β-Elemene Promotes Cisplatin-induced Cell Death in Human Bladder Cancer and Other Carcinomas

Cisplatin-based combination treatment is the most effective systemic chemotherapy for bladder cancer; however, resistance to cisplatin remains a significant problem in the treatment of this disease. β-Elemene is a new natural compound that blocks cell-cycle progression and has a broad spectrum of antitumor activity. This study was conducted to explore the potential of β-elemene as a chemosensitizer for enhancing the therapeutic efficacy and potency of cisplatin in bladder cancer and other solid carcinomas. β-Elemene not only markedly inhibited cell growth and proliferation but also substantially increased cisplatin cytotoxicity towards human bladder cancer 5637 and T-24 cells. Similarly, β-elemene also enhanced cisplatin sensitivity and augmented cisplatin cytotoxicity in small-cell lung cancer and carcinomas of the brain, breast, cervix, ovary, and colorectal tract in vitro, with dose-modifying factors ranging from 5 to 124. β-Elemene-enhanced cisplatin cytotoxicity was associated with increased apoptotic cell death, as determined by DNA fragmentation, and increased activities of caspase-3, -7, -8, -9, and -10 in bladder cancer cell lines. Collectively, these results suggest that β-elemene augments the antitumor activity of cisplatin in human bladder cancer by enhancing the induction of cellular apoptosis via a caspase-dependent mechanism. Cisplatin combined with β-elemene as a chemosensitizer warrants further pre-clinical therapeutic studies and may be useful for the treatment of cisplatin-resistant bladder cancer and other types of carcinomas. Urinary bladder cancer is the second most common malignant urological tumor, following prostate carcinoma, in the United States (1). During the past 30 years, there has been slow yet steady progress in the development of novel chemotherapeutic strategies for the management of advanced and metastatic bladder cancer (2-4). Nevertheless, current chemotherapy confers only a modest survival benefit on patients with bladder cancer; metastatic disease remains essentially incurable, with only a small number of patients achieving long-term disease control. Typical combination regimens such as cyclophosphamide-doxorubicin-cisplatin