Anticancer activity of β-Elemene and its synthetic analogs in human malignant brain tumor cells.

Malignant brain tumors are aggressive in both children and adults. Despite recent improvements in diagnostic techniques, therapeutic approaches remain disappointing and unsuccessful. There is an urgent need for promising anticancer agents to improve overall survival of patients with brain cancer. β-Elemene has been shown to have antiproliferative effects on many types of carcinomas. In this study, we compared the cytotoxic efficacy of β-elemene and its synthetic analogs in the brain tumor cell lines A172, CCF-STTG1, and U-87MG. β-Elemene exhibited cytotoxicity towards the tumor lines, effectively suppressing tumor cell survival. The inhibitory effect of β-elemene was mediated by the induction of apoptosis, as demonstrated by three assays. The annexin V assay showed that β-elemene increased the percentage of early- and late-apoptotic cells. Apoptotic nuclei were detected in cancer cells in situ by the terminal deoxynucleotidyltransferase-mediated deoxy-UTP-fluorescein nick end labeling (TUNEL) staining, and the number of TUNEL-positive cells was significantly increased at 24-72 h following drug treatment of the cell lines. Cell death enzyme-linked immunosorbent assay (ELISA) gave similar results. Furthermore, β-elemene increased caspase-3/7/10 activity, up-regulated protein expression of BAX, and down-regulated the one of BCL-2, BCL-XL, and of X-linked inhibitor of apoptosis (XIAP) in the cells, suggesting that apoptotic signaling pathways are involved in the responses triggered by β-elemene. Compared with β-elemene, only three of the 10 synthetic β-elemene analogs studied here, exerted comparable cytotoxic efficacy towards the three brain tumor lines: the analogs Lr-1 and Lr-2 had the same antitumor efficacy, while Lr-3 was less potent than β-elemene. Thus, some synthetic analogs of β-elemene may inhibit brain cancer cell growth and proliferation, and the synthetic analogs Lr-1 and Lr-2 may have great potential as alternatives to β-elemene for anticancer therapy. Overall, this study provides, to our knowledge, the first evidence showing that synthetic analogs of β-elemene hold promise for patients with brain tumors.