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Acetyl-11-keto-beta-boswellic acid (AKBA) is a naturally occurring pentacyclic triterpene isolated from the gum resin exudate from the stem of the tree Boswellia serrata (frankincense). AKBA has been recently identified as a novel, orally active, non-redox and non-competitive 5-lipoxygenase inhibitor that also inhibits topisomerase I and II in vitro. Because natural pentacyclic triterpenes have an antiproliferative effect against different tumor types, we investigated the effects of AKBA on the proliferation of 11 primary cell cultures established from human surgical specimens of meningiomas, common central nervous system tumors. Treatment of meningioma cells by AKBA revealed a potent cytotoxic activity with half-maximal inhibitory concentrations in the range of 2-8 microM. At similar, physiologically achievable concentrations, AKBA rapidly (within minutes) and potently inhibited the phosphorylation of extracellular signal-regulated kinase 1 and 2 (Erk-1 and Erk-2) in meningioma cells stimulated with platelet-derived growth factor BB. High expression level of 5-LO was detected in primary meningioma cells and surgical specimens by immunoblotting analysis, suggesting the possible role of 5-LO in meningioma tumorigenesis. Considering the critical importance of the Erk-1/2 signal transduction pathway not only in meningiomas but in other human neoplasms, the interruption of signaling through this evolutionarily conserved pathway might be one of the mechanisms by which AKBA induces suppression of proliferation and apoptosis of different tumor types.

Neurofibromin and p120 GTPase activating protein (p120 GAP) down-regulate the activity of cellular Ras proteins. How the activity of these two proteins is controlled is not yet clear. In this study, we analyzed the effects of eight nutritionally relevant fatty acids on GTPase stimulatory activity of full-length neurofibromin and p120 GAP. The fatty acids tested were: saturated stearic acid, monounsaturated oleic acid, three omega-6 and three omega-3 polyunsaturated fatty acids. The analysis was performed by Ras immunoprecipitation GTPase assay. The full-length p120 GAP expressed in insect Sf9 cells and the immunoaffinity purified full-length neurofibromin were used. Neurofibromin was readily inhibited by stearic and oleic acid, but p120 GAP was not inhibited even at high concentrations (> 80 microM). Neurofibromin was also inhibited by low concentrations of all the polyunsaturated fatty acids tested (IC50 of 6 to 16 microM). p120 GAP was 2-3 fold less sensitive to inhibition by these fatty acids. The GTPase stimulatory activity of neurofibromin was also inhibited by arachidonic and oleic acid in the presence of a lipid mixture representing the major lipid components of the cell membrane. Chimeric proteins of neurofibromin and p120 GAP were used to determine that differential sensitivity to fatty acid inhibition maps to the catalytic domain of the proteins. These results indicated that fatty acids can modulate the GTPase function of the c-Ha-Ras protein by inhibiting the GTPase stimulatory activity of two Ras regulators, full-length neurofibromin and p120 GAP, at physiologically relevant concentrations in vitro.