Emetine dihydrochloride: a novel therapy for bladder cancer

Abstract

Purpose: Current cisplatin based therapies for stage IV bladder cancer show 4% to 20% 5-year survival, underscoring the need to develop novel therapies for these patients. In the 1970s the natural alkaloid emetine dihydrochloride demonstrated modest anticancer efficacy as a single agent in clinical trials but this was not pursued. Groups recently reported that emetine induced apoptosis in leukemia cell lines, which was enhanced by cisplatin. We determined the antiproliferative effects of emetine with and without cisplatin in bladder cancer cells.

Materials and methods: Human bladder cancer cell lines and normal human urothelial cell cultures were treated with emetine and/or cisplatin. We measured cell proliferation and evaluated synergy using the Chou-Talalay method. The combination index was calculated. Cell cycle analysis was done and caspase activation was evaluated to assess growth arrest and apoptosis.

Results: Emetine and cisplatin individually inhibited bladder cancer cell proliferation. When combined, emetine and cisplatin acted synergistically to inhibit tumor cell proliferation with combination index values reflecting moderate to strong synergy. Normal urothelial cells were relatively resistant to this treatment. Emetine alone and combined with cisplatin appeared to primarily induce tumor cell growth arrest and not apoptosis.

Conclusions: To our knowledge this study demonstrates for the first time that emetine has in vitro antiproliferative activity against bladder cancer cell lines at nanomolar concentrations but little effect on normal urothelial cells. Moreover, emetine and cisplatin worked synergistically to inhibit tumor cell proliferation. Results suggest that combined emetine and cisplatin based chemotherapy may benefit patients with bladder cancer.

Keywords: 50% inhibitory concentration; ABC; CI; FBS; FITC; HIF; IC(50); PI; adenosine triphosphate binding cassette; carcinoma; cisplatin; combination index; emetine; fetal bovine serum; fluorescein isothiocyanate; hypoxia-inducible factor; propidium iodide; urinary bladder; urothelium.