title: Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity.
abstract: Steroids are essential for the control of oedema in human malignant glioma patients but may interfere with the efficacy of chemotherapy. Boswellic acids are phytotherapeutic anti-inflammatory agents that may be alternative drugs to corticosteroids in the treatment of cerebral oedema. Here, we report that boswellic acids are cytotoxic to malignant glioma cells at low micromolar concentrations. In-situ DNA end labelling and electron microscopy reveal that boswellic acids induce apoptosis. Boswellic acid-induced apoptosis requires protein, but not RNA synthesis, and is neither associated with free radical formation nor blocked by free radical scavengers. The levels of BAX and BCL-2 proteins remain unaltered during boswellic acid-induced apoptosis. p21 expression is induced by boswellic acids via a p53-independent pathway. Ectopic expression of wild-type p53 also induces p21, and facilitates boswellic acid-induced apoptosis. However, targeted disruption of the p21 genes in colon carcinoma cells enhances rather than decreases boswellic acid toxicity. Ectopic expression of neither BCL-2 nor the caspase inhibitor, CRM-A, is protective. In contrast to steroids, subtoxic concentrations of boswellic acids do not interfere with cancer drug toxicity of glioma cells in acute cytotoxicity or clonogenic cell death assays. Also, in contrast to steroids, boswellic acids synergize with the cytotoxic cytokine, CD95 ligand, in inducing glioma cell apoptosis. This effect is probably mediated by inhibition of RNA synthesis and is not associated with changes of CD95 expression at the cell surface. Further studies in laboratory animals and in human patients are required to determine whether boswellic acids may be a useful adjunct to the medical management of human malignant glioma.
authors.affiliation: Department of Neurology, University of Tübingen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Glaser
authors.forename: S
authors.initials: S
authors.lastname: Winter
authors.forename: P
authors.initials: P
authors.lastname: Groscurth
authors.forename: H
authors.initials: H
authors.lastname: Safayhi
authors.forename: E R
authors.initials: ER
authors.lastname: Sailer
authors.forename: H P
authors.initials: HP
authors.lastname: Ammon
authors.forename: M
authors.initials: M
authors.lastname: Schabet
authors.forename: M
authors.initials: M
authors.lastname: Weller
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D053222:Fas Ligand Protein; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology; D051028:bcl-2-Associated X Protein
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; C494827:Bax protein, mouse; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; C094432:acetyl-11-ketoboswellic acid; D051028:bcl-2-Associated X Protein; C054625:boswellic acid