Synergistic growth inhibition of human cancer cells with atrasentan and a Bcl-2 inhibitor

4893

Endothelin-1 (ET-1), acting through its receptor ET_AR, functions in normal tissue to regulate blood pressure and affect tissue differentiation and cell proliferation. It is also thought to play a role in the stimulation and metastasis of cancer cells. Atrasentan , an oral selective ET_AR antagonist currently in clinical trials, inhibits ET-1 activity. Inhibitors of Bcl-2, an anti-apoptotic protein overexpressed in numerous human tumors, have been shown to induce apoptosis and sensitize cancer cells to various therapies. The purpose of this study was to assess the in vitro effects of combining Atrasentan and a

Bcl-2 inhibitor (ABT-737: Abbott Laboratories) on the growth of MCF-7 human breast cancer cells and LNCaP human prostate cancer cells. Cells were exposed to Atrasentan (5 - 30 μM) or ABT-737 ( 1-10 μM) alone or in combination for 3 days (16 different dose combinations were tested). Cell growth was determined using the colorimetric MTT tetrazolium dye assay. The Chou-Talalay method of isobologram analysis was performed to determine synergism. Dose-dependent growth inhibition was observed in both cell lines after 3 days exposure to each agent alone. Exposure to the combination of Atrasentan and the ABT-737 Bcl-2 inhibitor resulted in synergistic growth inhibition in both the MCF-7 human breast and LNCaP human prostate cancer cells. These results suggest this combination may provide a novel therapeutic strategy for treating breast and prostate cancer patients.