Endothelin receptor A blockade enhances taxane effects in prostate cancer.

Endothelin (ET) 1 is important in the growth of prostate cancer cells through the activation of the endothelin A (ET(A)) receptor. ET receptor blockade is a new therapeutic target in treating advanced prostate cancer. This study investigates the impact of the combination of the ET(A) antagonist atrasentan (ABT-627) and taxane chemotherapy on prostate cancer cell survival in vitro and on the delay of prostate cancer in a xenograft mouse model. In vitro, PPC-1 cells transfected with an ET(A)-overexpressing vector were treated with ABT-627, paclitaxel/docetaxel, or both. Clonogenic viability and cell death assays were used to determine cell survival and apoptosis, respectively. ABT-627 and docetaxel combination treatment was used in vivo to treat mice with established ET(A)-overexpressing PPC-1 xenograft tumors, and tumor growth rates were assessed. Cell proliferation and vascularity were determined with Ki-67 and CD31 staining, respectively. Cells treated with combination therapy had significantly fewer viable cells and more programmed cell death than cells given monotherapy. Xenograft tumor growth rates were significantly lower in mice treated with combination therapy than in animals given a single agent. Ki-67 immunostaining demonstrated significantly fewer proliferative cells following combination therapy than following monotherapy. This study demonstrates ABT-627 to have additive antitumor effects when used in combination with taxane drugs both in vitro and in vivo.