Glioblastoma is the deadliest brain tumor in humans and it remains incurable. Conventional therapeutic strategies (surgery, radiation therapy, and chemotherapy) for glioblastoma still do not yield most satisfying results and the adjuvant chemotherapy fails to date to increase survival time significantly in glioblastoma patients. To improve the outcome of glioblastoma treatment, additional therapeutic strategies are urgently necessary. Boswellic acids are pentacyclic triterpenes found in gum resin of Boswellia serrata, which produces various phytochemical anti-inflammatory agents that may be alternative drugs to corticosteroids in the treatment of cerebral edema. Here, we report that two boswellic acids, beta-boswellic acid (BBA) and 11-keto-beta-boswellic acid (KBBA), at low micromolar concentrations show cytotoxic effects in two human glioblastoma T98G (p53 mutant) and U87MG (p53 wild-type) cell lines. We studied the abilities of BBA and KBBA for induction of apoptotic death in T98G and U87MG cells and the molecular pathways leading to apoptosis. The viability of T98G and U87MG cells decreased following treatment with increasing doses of BBA and KBBA. Our dose-response studies indicated that treatment of T98G and U87MG cells with 25 \#956;M BBA and 25 \#956;M KBBA for 24 h could produce morphological and biochemical features of apoptosis. Apoptosis was associated with an increase in intracellular free [Ca2+] as determined by fura-2 assay. Western blotting demonstrated that apoptosis occurred due to an increase in Bax:Bcl-2 ratio, mitochondrial release of cytochrome c into the cytosol, and activation of calpain, caspase-9, and caspase-3. Increased activities of caspase-9 and caspase-3 were also confirmed by colorimetric assays. These results indicated that BBA and KBBA could be used at low doses for activation of proteolytic activities of calpain and caspases for induction of apoptosis in human glioblastoma T98G and U87MG cells. Our studies also suggest that BBA and KBBA mediated induction of apoptosis does not depend on the functional p53 status of the human glioblastoma cells. Further studies in different animal models of glioblastoma are warranted to determine whether boswellic acids may be useful as highly potent phytotherapeutic agents for the management of human glioblastomas in vivo. This investigation was supported in part by the R01 grants (CA-91460 and NS-57811) from the National Institutes of Health (Bethesda, MD, USA).
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2675.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO