Neuroblastomas are high-risk primary brain tumors that are generally unresponsive or only weakly responsive to the currently available antineoplastic agents. The current median survival for glioblastoma patients is approximately one year, thus novel therapeutic agents are urgently needed. Oleanolic acid and ursolic acid are naturally occurring triterpenoids that have been used in traditional Asian medicine as anti-inflammatory and anti-cancer agents. Recently, synthetic oleanolic acid derivatives: 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CDDO-Me) and C-28 imidazole (CDDO-Im) have been shown to exhibit potent antitumor activity against diverse types of tumor cell lines, including leukemia, multiple myeloma, osteosarcoma, breast, lung, and pancreatic cancer cell lines; however, anticancer activity of these agents for brain tumors has not been reported. In the present study, we investigated the apoptosis-inducing activity of CDDOs in neuroblastoma cell lines U87MG, U251MG, and SK-N-MC. Cell growth/viability (MTS) and cytotoxicity (LDH release) assays demonstrated that neuroblastoma cell lines are least sensitive to the parent synthetic oleanolic acid triterpenoid (CDDO), but are highly sensitive to CDDO-Me and CDDO-Im at concentrations of 2.5-10 μM. CDDO-Me and CDDO-Im were equipotenent in their growth inhibitory activity. The primary mode of tumor cell destruction was apoptosis as demonstrated by significant increase in the number of hypo-diploid (sub-G1) and annexin V-binding cells. Induction of apoptosis was associated with activation of procaspases -3, -8, and -9, mitochondrial depolarization and the release of cytochrome c from the mitochondria. Furthermore, CDDO-Me inhibited the levels of anti-apoptotic and prosurvival p-Akt, NF-κB (p65) and Notch1 signaling molecules. These studies provide preliminary evidence for the potential use of these novel triterpenoids for clinical management of lethal brain neoplasms.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA