RESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Neoplasias Meníngeas/patología , Meningioma/patología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Triterpenos/farmacología , Araquidonato 5-Lipooxigenasa/genética , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de la Lipooxigenasa , Neoplasias Meníngeas/genética , Meningioma/enzimología , Meningioma/genética , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Fosforilación , Fitoterapia , ARN Mensajero/genética , Células Tumorales CultivadasRESUMEN
OBJECTIVE: 5-Lipoxygenase (5-LO) oxidizes arachidonic acid into proinflammatory eicosanoids that may promote tumorigenesis. In this study, we investigated whether 5-LO is expressed in human astrocytomas and what effect its expression may have on patient outcome. METHODS: Increased 5-LO messenger ribonucleic acid and protein expression was detected by the polymerase chain reaction and antibody-based approaches, respectively, in surgical astrocytoma specimens and established glioblastoma multiforme cell lines compared with primary cell culture from the human white matter. RESULTS: Immunohistochemical analysis revealed predominantly nuclear 5-LO staining in 44 of 49 glioblastoma multiforme samples (90%), 8 of 10 (80%) anaplastic astrocytomas samples, and 3 of 13 (23%) low-grade astrocytoma samples analyzed. Double-staining experiments with anti-CD-68 (macrophage/microglial marker) and anti-5-LO antibodies suggest that both CD-68-positive and CD-68-negative tumor cells express 5-LO protein. Staining of 5-LO was significantly more frequent in high-grade than in low-grade tumors (P = 0.001). Patients whose tumors expressed 5-LO were significantly older, had lower preoperative Karnofsky performance scores and shorter survival than patients whose tumors did not express 5-LO. After adjusting for pathological diagnosis and age, respectively, neither Karnofsky performance score nor survival were significantly associated with 5-LO staining. CONCLUSION: These data indicate that 5-LO is overexpressed in high-grade astrocytomas and supports the idea that eicosanoids may play a role in tumorigenesis of these brain tumors.
Asunto(s)
Araquidonato 5-Lipooxigenasa/biosíntesis , Astrocitoma/enzimología , Neoplasias Encefálicas/enzimología , Regulación Neoplásica de la Expresión Génica/fisiología , Adulto , Anciano , Araquidonato 5-Lipooxigenasa/genética , Astrocitoma/genética , Encéfalo/citología , Encéfalo/enzimología , Neoplasias Encefálicas/genética , Células Cultivadas , Células HL-60 , Humanos , Masculino , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Estudios Retrospectivos , Células Tumorales CultivadasRESUMEN
Acetyl-11-keto-beta-boswellic acid (AKBA) is a naturally occurring pentacyclic triterpene isolated from the gum resin exudate of the tree Boswellia serrata (frankincense). Because pentacyclic triterpenes have antiproliferative and cytotoxic effects against different tumor types, we investigated whether AKBA would act in a similar fashion on primary human meningioma cell cultures. Primary cell cultures were established from surgically removed meningioma specimens. The number of viable cells in the absence/presence of AKBA was determined by the non-radioactive cell proliferation assay. The activation status of the proliferative cell marker, extracellular signal-regulated kinase-1 and -2 (Erk-1 and Erk-2) was determined by immunoblotting with the antibody that recognizes the activated form of these proteins. Treatment of meningioma cells by AKBA revealed a potent cytotoxic activity with half-maximal inhibitory concentrations in the range of 2 - 8 microM. At low micromolar concentrations, AKBA rapidly and potently inhibited the phosphorylation of Erk-1/2 and impaired the motility of meningioma cells stimulated with platelet-derived growth factor BB. The cytotoxic action of AKBA on meningioma cells may be mediated, at least in part, by the inhibition of the Erk signal transduction pathway. Because of the central role the Erk pathway plays in signal transduction and tumorigenesis, further investigation into the potential clinical use for AKBA and related boswellic acids is warranted.