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1.  Acetyl-11-keto-β-boswellic acid (AKBA); targeting oral cavity pathogens 
BMC Research Notes  2011;4:406.
Boswellic acids mixture of triterpenic acids obtained from the oleo gum resin of Boswellia serrata and known for its effectiveness in the treatment of chronic inflammatory disease including peritumor edema. Boswellic acids have been extensively studied for a number of activities including anti inflammatory, antitumor, immunomodulatory, and inflammatory bowel diseases. The present study describes the antimicrobial activities of boswellic acid molecules against oral cavity pathogens. Acetyl-11-keto-β-boswellic acid (AKBA), which exhibited the most potent antibacterial activity, was further evaluated in time kill studies, mutation prevention frequency, postantibiotic effect (PAE) and biofilm susceptibility assay against oral cavity pathogens.
AKBA exhibited an inhibitory effect on all the oral cavity pathogens tested (MIC of 2-4 μg/ml). It exhibited concentration dependent killing of Streptococcus mutans ATCC 25175 up to 8 × MIC and also prevented the emergence of mutants of S.mutans ATCC 25175 at 8× MIC. AKBA demonstrated postantibiotic effect (PAE) of 5.7 ± 0.1 h at 2 × MIC. Furthermore, AKBA inhibited the formation of biofilms generated by S.mutans and Actinomyces viscosus and also reduced the preformed biofilms by these bacteria.
AKBA can be useful compound for the development of antibacterial agent against oral pathogens and it has great potential for use in mouthwash for preventing and treating oral infections.
PMCID: PMC3201914  PMID: 21992439
Streptococcus mutans; Biofilm; PAE; Boswellia serrata
2.  Boswellic acid induces epigenetic alterations by modulating DNA methylation in colorectal cancer cells 
Cancer Biology & Therapy  2012;13(7):542-552.
Accumulating evidence suggests that chemopreventive effects of some dietary polyphenols may in part be mediated by their ability to influence epigenetic mechanisms in cancer cells. Boswellic acids, derived from the plant Boswellia serrata, have long been used for the treatment of various inflammatory diseases due to their potent anti-inflammatory activities. Recent preclinical studies have also suggested that this compound has anti-cancer potential against various malignancies. However, the precise molecular mechanisms underlying their anti-cancer effects remain elusive. Herein, we report that boswellic acids modulate DNA methylation status of several tumor suppressor genes in colorectal cancer (CRC) cells. We treated RKO, SW48 and SW480 CRC cell lines with the active principle present in boswellic acids, acetyl-keto-β-boswellic acid (AKBA). Using genome-wide DNA methylation and gene expression microarray analyses, we discovered that AKBA induced a modest genome-wide demethylation that permitted simultaneous re-activation of the corresponding tumor suppressor genes. The quantitative methylation-specific PCR and RT-PCR validated the gene demethylation and re-expression in several putative tumor suppressor genes including SAMD14 and SMPD3. Furthermore, AKBA inhibited DNMT activity in CRC cells. Taken together, these results lend further support to the growing notion that anti-cancer effect of boswellic acids may in part be due to its ability to demethylate and reactivate methylation-silenced tumor suppressor genes. These results suggest that not only boswellic acid might be a promising epigenetic modulator in the chemoprevention and treatment of CRC, but also provide a rationale for future investigations on the usefulness of such botanicals for epigenetic therapy in other human malignancies.
PMCID: PMC3364790  PMID: 22415137
acetyl-keto-beta-boswellic acid (AKBA); boswellic acid; chemoprevention; colorectal cancer; DNA Methylation; epigenetics
3.  Boswellic acid inhibits expression of acid sphingomyelinase in intestinal cells 
Boswellic acid is a type of triterpenoids with antiinflammatory and antiproliferative properties. Sphingomyelin metabolism generates multiple lipid signals affecting cell proliferation, inflammation, and apoptosis. Upregulation of acid sphingomyelinase (SMase) has been found in several inflammation-related diseases such as inflammatory bowel diseases, atherosclerosis, and diabetes.
The present study is to examine the effect of 3-acetyl-11-keto-β-boswellic acids (AKBA), a potent boswellic acid, on acid SMase activity and expression in intestinal cells. Both transformed Caco-2 cells and non-transformed Int407 cells were incubated with AKBA. After incubation, the change of acid SMase activity was assayed biochemically, the enzyme protein was examined by Western blot, and acid SMase mRNA was quantified by qPCR.
We found that AKBA decreased acid SMase activity in both intestinal cell lines in dose and time dependent manners without affecting the secretion of the enzyme to the cell culture medium. The effect of AKBA was more effective in the fetal bovine serum-free culture medium. Among different types of boswellic acid, AKBA was the most potent one. The inhibitory effect on acid SMase activity occurred only in the intact cells but not in cell-free extract in the test tubes. At low concentration, AKBA only decreased the acid SMase activity but not the quantity of the enzyme protein. However, at high concentration, AKBA decreased both the mass of acid SMase protein and the mRNA levels of acid SMase in the cells, as demonstrated by Western blot and qPCR, respectively. Under the concentrations decreasing acid SMase activity, AKBA significantly inhibited cell proliferation.
We identified a novel inhibitory effect of boswellic acids on acid SMase expression, which may have implications in human diseases and health.
PMCID: PMC2789714  PMID: 19951413
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
5.  Antistaphylococcal and biofilm inhibitory activities of acetyl-11-keto-β-boswellic acid from Boswellia serrata 
BMC Microbiology  2011;11:54.
Boswellic acids are pentacyclic triterpenes, which are produced in plants belonging to the genus Boswellia. Boswellic acids appear in the resin exudates of the plant and it makes up 25-35% of the resin. β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid have been implicated in apoptosis of cancer cells, particularly that of brain tumors and cells affected by leukemia or colon cancer. These molecules are also associated with potent antimicrobial activities. The present study describes the antimicrobial activities of boswellic acid molecules against 112 pathogenic bacterial isolates including ATCC strains. Acetyl-11-keto-β-boswellic acid (AKBA), which exhibited the most potent antibacterial activity, was further evaluated in time kill studies, postantibiotic effect (PAE) and biofilm susceptibility assay. The mechanism of action of AKBA was investigated by propidium iodide uptake, leakage of 260 and 280 nm absorbing material assays.
AKBA was found to be the most active compound showing an MIC range of 2-8 μg/ml against the entire gram positive bacterial pathogens tested. It exhibited concentration dependent killing of Staphylococcus aureus ATCC 29213 up to 8 × MIC and also demonstrated postantibiotic effect (PAE) of 4.8 h at 2 × MIC. Furthermore, AKBA inhibited the formation of biofilms generated by S. aureus and Staphylococcus epidermidis and also reduced the preformed biofilms by these bacteria. Increased uptake of propidium iodide and leakage of 260 and 280 nm absorbing material by AKBA treated cells of S aureus indicating that the antibacterial mode of action of AKBA probably occurred via disruption of microbial membrane structure.
This study supported the potential use of AKBA in treating S. aureus infections. AKBA can be further exploited to evolve potential lead compounds in the discovery of new anti-Gram-positive and anti-biofilm agents.
PMCID: PMC3066120  PMID: 21406118
6.  Urease inhibitory activities of β-boswellic acid derivatives 
Background and the purpose of the study
Boswellia carterii have been used in traditional medicine for many years for management different gastrointestinal disorders. In this study, we wish to report urease inhibitory activity of four isolated compound of boswellic acid derivative.
4 pentacyclic triterpenoid acids were isolated from Boswellia carterii and identified by NMR and Mass spectroscopic analysis (compounds 1, 3-O-acetyl-9,11-dehydro-β-boswellic acid; 2, 3-O-acetyl-11-hydroxy-β-boswellic acid; 3. 3-O- acetyl-11-keto-β-boswellic acid and 4, 11-keto-β-boswellic acid. Their inhibitory activity on Jack bean urease were evaluated. Docking and pharmacophore analysis using AutoDock 4.2 and Ligandscout 3.03 programs were also performed to explain possible mechanism of interaction between isolated compounds and urease enzyme.
It was found that compound 1 has the strongest inhibitory activity against Jack bean urease (IC50 = 6.27 ± 0.03 μM), compared with thiourea as a standard inhibitor (IC50 = 21.1 ± 0.3 μM).
The inhibition potency is probably due to the formation of appropriate hydrogen bonds and hydrophobic interactions between the investigated compounds and urease enzyme active site and confirms its traditional usage.
PMCID: PMC3575251  PMID: 23351363
Boswellia carterii; Urease inhibitor; Boswellic acid; Docking; Autodock
7.  Efficacy of boswellic acid on lysosomal acid hydrolases, lipid peroxidation and anti-oxidant status in gouty arthritic mice 
To evaluate the efficacy of boswellic acid against monosodium urate crystal-induced inflammation in mice.
The mice were divided into four experimental groups. Group I served as control; mice in group II were injected with monosodium urate crystal; group III consisted of monosodium urate crystal-induced mice who were treated with boswellic acid (30 mg/kg/b.w.); group IV comprised monosodium urate crystal-induced mice who were treated with indomethacin (3 mg/kg/b.w.). Paw volume and levels/activities of lysosomal enzymes, lipid peroxidation, anti-oxidant status and inflammatory mediator TNF-α were determined in control and monosodium urate crystal-induced mice. In addition, the levels of β-glucuronidase and lactate dehydrogenase were also measured in monosodium urate crystal-incubated polymorphonuclear leucocytes (PMNL) in vitro.
The activities of lysosomal enzymes, lipid peroxidation, and tumour necrosis factor-α levels and paw volume were increased significantly in monosodium urate crystal-induced mice, whereas the activities of antioxidant status were in turn decreased. However, these changes were modulated to near normal levels upon boswellic acid administration. In vitro, boswellic acid reduced the level of β-glucuronidase and lactate dehydrogenase in monosodium urate crystal-incubated PMNL in concentration dependent manner when compared with control cells.
The results obtained in this study further strengthen the anti-inflammatory/antiarthritic effect of boswellic acid, which was already well established by several investigators.
PMCID: PMC3609259  PMID: 23569882
Boswellic acid; Gouty arthritis; Indomethacin; Lysosomal enzymes; Polymorphonuclear leucocytes; Monosodium urate; Lipid peroxidation; Antioxidant status; Anti-inflammatory effect; Antiarthritic effect; Inflammation
8.  Boswellic Acid Inhibits Growth and Metastasis of Human Colorectal Cancer in Orthotopic Mouse Model By Downregulating Inflammatory, Proliferative, Invasive, and Angiogenic Biomarkers 
Numerous cancer therapeutics were originally identified from natural products used in traditional medicine. One such agent is acetyl-11-keto-beta-boswellic acid (AKBA), derived from the gum resin of the Boswellia serrata known as Salai guggal or Indian frankincense. Traditionally it has been used in Ayurvedic medicine to treat proinflammatory conditions. In the present report, we hypothesized that AKBA can affect the growth and metastasis of colorectal cancer (CRC) in orthotopically-implanted tumors in nude mice. We found that the oral administration of AKBA (50-200 mg/kg) dose-dependently inhibited the growth of CRC tumors in mice, resulting in decrease in tumor volumes than those seen in vehicle-treated mice without significant decreases in body weight. In addition, we observed that AKBA was highly effective in suppressing ascites and distant metastasis to the liver, lungs, and spleen in orthotopically-implanted tumors in nude mice. When examined for the mechanism, we found that markers of tumor proliferation index Ki-67 and the microvessel density CD31; were significantly downregulated by AKBA treatment. We also found that AKBA significantly suppressed NF-κB activation in the tumor tissue and expression of pro-inflammatory (COX2), tumor survival (bcl-2, bcl-xL, IAP-1, survivin), proliferative (cyclin D1), invasive (ICAM-1, MMP-9) and angiogenic (CXCR4 and VEGF) biomarkers. When examined for serum and tissue levels of AKBA, a dose-dependent increase in the levels of the drug was detected, indicating its bioavailability. Thus, our findings suggest that this boswellic acid analogue can inhibit the growth and metastasis of human CRC in vivo through downregulation of cancer-associated biomarkers.
PMCID: PMC3246525  PMID: 21702037
AKBA; colorectal cancer; NF-κB; growth; metastasis
9.  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
10.  Structure-Dependent Inhibition of Bladder and Pancreatic Cancer Cell Growth by 2-Substituted Glycyrrhetinic and Ursolic Acid Derivatives 
Derivatives of oleanolic acid, ursolic acid and glycyrrhetinic acid substituted with electron withdrawing groups at the 2-position in the A-ring which also contains a 1-en-3-one structure are potent inhibitors of cancer cell growth. In this study, we have compared the effects of several 2-substituted analogs of triterpenoid acid methyl esters derived from ursolic and glycyrrhetinic acid on proliferation of KU7 and 253JB-V bladder and Panc-1 and Panc-28 pancreatic cancer cells. The results show that the 2-cyano and 2-trifluoromethyl derivatives were the most active compounds. The glycyrrhetinic acid derivatives with the rearranged C-ring containing the 9(11)-en-12-one structure were generally more active than the corresponding 12-en-11-one isomers. However, differences in growth inhibitory IC50 values were highly variable and dependent on the 2- substitutent (CN vs. CF3) and cancer cell context.
PMCID: PMC2408873  PMID: 18359628
glycyrrhetinate analogs; growth inhibition; bladder cancer; pancreatic cancer
11.  Boswellic acid exerts antitumor effects in colorectal cancer cells by modulating expression of the let-7 and miR-200 microRNA family 
Carcinogenesis  2012;33(12):2441-2449.
Colorectal cancer (CRC) is a complex disease with genetic and epigenetic alterations in many key oncogenes and tumor suppressor genes. The active principle of a gum resin from Boswellia serrata, 3-acetyl-11-keto-β-boswellic acid (AKBA), has recently gained attention as a chemopreventive compound due to its ability to target key oncogenic proteins such as 5-lipoxygenase and nuclear factor-kappaB. AKBA has been shown to inhibit the growth of CRC cells; however, the precise molecular mechanisms underlying its anticancer activities in CRC remain unclear. We hypothesized that boswellic acids may achieve their chemopreventive effects by modulating specific microRNA (miRNA) pathways. We found that AKBA significantly up-regulated expression of the let-7 and miR-200 families in various CRC cell lines. Both let-7 and miR-200 are putative tumor-suppressive miRNAs. AKBA modulated the expression of several downstream targets of the let-7 and miR-200 families, such as CDK6, vimentin and E-cadherin. These data were further strengthened by miRNA knockdown studies, which revealed that inhibition of let-7i facilitated enhanced cancer cell proliferation, migration and invasion. In addition, AKBA also induced similar modulation of the let-7 and miR-200 downstream genes in CRC tumors orthotopically implanted in nude mice. These results indicate that AKBA-induced antitumor effects in CRC occur, at least partly through the up-regulation of specific miRNA pathways. Our data provide novel evidence that anticancer effects of boswellic acids are due in part to their ability to regulate cellular epigenetic machinery and further highlight the promise for this phytochemical in the preventative and therapeutic applications of CRC.
PMCID: PMC3510738  PMID: 22983985
12.  Boswellic Acid Blocks STAT3 Signaling, Proliferation, and Survival of Multiple Myeloma via the Protein Tyrosine Phosphatase SHP-1 
Molecular cancer research : MCR  2009;7(1):118-128.
Activation of signal transducers and activators of transcription (STAT)-3 factors has been linked with survival, proliferation, chemoresistance and angiogenesis of tumor cells, including human multiple myeloma (MM). Thus agents that can suppress STAT3 activation have potential as cancer therapeutics. In our search for such agents, we identified acetyl-11-keto-β-boswellic acid (AKBA), originally isolated from Boswellia serrata. Our results show that AKBA inhibited constitutive STAT3 activation in human MM cells. AKBA suppressed IL-6-induced STAT3 activation, and the inhibition was reversible. The phosphorylation of both Jak 2 and Src, constituents of the STAT3 pathway, was inhibited by AKBA. Interestingly, treatment of cells with pervanadate suppressed AKBA’s effect to inhibit the phosphorylation of STAT3, thus suggesting the involvement of a protein tyrosine phosphatase. We found that AKBA induced Src homology region 2 domain-containing phosphatase 1 (SHP-1), which may account for its role in dephosphorylation of STAT3. Moreover, deletion of SHP-1 gene by SiRNA abolished the ability of AKBA to inhibit STAT3 activation. The inhibition of STAT3 activation by AKBA led to the suppression of gene products involved in proliferation (cyclin D1), survival (Bcl-2, Bcl-xL and Mcl-1), and angiogenesis (VEGF). This affect correlated with the inhibition of proliferation and apoptosis in MM cells. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the AKBA induced apoptosis. Overall, our results suggest that AKBA is a novel inhibitor of STAT3 activation and has potential in the treatment of cancer.
PMCID: PMC2677182  PMID: 19147543
Acetyl-11-Keto-{beta}-Boswellic Acid; STAT3; c-Src; JAK2; SHP-1; Apoptosis
13.  Acetyl-11-keto-β-Boswellic Acid Suppresses Invasion of Pancreatic Cancer Cells Through The Downregulation of CXCR4 Chemokine Receptor Expression 
Ninety percent of cancer-mediated deaths are due to metastasis of the tumor, but the mechanisms controlling metastasis remain poorly understood. Thus, no therapy targeting this process has yet been approved. Chemokines and their receptors are mediators of chronic inflammation and have been linked to the metastasis of numerous cancers. More recently, the CXC chemokine receptor 4 (CXCR4) has emerged as a key mediator of tumor metastasis; therefore, identification of inhibitors of this receptor has the potential to abrogate metastasis. In this report, we demonstrate that acetyl-11-keto-β-boswellic acid (AKBA), a component of the therapeutic plant Boswellia serrata, can downregulate CXCR4 expression in pancreatic cancer cells. The reduction in CXCR4 induced by this terpenoid was found to be cell-type specific, as its expression was also abrogated in leukemia, myeloma, and breast cancer cell lines. Neither proteasome inhibitors nor lysosomal stabilization could prevent the AKBA-induced reduction in CXCR4 expression, and downregulation occurred at the transcriptional level. Suppression of CXCR4 by AKBA was accompanied by the inhibition of pancreatic cancer cell invasion, which is induced by CXCL12, the ligand for CXCR4. In addition, abrogation of the expression of chemokine receptor by AKBA was found in human pancreatic tissues from orthotopic animal model. AKBA also abolished breast tumor cell invasion, and this effect correlated with the disappearance of both the CXCR4 mRNA and CXCR4 protein. Overall, our results show that AKBA is a novel inhibitor of CXCR4 expression and, thus, has the potential to suppress the invasion and metastasis of cancer cells.
PMCID: PMC3082612  PMID: 21448932
CXCR4; CXCL12; AKBA; Metastasis
14.  Micropropagation and non-steroidal anti-inflammatory and anti-arthritic agent boswellic acid production in callus cultures of Boswellia serrata Roxb. 
Micropropagation through cotyledonary and leaf node and boswellic acid production in stem callus of a woody medicinal endangered tree species Boswellia serrata Roxb. is reported. The response for shoots, roots and callus formation were varied in cotyledonary and leafy nodal explants from in vitro germinated seeds, if inoculated on Murshige and Skoog’s (MS) medium fortified with cytokinins and auxins alone or together. A maximum of 8.0 ± 0.1 shoots/cotyledonary node explant and 6.9 ± 0.1 shoots/leafy node explants were produced in 91 and 88 % cultures respectively on medium with 2.5 μM 6-benzyladenine (BA) and 200 mg l−1 polyvinylpyrrolidone (PVP). Shoots treated with 2.5 μM IBA showed the highest average root number (4.5) and the highest percentage of rooting (89 %). Well rooted plantlets were acclimatized and 76.5 % of the plantlets showed survival upon transfer to field conditions. Randomly amplified polymorphic DNA (RAPD) analysis of the micropropagated plants compared with mother plant revealed true-to-type nature. The four major boswellic acid components in calluses raised from root, stem, cotyledon and leaf explants were analyzed using HPLC. The total content of four boswellic acid components was higher in stem callus obtained on MS with 15.0 μM IAA, 5.0 μM BA and 200 mg l−1 PVP. The protocol reported can be used for conservation and exploitation of in vitro production of medicinally important non-steroidal anti-inflammatory metabolites of B. serrata.
PMCID: PMC3550693  PMID: 24381442
Anti-arthritic; Anti-inflammatory; Boswellia serrata; Boswellic acid; Burseraceae; Callus; Indian olibanum; Micropropagation; Salai guggul; Steroids
15.  Acetyl-11-Keto-β-Boswellic Acid Inhibits Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis 
Cancer research  2009;69(14):5893-5900.
The role of angiogenesis in tumor growth and metastasis is well established. Identification of small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we demonstrated that acetyl-11-keto-β-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg/kg of AKBA) after solid tumors reached about 100 mm3 (n=5). The inhibitory effect of AKBA on tumor growth was well correlated with suppression of angiogenesis. When examined for the molecular mechanism, we found that AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively and suppressed vascular endothelial growth factor (VEGF)-induced microvessel sprouting in rat aortic ring assay ex vivo. Furthermore, AKBA inhibited VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures from primary cultured human umbilical vascular endothelial cells (HUVECs) in a dose-dependent manner. Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 kinase (KDR/Flk-1) with IC50 of 1.68 μmol/L. Specifically, AKBA suppressed the downstream protein kinases of VEGFR2, including Src family kinase, focal adhesion kinase, extracellular signal-related kinase, AKT, mTOR, and ribosomal protein S6 kinase. Our findings suggest that AKBA potently inhibits human prostate tumor growth through inhibition of angiogenesis induced by VEGFR2 signaling pathways.
PMCID: PMC2724674  PMID: 19567671
AKBA; KDR/Flk-1; tumor angiogenesis; mTOR; prostate tumor
16.  Boswellic Acid Suppresses Growth and Metastasis of Human Pancreatic Tumors in an Orthotopic Nude Mouse Model through Modulation of Multiple Targets 
PLoS ONE  2011;6(10):e26943.
Pancreatic cancer (PaCa) is one of the most lethal cancers, with an estimated 5-year survival of <5% even when patients are given the best treatment available. In addition, these treatments are often toxic and expensive, thus new agents which are safe, affordable and effective are urgently needed. We describe here the results of our study with acetyl-11-keto-β-boswellic acid (AKBA), an agent obtained from an Ayurvedic medicine, gum resin of Boswellia serrata. Whether AKBA has an activity against human PaCa, was examined in in vitro models and in an orthotopic nude mouse model of PaCa. We found that AKBA inhibited the proliferation of four different PaCa cell lines (AsPC-1, PANC-28, and MIA PaCa-2 with K-Ras and p53 mutations, and BxPC-3 with wild-type K-Ras and p53 mutation). These effects correlated with an inhibition of constitutively active NF-κB and suppression of NF-κB regulating gene expression. AKBA also induced apoptosis, and sensitized the cells to apoptotic effects of gemcitabine. In the orthotopic nude mouse model of PaCa, p.o. administration of AKBA alone (100 mg/kg) significantly inhibited the tumor growth; this activity was enhanced by gemcitabine. In addition, AKBA inhibited the metastasis of the PaCa to spleen, liver, and lungs. This correlated with decreases in Ki-67, a biomarker of proliferation, and CD31, a biomarker of microvessel density, in the tumor tissue. AKBA produced significant decreases in the expression of NF-κB regulating genes in the tissues. Immunohistochemical analysis also showed AKBA downregulated the expression of COX-2, MMP-9, CXCR4, and VEGF in the tissues. Overall these results demonstrate that AKBA can suppress the growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model that correlates with modulation of multiple targets.
PMCID: PMC3204996  PMID: 22066019
17.  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
18.  In vitro zygotic embryo germination and propagation of an endangered Boswellia serrata Roxb., a source of boswellic acid 
This study aims to establish an efficient protocol for development of seedlings of an endangered medicinally important forest tree Boswellia serrata Roxb., for mass plantation and consistent supply of salai guggul. The green mature fruits served as source of seeds. The excised green zygotic embryos were cultured on Gamborg (B5), McCown and Loyd (WPM) and Schenk and Hildebrandt (SH) media fortified with different concentration of sucrose and on Murashige and Skoog (MS) medium containing 3 % sucrose, polyvinylpyrrolidone (PVP) (0–300 mg l−l), Gibberellic acid (GA3), Indoleacetic acid (IAA), Naphthaleneacetic acid (NAA), Indole-3-Butyric acid (IBA) or 2,4-dichlorophenoxyacetic acid (2,4 D) and 6-benzylaminopurine (BA) or kinetin (Kin) individually. The highest frequency of embryo germination (96 %) and conversion into seedling was obtained on MS medium containing 3 % sucrose together with 200 mg l−l PVP; other media were either inferior or induced abnormalities in the seedlings including callus formation from the zygotic embryos. Fully developed seedlings could be successfully established in soil with about 94 % survival. The embryos from mature dry seeds did not respond for germination in any of the experiments. In conclusion, selection of zygotic embryo from green mature seeds and their in vitro germination is important for propagation of B. serrata.
PMCID: PMC3550602  PMID: 23572965
Endangered; frankincense; green mature embryo; mass plantation; seed viability
19.  Boswellic acids extract attenuates pulmonary fibrosis induced by bleomycin and oxidative stress from gamma irradiation in rats 
Chinese Medicine  2011;6:36.
Interstitial pulmonary fibrosis is characterized by an altered cellular composition of the alveolar region with excessive deposition of collagen. Lung inflammation is also common in pulmonary fibrosis. This study aims to test the inhibition of 5-lipooxygenase (5-LOX) by boswellic acid (BA) extract in an experimental model of pulmonary fibrosis using bleomycin (BL).
Boswellic acid extract (1 g/kg) was force-fed to rats seven days prior to administration of BL or gamma irradiation or both. BL (0.15 U/rat) in 25 μl of 0.9% normal saline (NS) or 0.9% NS alone was administered intratracheally. Rats were exposed to two fractionated doses of gamma irradiation (0.5 Gy/dose/week) with a gamma cell-40 (Cesium-137 irradiation units, Canada) during the last two weeks of the experiment. BA was administered during BL or irradiation treatment or both. After the animals were sacrificed, bronchoalveolar lavage was performed; lungs were weighed and processed separately for biochemical and histological studies.
In rats treated with BL, levels of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) were significantly elevated (P = 0.05 and P = 0.005). Hydroxyproline was highly and extensively expressed. Immunoreactive compounds were abundantly expressed, represented in the levels of macrophages infiltrate, accumulation of eosinophils and neutrophils in the lung as well as the aggregation of fibroblasts in the fibrotic area. The levels of lipoxygenase enzyme activity were significantly increased (P = 0.005). Antioxidant activities measured in BL-treated rats deteriorated, coupled with the elevation of both levels of plasma lipid peroxide (LP) content and bronchoalveolar lavage lactate dehydrogenase activity. BA-treated rats had reduced number of macrophages, (P = 0.01), neutrophils in bronchoalveolar lavage (P = 0.01) and protein (P = 0.0001). Moreover, the hydroxyproline content was significantly lowered in BA-treated rats (P = 0.005). BA extract inhibited the TGF-ß induced fibrosis (P = 0.01) and 5-LOX activity levels (P = 0.005).
Histologically, BA reduced the number of infiltrating cells, ameliorated the destruction of lung architecture and attenuated lung fibrosis.
BA attenuates the BL-induced injury response in rats, such as collagen accumulation, airway dysfunction and injury. This study suggests that the blocking of 5-LOX may prevent the progression of fibrosis.
PMCID: PMC3199276  PMID: 21961991
20.  New Synthetic Triterpenoids: Potent Agents for Prevention and Treatment of Tissue Injury Caused by Inflammatory and Oxidative Stress 
Journal of Natural Products  2011;74(3):537-545.
We review the original rationale for the development and the chemistry of a series of new synthetic oleanane triterpenoids (SO), based on oleanolic acid (1) as a starting material. Many of the new compounds that have been made, such as 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (“CDDO”, 8), are highly potent (activities found at levels below 1 nM) anti-inflammatory agents, as measured by their ability to block the cellular synthesis of the enzyme inducible nitric oxide synthase (iNOS) in activated macrophages. Details of the organic synthesis of new SO and their chemical mechanisms of biological activity are reviewed, as is formation of biotin conjugates for investigation of protein targets. Finally, we give a brief summary of important biological activities of SO in many organ systems in numerous animal models. Clinical investigation of a new SO (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, “CDDO-Me”, bardoxolone methyl, 13) is currently in progress.
PMCID: PMC3064114  PMID: 21309592
21.  18beta-Glycyrrhetinic Acid Inhibits Periodontitis Via Glucocorticoid-Independent NF–κB Inactivation In IL-10 Deficient Mice 
Journal of periodontal research  2010;45(6):757-763.
Background and objective
18beta-glycyrrhetinic acid (GA) is a natural anti-inflammatory compound derived from licorice root extract (Glycyrrhiza glabra). The effect of GA on experimental periodontitis and its mechanism of action were determined in the present study.
Periodontitis was induced by oral infection with Porphyromonas gingivalis W83 in IL-10 deficient mice. The effect of GA, which was delivered by subcutaneous injections in either prophylactic or therapeutic regimens, on alveolar bone loss and gingival gene expressions was determined on day 42 after initial infection. The effect of GA on LPS-stimulated macrophages, T cell proliferation, and osteoclastogenesis was also examined in vitro.
GA administered either prophylactically or therapeutically dramatically reduced infection-induced bone loss in IL-10 deficient mice, which are highly disease-susceptible. Although GA has been reported to exert its anti-inflammatory activity via down-regulation of 11-beta hydroxysteroid dehydrogenase-2 (HSD2), which converts active glucocorticoids (GC) to their inactive forms, GA did not reduce HSD2 gene expression in gingival tissue. Rather, under GC-free conditions, GA potently inhibited LPS-stimulated proinflammatory cytokine production and RANKL-stimulated osteoclastogenesis, both of which are NF–κB-dependent. GA furthermore suppressed LPS- and RANKL-stimulated phosphorylation of NF–κB p105 in vitro.
These findings indicate that GA inhibits periodontitis by inactivation of NF–κB in an IL-10 and GC-independent fashion.
PMCID: PMC3075584  PMID: 20682015
18beta-glycyrrhetinic acid; periodontal disease; NF–κB; IL-10 deficient mouse
22.  In Silico and In Vivo Anti-Malarial Studies of 18β Glycyrrhetinic Acid from Glycyrrhiza glabra 
PLoS ONE  2013;8(9):e74761.
Malaria is one of the most prevailing fatal diseases causing between 1.2 and 2.7 million deaths all over the world each year. Further, development of resistance against the frontline anti-malarial drugs has created an alarming situation, which requires intensive drug discovery to develop new, more effective, affordable and accessible anti-malarial agents possessing novel modes of action. Over the past few years triterpenoids from higher plants have shown a wide range of anti-malarial activities. As a part of our drug discovery program for anti-malarial agents from Indian medicinal plants, roots of Glycyrrhizaglabra were chemically investigated, which resulted in the isolation and characterization of 18β-glycyrrhetinic acid (GA) as a major constituent. The in vitro studies against P. falciparum showed significant (IC50 1.69µg/ml) anti-malarial potential for GA. Similarly, the molecular docking studies showed adequate docking (LibDock) score of 71.18 for GA and 131.15 for standard anti-malarial drug chloroquine. Further, in silico pharmacokinetic and drug-likeness studies showed that GA possesses drug-like properties. Finally, in vivo evaluation showed a dose dependent anti-malarial activity ranging from 68–100% at doses of 62.5–250mg/kg on day 8. To the best of our knowledge this is the first ever report on the anti-malarial potential of GA. Further work on optimization of the anti-malarial lead is under progress.
PMCID: PMC3782471  PMID: 24086367
23.  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
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
25.  Efficient synthesis and biological evaluation of epiceanothic acid and related compounds 
Epiceanothic acid (1) is a naturally occurring, but very rare pentacyclic triterpene with a unique pentacyclic triterpene (PT) structure. An efficient synthesis of 1 starting from betulin (3) has been accomplished in 12 steps with a total yield of 10% in our study. Compound 1 and selected synthetic intermediates were further evaluated as anti-HIV-1 agents, inhibitors of glycogen phosphorylase (GP), and cytotoxic agents. Compound 1 exhibited moderate HIV-1 inhibition. Most importantly, compound 5, with an opened A-ring, showed significant GP inhibitory activity with an IC50 of 0.21 μM, suggesting a potential for development as an anti-diabetic agent. On the other hand, compound 12, with a closed A-ring, showed potent cytotoxicity against A549 and MCF-7 human tumor cell lines, with IC50 values of 0.89 and 0.33 μM, respectively. These results suggest that the A-ring of PTs is an important pharmacophore that could be modified to involve different biological activities.
PMCID: PMC3010304  PMID: 21123066
epiceanothic acid; pentacyclic triterpene; anti-HIV agents; glycogen phosphorylase inhibitors; cytotoxic agents

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