The Iĸb-NF-ĸb-Complex As A Common Target of Boswellic Extracts and Boswellic Acids in Chronic Inflammatory Diseases, Diabetes Mellitus and Cancer

Boswellic extracts and some of its ingredients, especially boswellic acids, have been shown to be effective in inflammatory diseases, diabetes mellitus and cancer. Though clinical studies are rare in case of diabetes mellitus and cancer, preclinical studies suggest, that boswellic extracts and some of its active constituents, use a variety of targets and mechanisms of action, that could attack these disorders. One common target is NF-ĸB. In inflammatory diseases these targets are the immune competent cells [suppression of proinflammatory cytokines via inhibition of NF-ĸB activation], the complement system [inhibition of C3-convertase] the arachidonic acid cascade [especially inhibition of 5-LO] and last not least antioxidative effects and inhibition of proteolytic enzymes. In case of diabetes mellitus, secundar targets are insulitis and insulin resistance. Both cases are related to the suppression of proinflammatory cytokines. As far as insulitis is concerned, boswellic extracts and boswellic acids [AKBA, KBA] prevent infiltration of immune cells into pancreatic islets, causing inflammation and finally ß-cell death and insulin deficiency. Insulin resistance which is closely related to overweight, inflammation of visceral adipose tissue here, infiltration of immune cells is associated with release of proinflammatory cytokines into blood where they produce insulin resistance in peripheral tissues. As far as the effects of boswellic extracts and active constituents in cancer are concerned, they are inhibiting proliferation/growth, apoptosis, angiogenesis and migration/metastasis. Here, inhibition of signal pathways [ATM/P53; Aurora B/TOP2A; p21/FOX M2/cyclin B1; P13 K-AKT; STAT3; Erk 1⁄2; Wnt/ß-catenin], growth factors [EGRF; VEGF; BFGF; HGF], receptors [AR; DR5], enzymes [topoisomerases; caspases; Cde 2; Cde 25; Pin 1] and proteins [BCL-2; cyclin family] have been reported. In some of these targets, where nuclear factor kappa B [NF-ĸB] has emerged to be a major regulator, inhibition of its seems to be a important mechanism of this anticancer activity.

[1]  H. Ammon.  Boswellic extracts and 11-keto-ß-boswellic acids prevent type 1 and type 2 diabetes mellitus by suppressing the expression of proinflammatory cytokines. , 2019, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[2]  M. Morsy,et al.  Computational and Biological Comparisons of Plant Steroids as Modulators of Inflammation through Interacting with Glucocorticoid Receptor , 2019, Mediators of inflammation.

[3]  M. Bužga,et al.  Visceral fat and insulin resistance - what we know? , 2019, Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia.

[4]  C. Parr,et al.  Boswellia frereana suppresses HGF-mediated breast cancer cell invasion and migration through inhibition of c-Met signalling , 2018, Journal of Translational Medicine.

[5]  Dan Liu,et al.  Design, synthesis and biological evaluation of ring A modified 11-keto-boswellic acid derivatives as Pin1 inhibitors with remarkable anti-prostate cancer activity. , 2018, Bioorganic & medicinal chemistry letters.

[6]  Z. Al-Abri,et al.  New α-Glucosidase inhibitors from the resins of Boswellia species with structure-glucosidase activity and molecular docking studies. , 2018, Bioorganic chemistry.

[7]  Rong Wang,et al.  Acetyl-11-keto-β-boswellic acid suppresses docetaxel-resistant prostate cancer cells in vitro and in vivo by blocking Akt and Stat3 signaling, thus suppressing chemoresistant stem cell-like properties , 2018, Acta Pharmacologica Sinica.

[8]  Tengfei Ji,et al.  3-O-acetyl-11-keto-β-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase , 2018, Journal of experimental & clinical cancer research : CR.

[9]  O. Werz,et al.  Triterpene Acids from Frankincense and Semi-Synthetic Derivatives That Inhibit 5-Lipoxygenase and Cathepsin G , 2018, Molecules.

[10]  Chi-Tang Ho,et al.  Boswellia serrata resin extract alleviates azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumorigenesis. , 2017, Molecular nutrition & food research.

[11]  W. Scherbaum,et al.  11-Keto-β-Boswellic Acid Inhibits Lymphocyte (CD3) Infiltration Into Pancreatic Islets of Young None Obese Diabetic (NOD) Mice , 2017, Hormone and Metabolic Research.

[12]  M. Saidijam,et al.  Methanolic extract of Boswellia serrata exhibits anti-cancer activities by targeting microsomal prostaglandin E synthase-1 in human colon cancer cells. , 2017, Prostaglandins & other lipid mediators.

[13]  T. Golakoti,et al.  Synthesis of new analogs of AKBA and evaluation of their anti-inflammatory activities. , 2017, Bioorganic & medicinal chemistry.

[14]  Ashok Kumar,et al.  Interplay between cell cycle and autophagy induced by boswellic acid analog , 2016, Scientific Reports.

[15]  M. Heydari,et al.  The Efficacy of Boswellia Serrata Gum Resin for Control of Lipid Profile and Blood Glucose in Diabetic Patients , 2016, Iranian Journal of Medical Sciences.

[16]  K. Azab,et al.  Boswellic acid disables signal transduction of IL-6-STAT-3 in Ehrlich ascites tumor bearing irradiated mice. , 2016, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[17]  I. Cózar-Castellano,et al.  Ghrelin's Effects on Proinflammatory Cytokine Mediated Apoptosis and Their Impact on β-Cell Functionality , 2015, International journal of endocrinology.

[18]  W. Scherbaum,et al.  11-Keto-β-Boswellic Acids Prevent Development of Autoimmune Reactions, Insulitis and Reduce Hyperglycemia During Induction of Multiple Low-Dose Streptozotocin (MLD-STZ) Diabetes in Mice , 2015, Hormone and Metabolic Research.

[19]  A. Al-Harrasi,et al.  Synthesis and antitumor activity of ring A modified 11-keto-β-boswellic acid derivatives. , 2015, European journal of medicinal chemistry.

[20]  M. Fawzy,et al.  Protective effect of boswellic acids versus pioglitazone in a rat model of diet-induced non-alcoholic fatty liver disease: influence on insulin resistance and energy expenditure , 2015, Naunyn-Schmiedeberg's Archives of Pharmacology.

[21]  L. Meurer,et al.  Boswellia serrata has Beneficial Anti‐Inflammatory and Antioxidant Properties in a Model of Experimental Colitis , 2014, Phytotherapy research : PTR.

[22]  Ashutosh Kumar,et al.  Boswellia ovalifoliolata abrogates ROS mediated NF-κB activation, causes apoptosis and chemosensitization in Triple Negative Breast Cancer cells. , 2014, Environmental toxicology and pharmacology.

[23]  S. Laufer,et al.  Extract from gum resin of Boswellia serrata decreases IA(2)-antibody in a patient with "Late onset Autoimmune Diabetes of the Adult" (LADA). , 2014, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[24]  C. Katiyar,et al.  Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen induced arthritis. , 2014, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[25]  Xian-Jun Qu,et al.  The comparative study of acetyl-11-keto-beta-boswellic acid (AKBA) and aspirin in the prevention of intestinal adenomatous polyposis in APC(Min/+) mice. , 2014, Drug discoveries & therapeutics.

[26]  D. Hallinger,et al.  Association of proinflammatory cytokines and islet resident leucocytes with islet dysfunction in type 2 diabetes , 2014, Diabetologia.

[27]  Zu-hua Gao,et al.  Chemoprevention of intestinal adenomatous polyposis by acetyl‐11‐keto‐beta‐boswellic acid in APCMin/+ mice , 2013, International journal of cancer.

[28]  Shashank K Singh,et al.  NF-κB down-regulation and PARP cleavage by novel 3-α-butyryloxy-β-boswellic acid results in cancer cell specific apoptosis and in vivo tumor regression. , 2013, Anti-Cancer Agents in Medicinal Chemistry.

[29]  R. Postier,et al.  Frankincense essential oil prepared from hydrodistillation of Boswellia sacra gum resins induces human pancreatic cancer cell death in cultures and in a xenograft murine model , 2012, BMC Complementary and Alternative Medicine.

[30]  S. Jain,et al.  A Novel cyano derivative of 11‐Keto‐β‐Boswellic acid causes apoptotic death by disrupting PI3K/AKT/Hsp‐90 cascade, mitochondrial integrity, and other cell survival signaling events in HL‐60 cells , 2012, Molecular carcinogenesis.

[31]  C. Boland,et al.  Boswellic acid induces epigenetic alterations by modulating DNA methylation in colorectal cancer cells , 2012, Cancer biology & therapy.

[32]  B. Aggarwal,et al.  Boswellic Acid Suppresses Growth and Metastasis of Human Pancreatic Tumors in an Orthotopic Nude Mouse Model through Modulation of Multiple Targets , 2011, PloS one.

[33]  H. Ammon,et al.  Prevention of multiple low-dose streptozotocin (MLD-STZ) diabetes in mice by an extract from gum resin of Boswellia serrata (BE). , 2011, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[34]  M. Pandey,et al.  Antitumor properties of Boswellic acid against Ehrlich ascites cells bearing mouse. , 2011, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[35]  Mingyao Liu,et al.  Acetyl‐11‐keto‐β‐boswellic acid suppresses invasion of pancreatic cancer cells through the downregulation of CXCR4 chemokine receptor expression , 2011, International journal of cancer.

[36]  S. Jain,et al.  A cyano analogue of boswellic acid induces crosstalk between p53/PUMA/Bax and telomerase that stages the human papillomavirus type 18 positive HeLa cells to apoptotic death. , 2011, European journal of pharmacology.

[37]  Shashank K Singh,et al.  A propionyloxy derivative of 11-keto-β-boswellic acid induces apoptosis in HL-60 cells mediated through topoisomerase I & II inhibition. , 2011, Chemico-biological interactions.

[38]  O. Werz,et al.  Inhibition of microsomal prostaglandin E2 synthase‐1 as a molecular basis for the anti‐inflammatory actions of boswellic acids from frankincense , 2011, British journal of pharmacology.

[39]  Ping Li,et al.  [Acetyl-11-keto-beta-boswellic acid and arsenic trioxide regulate the productions and activities of matrix metalloproteinases in human skin fibroblasts and human leukemia cell line THP-1]. , 2010, Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine.

[40]  B. Aggarwal,et al.  Targeting Inflammatory Pathways by Triterpenoids for Prevention and Treatment of Cancer , 2010, Toxins.

[41]  V. Duance,et al.  Boswellia frereana (frankincense) suppresses cytokine‐induced matrix metalloproteinase expression and production of pro‐inflammatory molecules in articular cartilage , 2010, Phytotherapy research : PTR.

[42]  G. Schneider,et al.  Identification of Human Cathepsin G As a Functional Target of Boswellic Acids from the Anti-Inflammatory Remedy Frankincense1 , 2009, The Journal of Immunology.

[43]  Huiqing Yuan,et al.  Inhibitory effect of acetyl-11-keto-beta-boswellic acid on androgen receptor by interference of Sp1 binding activity in prostate cancer cells. , 2008, Biochemical pharmacology.

[44]  D. Scott‐Algara,et al.  Antiinflammatory and antiatherogenic effects of the NF-kappaB inhibitor acetyl-11-keto-beta-boswellic acid in LPS-challenged ApoE-/- mice. , 2008, Arteriosclerosis, Thrombosis and Vascular Biology.

[45]  G. Schneider,et al.  Identification and functional analysis of cyclooxygenase-1 as a molecular target of boswellic acids. , 2008, Biochemical pharmacology.

[46]  Shashank K Singh,et al.  Effect of acetyl 11-keto beta-boswellic acid on metastatic growth factor responsible for angiogenesis. , 2007, Vascular pharmacology.

[47]  B. Lakshmi,et al.  Pure compound from Boswellia serrata extract exhibits anti-inflammatory property in human PBMCs and mouse macrophages through inhibition of TNFalpha, IL-1beta, NO and MAP kinases. , 2007, International immunopharmacology.

[48]  Nils Welsh,et al.  Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. , 2005, Diabetes.

[49]  L. Lao,et al.  Effects of an acetone extract of Boswellia carterii Birdw. (Burseraceae) gum resin on adjuvant-induced arthritis in lewis rats. , 2005, Journal of ethnopharmacology.

[50]  D. Y. Lee,et al.  Boswellia carterii Extract Inhibits TH1 Cytokines and Promotes TH2 Cytokines In Vitro , 2005, Clinical Diagnostic Laboratory Immunology.

[51]  O. Werz,et al.  Phosphorylation‐ and stimulus‐dependent inhibition of cellular 5‐lipoxygenase activity by nonredox‐type inhibitors , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[52]  S. Oredsson,et al.  Keto- and acetyl-keto-boswellic acids inhibit proliferation and induce apoptosis in Hep G2 cells via a caspase-8 dependent pathway. , 2002, International journal of molecular medicine.

[53]  R. Saller,et al.  Cytostatic and apoptosis-inducing activity of boswellic acids toward malignant cell lines in vitro. , 2002, Anticancer research.

[54]  J. Slupsky,et al.  Acetyl-boswellic acids are novel catalytic inhibitors of human topoisomerases I and IIalpha. , 2000, Molecular pharmacology.

[55]  T. Orlikowsky,et al.  Acetyl-11-keto-beta-boswellic acid induces apoptosis in HL-60 and CCRF-CEM cells and inhibits topoisomerase I. , 1999, The Journal of pharmacology and experimental therapeutics.

[56]  Gupta,et al.  Effects of Boswellia serrata gum resin in patients with bronchial asthma: results of a double-blind, placebo-controlled, 6-week clinical study. , 1998, European Journal of Medical Research.

[57]  Chi-Tang Ho,et al.  Inhibitory activity of boswellic acids from Boswellia serrata against human leukemia HL-60 cells in culture. , 1998, Planta medica.

[58]  H. Ammon,et al.  Inhibition by boswellic acids of human leukocyte elastase. , 1997, The Journal of pharmacology and experimental therapeutics.

[59]  R. Etzel.  Special extract of BOSWELLIA serrata (H 15) in the treatment of rheumatoid arthritis. , 1996, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[60]  J. Miyazaki,et al.  Non-obese diabetic transgenic mouse , 1992, Springer Seminars in Immunopathology.

[61]  A. Kapil,et al.  Anticomplementary activity of boswellic acids--an inhibitor of C3-convertase of the classical complement pathway. , 1992, International journal of immunopharmacology.

[62]  M. Anazodo,et al.  Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase. , 1992, The Journal of pharmacology and experimental therapeutics.

[63]  H. Ammon,et al.  Inhibition of leukotriene B4 formation in rat peritoneal neutrophils by an ethanolic extract of the gum resin exudate of Boswellia serrata. , 1991, Planta medica.

[64]  L. G. Wang,et al.  Determination of DNA topoisomerase II activity from L1210 cells--a target for screening antitumor agents. , 1991, Zhongguo yao li xue bao = Acta pharmacologica Sinica.

[65]  G. B. Singh,et al.  Pharmacology of an extract of salai guggal ex-Boswellia serrata, a new non-steroidal anti-inflammatory agent , 1986, Agents and Actions.

[66]  Shashank K Singh,et al.  Acyl derivatives of boswellic acids as inhibitors of NF-κB and STATs. , 2012, Bioorganic & medicinal chemistry letters.

[67]  T. Syrovets,et al.  Acetyl-boswellic acids inhibit lipopolysaccharide-mediated TNF-alpha induction in monocytes by direct interaction with IkappaB kinases. , 2005, Journal of immunology.

[68]  Hongyan Liu,et al.  Boswellic acid acetate induces differentiation and apoptosis in highly metastatic melanoma and fibrosarcoma cells. , 2003, Cancer detection and prevention.

[69]  J. Harwalkar,et al.  Cytotoxic action of acetyl-11-keto-beta-boswellic acid (AKBA) on meningioma cells. , 2002, Planta medica.

[70]  R. Repges,et al.  [Therapy of active Crohn disease with Boswellia serrata extract H 15]. , 2001, Zeitschrift fur Gastroenterologie.

[71]  R. Lüdtke,et al.  Effects of Boswellia serrata gum resin in patients with ulcerative colitis. , 1997, European journal of medical research.

[72]  D. Martinetz,et al.  Weihrauch und Myrrhe : Kulturgeschichte und wirtschaftliche Bedeutung : Botanik, Chemie, Medizin , 1989 .