leukotriene-b4 and boswellic-acid

Glioblastoma multiforme (GBM) is the most aggressive brain tumor. Current therapeutic strategies are based on the use of Temozolomide (TMZ) and antihuman epidermal growth factor receptor (EGFR) drugs, such as Afatinib. However, clinically relevant drug-resistance events are still present and closely related to a proinflammatory cancer brain microenvironment. The primary aim of this study is the association of Boswellic acid (BA), a molecule derived from Boswellia Serrata, with TMZ and Afatinibin different human GBM cells. We performed cell viability studies evaluating its antioxidant and anti-inflammatory effects analyzing p65/NF-κB and Leukotriene B4 expression and production of interleukins and growth factors (IL-8, IL-6, vascular endothelial growth factor, CXCL-12, and MMP-9). Considering the cardiotoxicity of TMZ and anti-EGFR drugs, we evaluated the putative cardioprotective effects of BA in adult cardiomyocytes. BA significantly increased the anticancer activities of TMZ and Afatinib. These effects are related to its anti-inflammatory and antioxidant effects, based on the inhibition of growth factors and proinflammatory interleukins. Notably, BA exerts also cardioprotective effects in combination to both drugs. This study provides evidences of anti-inflammatory, cardioprotective, and chemo sensitizing effects of BA in glioblastoma cells giving a rationale for new translational studies based on the use of this natural molecule during conventional therapies.

Topics: Afatinib; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Boswellia; Cardiotonic Agents; Cell Line, Tumor; Chemokine CXCL12; ErbB Receptors; Glioblastoma; Humans; Interleukin-6; Interleukin-8; Leukotriene B4; Lipid Peroxidation; Myocytes, Cardiac; Reactive Oxygen Species; Temozolomide; Transcription Factor RelA; Triterpenes

To evaluate the chemopreventive effects of boswellic acid and curcumin on 7,12-dimethyl benzanthracene(DMBA)-induced oral carcinogenesis in the hamster cheek pouch model.. Male Syrian golden hamsters (6 - 8 weeks old, 80 - 130 g in weight) were randomly divided into seven groups, with group A serving as the untreated negative control. The left cheek pouch of the remaining hamsters was topically treated with 0.5% DMBA in mineral oil three times a week for 6 weeks. They were then randomized to six groups with group B serving as a positive control and receiving no further treatment. Groups C-G were treated topically with 5, 10 mg/L boswellic acid, 5, 10 µmol/L curcumin, or the combination of 5 mg/L boswellic acid and 5 µmol/L curcumin three times per week for 18 weeks. The animals were injected with bromodeoxyuridine intraperitoneally at 50 mg/kg 2 h prior to killing. At the 25 th week all the hamsters were sacrificed and cheek pouch tissue was harvested. One half of the tissue was snap frozen in liquid nitrogen for analysis of arachidonic acid metabolites, and the other half was fixed in 10% phosphate-buffered saline(PBS)-buffered formalin for histopathological examination.. Six-weeks of DMBA followed by 18-weeks of topical application of boswellic acid and curcumin, both boswellic acid (5, 10 mg/L) and curcumin (5, 10 µmol/L) significantly inhibited the incidence from 93.8% to 73.9% (P > 0.05), numbers from 2.19 ± 0.98 to 1.13 ± 0.81 (P < 0.01) and size of visible tumors. Microscopically the incidence of squamous cell carcinoma and BrdU index were also significantly suppressed by boswellic acid and curcumin.. Both boswellic acid and curcumin were effective in preventing oral carcinogenesis in DMBA-induced hamster cheek pouch model.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Bromodeoxyuridine; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell; Cheek; Cricetinae; Curcumin; Hyperplasia; Leukotriene B4; Male; Mesocricetus; Mouth Neoplasms; Precancerous Conditions; Random Allocation; Triterpenes

Boswellic acids are pharmacologically active ingredients of frankincense with anti-inflammatory properties. It was shown that in vitro 11-keto-boswellic acids inhibit 5-lipoxygenase (5-LO, EC 1.13.11.34), the key enzyme in leukotriene biosynthesis, which may account for their anti-inflammatory effectiveness. However, whether 11-keto-boswellic acids interfere with 5-LO under physiologically relevant conditions (i.e., in whole blood assays) and whether they inhibit 5-LO in vivo is unknown. Inhibition of human 5-LO by the major naturally occurring boswellic acids was analyzed in cell-free and cell-based activity assays. Moreover, interference of boswellic acids with 5-LO in neutrophil incubations in the presence of albumin and in human whole blood was assessed, and plasma leukotriene B(4) of frankincense-treated healthy volunteers was determined. Factors influencing 5-LO activity (i.e., Ca(2+), phospholipids, substrate concentration) significantly modulate the potency of 11-keto-boswellic acids to inhibit 5-LO. Moreover, 11-keto-boswellic acids efficiently suppressed 5-LO product formation in isolated neutrophils (IC(50)=2.8 to 8.8 muM) but failed to inhibit 5-LO product formation in human whole blood. In the presence of albumin (10 mg/ml), 5-LO inhibition by 11-keto-boswellic acids (up to 30 muM) in neutrophils was abolished, apparently due to strong albumin-binding (>95%) of 11-keto-boswellic acids. Finally, single dose (800 mg) oral administration of frankincense extracts to human healthy volunteers failed to suppress leukotriene B(4) plasma levels. Our data show that boswellic acids are direct 5-LO inhibitors that efficiently suppress 5-LO product synthesis in common in vitro test models, however, the pharmacological relevance of such interference in vivo seems questionable.

Topics: Animals; Anti-Inflammatory Agents; Boswellia; Cattle; Cell-Free System; Enzyme Inhibitors; Humans; Leukotriene B4; Lipoxygenase Inhibitors; Neutrophils; Plant Extracts; Serum Albumin, Bovine; Triterpenes