associated with cyanoenones of boswellic acid and glycyrrhetinic acid.
PMCID: PMC2900779  PMID: 20622928
19.  Phytochemistry and bioactivity of aromatic and medicinal plants from the genus Agastache (Lamiaceae) 
Phytochemistry Reviews  2014;13(2):391-416.
Agastache is a small genus of Lamiaceae, comprising 22 species of perennial aromatic medicinal herbs. In this article, we review recent advances in phytochemical, pharmacological, biotechnological and molecular research on Agastache. The phytochemical profile of all Agastache species studied to date is generally similar, consisted of two main metabolic classes—phenylpropanoids and terpenoids. In the relatively variable essential oils, most populations of different Agastache species contain over 50 % of a phenylallyl compound—estragole. Also, other volatile compounds (methyleugenol, pulegone, menthone, isomenthone and spathulenol) were reported in various proportions. Major non-volatile metabolites belong to phenolic compounds, such as caffeic acid derivatives, especially rosmarinic acid as well as several flavones and flavone glycosides like acacetin, tilianin, agastachoside, and a rare dimeric malonyl flavone (agastachin). Two unique lignans—agastenol and agastinol—were also isolated. Terpenoids include triterpenoids of oleanane-type (maslinic acid, oleanolic acid and β-amyrin), ursane-type (ursolic acid, corosolic acid and α-amyrin), and typical plant sterols, as well as abietane-type oxidized diterpenes (e.g., agastaquinone, agastol, and others). The bioactivity of various extracts or individual compounds in vitro and in vivo include antimicrobial, antiviral and anti-mutagenic activity, cytotoxic activity to cancer cell lines, and anti-nociceptive, anti-inflammatory, anti-atherogenic, antioxidant as well as biocidal activity to several foodstuff pests. Biotechnological and molecular studies have focused on in vitro propagation and enhancing the biosynthesis of bioactive metabolites in cell or organ cultures, as well as on the expression of genes involved in phenolic biosynthesis.
PMCID: PMC4032471  PMID: 24899872
Essential oil; Estragole; Giant hyssop; Phenylpropanoids; Tilianin
20.  (3β,18β,20β)-N-Eth­oxy­carbonyl­methyl-3-nitrato-11-oxoolean-12-ene-29-carboxamide methanol monosolvate 
The title compound, C34H52N2O7·CH4O, is the methanol solvate of a difunctionalized derivative of the therapeutic agent 18β-glycyrrhetinic acid, a penta­cyclic triterpene. The five six-membered rings of the glycyrrhetinic acid moiety show normal geometries, with four rings in chair conformations and the unsaturated ring in a half-chair conformation. This moiety is substituted by a nitrate ester group and an O-ethyl­glycine group. In the crystal, the nonsolvent mol­ecules are packed parallel to (010) in a herringbone fashion with the nitrato, ethyl­glycine and methanol-O atom being proximate. The methanol solvent mol­ecule is anchored via a donated O—H⋯Oac­yl and an accepted N—H⋯O hydrogen bond, giving rise to infinite zigzag chains of hydrogen bonds parallel to [100]. Two weak intermolecular C—H⋯O interactions to the methanol and to an acyl oxygen establish links along [100] and [010], respectively.
PMCID: PMC3344161  PMID: 22606164
21.  Modulation by glycyrrhetinic acid derivatives of TPA-induced mouse ear oedema. 
British Journal of Pharmacology  1989;96(1):204-210.
1. The anti-inflammatory effects of glycyrrhetinic acid and its derivatives on TPA (12-O-tetradecanoylphorbol-13-acetate)-induced mouse ear oedema were studied. The mechanisms of TPA-induced ear oedema were first investigated with respect to the chemical mediators. 2. The formation of ear oedema reached a maximum 5 h after TPA application (2 micrograms per ear) and the prostaglandin E2 (PGE2) production of mouse ear increased with the oedema formation. 3. TPA-induced ear oedema was prevented by actinomycin D and cycloheximide (0.1 mg per ear, respectively) when applied during 60 min after TPA treatment. 4. Of glycyrrhetinic acid derivatives examined, dihemiphthalate derivatives (IIe, IIe', IIIa, IIIa', IVa, IVa') most strongly inhibited ear oedema on both topical (ID50, 1.6 mg per ear for IIe, 2.0 mg per ear for IIIa and 1.6 mg per ear for IVa) and oral (ID50, 88 mg kg-1 for IIe', 130 mg kg-1 for IIIa' and 92 mg kg-1 for IVa') administration. 5. Glycyrrhetinic acid (Ia) and its derivatives applied 30 min before TPA treatment were much more effective in inhibiting oedema than when applied 30 min after TPA. A dihemiphthalate of triterpenoid compound IVa completely inhibited oedema, even when applied 3 h before TPA treatment. 6. Glycyrrhetinic acid (Ia) and deoxoglycyrrhetol (IIa), the parent compounds, produced little inhibition by oral administration at less than 200 mg kg-1. 7. These results suggest that the dihemiphthalate derivatives of triterpenes derived from glycyrrhetinic acid by chemical modification are useful for the treatment of skin inflammation by both topical and oral application.
PMCID: PMC1854326  PMID: 2924072
22.  Endothelium-dependent vasorelaxation independent of nitric oxide and K+ release in isolated renal arteries of rats 
British Journal of Pharmacology  2001;132(7):1558-1564.
We investigated whether K+ can act as an endothelium-derived hyperpolarizing factor (EDHF) in isolated small renal arteries of Wistar-Kyoto rats.Acetylcholine (0.001 – 3 μM) caused relaxations that were abolished by removal of the endothelium. However, acetylcholine-induced relaxations were not affected by the nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME, 100 μM), by L-NAME plus the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 1 μM) or by L-NAME plus the cyclo-oxygenase inhibitor indomethacin (10 μM). In rings precontracted with high-K+(60 mM) physiological salt solution in the presence of L-NAME, acetylcholine-induced relaxations were abolished.L-NAME-resistant relaxations were abolished by the large-conductance Ca2+-activated K+ channel inhibitor charybdotoxin plus the small-conductance Ca2+-activated K+ channel inhibitor apamin, while the inward rectifier K+ channel inhibitor Ba2+ or the gap junction inhibitor 18α-glycyrrhetinic acid had no effect. Acetylcholine-induced relaxation was unchanged by ouabain (10 μM) but was partially inhibited by a higher concentration (100 μM).In half of the tissues tested, K+(10 mM) itself produced L-NAME-resistant relaxations that were blocked by ouabain (10 μM) and partially reduced by charybdotoxin plus apamin, but not affected by 18α-glycyrrhetinic acid or Ba2+. However, K+ did not induce relaxations in endothelium-denuded tissues.In conclusion, acetylcholine-induced relaxations in this tissue are largely dependent upon hyperpolarization mechanisms that are initiated in the endothelium but do not depend upon NO release. K+ release cannot account for endothelium-dependent relaxation and cannot be an EDHF in this artery. However, K+ itself can initiate endothelium-dependent relaxations via a different pathway from acetylcholine, but the mechanisms of K+-induced relaxations remain to be clarified.
PMCID: PMC1572700  PMID: 11264250
Acetylcholine; Ba2+; endothelium-dependent; hyperpolarization; EDHF; 18α-glycyrrhetinic acid; K+; nitric oxide; ouabain; renal arteries
23.  Ursolic Acid Inhibits Adipogenesis in 3T3-L1 Adipocytes through LKB1/AMPK Pathway 
PLoS ONE  2013;8(7):e70135.
Ursolic acid (UA) is a triterpenoid compound with multiple biological functions. This compound has recently been reported to possess an anti-obesity effect; however, the mechanisms are less understood.
As adipogenesis plays a critical role in obesity, the present study was conducted to investigate the effect of UA on adipogenesis and mechanisms of action in 3T3-L1 preadipocytes.
Methods and Results
The 3T3-L1 preadipocytes were induced to differentiate in the presence or absence of UA for 6 days. The cells were determined for proliferation, differentiation, fat accumulation as well as the protein expressions of molecular targets that regulate or are involved in fatty acid synthesis and oxidation. The results demonstrated that ursolic acid at concentrations ranging from 2.5 µM to 10 µM dose-dependently attenuated adipogenesis, accompanied by reduced protein expression of CCAAT element binding protein β (C/EBPβ), peroxisome proliferator-activated receptor γ (PPARγ), CCAAT element binding protein α (C/EBPα) and sterol regulatory element binding protein 1c (SREBP-1c), respectively. Ursolic acid increased the phosphorylation of acetyl-CoA carboxylase (ACC) and protein expression of carnitine palmitoyltransferase 1 (CPT1), but decreased protein expression of fatty acid synthase (FAS) and fatty acid-binding protein 4 (FABP4). Ursolic acid increased the phosphorylation of AMP-activated protein kinase (AMPK) and protein expression of (silent mating type information regulation 2, homolog) 1 (Sirt1). Further studies demonstrated that the anti-adipogenic effect of UA was reversed by the AMPK siRNA, but not by the Sirt1 inhibitor nicotinamide. Liver kinase B1 (LKB1), the upstream kinase of AMPK, was upregulated by UA. When LKB1 was silenced with siRNA or the inhibitor radicicol, the effect of UA on AMPK activation was diminished.
Ursolic acid inhibited 3T3-L1 preadipocyte differentiation and adipogenesis through the LKB1/AMPK pathway. There is potential to develop UA into a therapeutic agent for the prevention or treatment of obesity.
PMCID: PMC3724828  PMID: 23922935
24.  Evaluation of antimicrobial activity of extracts of Tibouchina candolleana (melastomataceae), isolated compounds and semi-synthetic derivatives against endodontic bacteria 
Brazilian Journal of Microbiology  2012;43(2):793-799.
This work describes the phytochemical study of the extracts from aerial parts of Tibouchina candolleana as well as the evaluation of the antimicrobial activity of extracts, isolated compounds, and semi-synthetic derivatives of ursolic acid against endodontic bacteria. HRGC analysis of the n-hexane extract of T. candolleana allowed identification of β-amyrin, α-amyrin, and β-sitosterol as major constituents. The triterpenes ursolic acid and oleanolic acid were isolated from the methylene chloride extract and identified. In addition, the flavonoids luteolin and genistein were isolated from the ethanol extract and identified. The antimicrobial activity was investigated via determination of the minimum inhibitory concentration (MIC) using the broth microdilution method. Amongst the isolated compounds, ursolic acid was the most effective against the selected endodontic bacteria. As for the semi-synthetic ursolic acid derivatives, only the methyl ester derivative potentiated the activity against Bacteroides fragilis.
PMCID: PMC3768843  PMID: 24031892
Tibouchina candolleana; ursolic acid; antimicrobial activity
25.  Studies on the Identification of Constituents in Ethanol Extract of Radix Glycyrrhizae and Their Anticancer Activity 
The main functions of Radix Glycyrrhizae include regulating middle warmer, moistening lung, relieving toxicity, harmonizing property of drugs which is a traditional Chinese medicine widely used in clinical settings. The objective of the paper is to isolate and identify the constituents in ethanol extract of Radix Glycyrrhizae, and to study their anticancer activity.
Materials and Methods
Column chromatography, ODS column chromatography, preparative thin layer chromatography and NMR spectroscopy techniques were used to isolate compounds from ethanol extract of Radix Glycyrrhizae; optical microscopy and flow cytometry were used to determine the anticancer effect of Radix Glycyrrhizae extract.
Four compounds were isolated from the ethanol extract of Radix Glycyrrhizae, namely oleanolic acid, isoliquiritin, glycyrrhetinic acid and licochalcone A. Optical microscopic observation showed that the growth of gastric cancer cell line SGC-7901 was inhibited in the experimental groups, and apoptotic morphological changes were observed in adherent cells; flow cytometry with PI staining showed that Radix Glycyrrhizae extract could induce SGC-7901 cell apoptosis within a concentration range of 0.5–1.5 mg/mL, compared with the control group, the apoptosis was positively correlated with the drug concentration, which exhibited an apparent dose-dependence.
We conclude Ethanol extract of Radix Glycyrrhizae has an anti-proliferative activity on SGC-7901 cells.
PMCID: PMC4202642  PMID: 25435618
Radix Glycyrrhizae; oleanolic acid; isoliquiritin; glycyrrhetinic acid; licochalcone A; SGC-7901 cell

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