Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity

Steroids are essential for the control of oedema in human malignant glioma patients but may interfere with the efficacy of chemotherapy. Boswellic aci ds are phytotherapeutic anti-inflammatory agents that may be alternative dr ugs to corticosteroids in the treatment of cerebral oedema. Here, we report that boswellic acids are cytotoxic to malignant glioma cells at low microm olar concentrations. In-situ DNA end labelling and electron microscopy reve al that boswellic acids induce apoptosis, Boswellic acid-induced apoptosis requires protein, but not RNA synthesis, and is neither associated with fre e radical formation nor blocked by free radical scavengers, The levels of B AX and BCL-2 proteins remain unaltered during boswellic acid-induced apopto sis. p21 expression is induced by boswellic acids via a p53-independent pat hway. 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 aci d toxicity. Ectopic expression of neither BCL-2 nor the caspase inhibitor, CRM-A, is protective. In contrast to steroids, subtoxic concentrations of b oswellic acids do not interfere with cancer drug toxicity of glioma cells i n acute cytotoxicity or clonogenic cell death assays. Also, in contrast to steroids, boswellic acids synergize with the cytotoxic cytokine, CD95 ligan d, in inducing glioma cell apoptosis, This effect is probably mediated by i nhibition of RNA synthesis and is not associated with changes of CD95 expre ssion at the cell surface. Further studies in laboratory animals and in hum an patients are required to determine whether boswellic acids may be a usef ul adjunct to the medical management of human malignant glioma.