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Acidic Triterpenes Compromise Growth and Survival of Astrocytoma Cell Lines by Regulating Reactive Oxygen Species Accumulation

¹ Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas-Universidad de Valladolid, Valladolid, Spain and ² Instituto de la Grasa de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain

Requests for reprints: María Luisa Nieto, Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas-Universidad de Valladolid, C/Sanz y Forés s/n, 47003 Valladolid, Spain. Phone: 34-983-184836; Fax: 34-983-184800; E-mail: mlnieto{at}ibgm.uva.es.

Several studies have shown how pentacyclic triterpenes can inhibit proliferation and induce apoptosis of some tumor cell lines; however, its effect on astrocytic tumors, one of the most malignant forms of cancer, has rarely been reported. The aim of this study was to examine how the pentacyclic triterpenes, oleanolic acid and maslinic acid, isolated from olive juice, affected astrocytoma cell morphology and survival. Cell proliferation was inhibited in 1321N1 astrocytoma cells by using 1 to 50 µmol/L of either oleanolic acid or maslinic acid, with an average IC₅₀ of 25 µmol/L. Growth inhibition led to morphologic and cytoskeletal alterations associated with the loss of stellate morphology and characterized by a retraction of the cytoplasm and collapse of actin stress fibers. Using 4',6-diamidino-2-phenylindole and Annexin V, we showed that astrocytoma cell death induced by oleanolic acid or maslinic acid were mainly due to apoptotic events. Furthermore, we showed that caspase-3 is activated as a consequence of triterpene treatment. Finally, we found that exposure of the cells to oleanolic acid or maslinic acid resulted in a significant increase of intracellular reactive oxygen species, followed by loss of mitochondrial membrane integrity. Importantly, enzymatic scavengers, such as catalase, or phenolic antioxidants, such as butylated hydroxytoluene, rescued cells from the triterpene-mediated apoptosis, suggesting that the potential therapeutic effect of these acidic triterpenes is dependent on oxidative stress. Our data show that acidic triterpenes play a major role in 1321N1 astrocytoma morphology and viability and support the conclusion that oleanolic acid and maslinic acid may thus be promising new agents in the management of astrocytomas. [Cancer Res 2007;67(8):3741–51]