BACKGROUND: Mitogenic and anti-apoptotic actions of endothelin-1 (ET-1) are mediated through endothelin A (ET(A)) receptors. We investigated endothelin receptor expression in increasingly aggressive phenotype and in vivo effects of combination therapy using ET(A) antagonist with paclitaxel. METHODS: Dunning prostate cancer cells ranged in aggressiveness from non-tumorigenic G, to tumorigenic, non-metastatic AT-1, and to tumorigenic and metastatic MLL. Binding assays were performed alongside Q-PCR to assess receptor density. MLL xenografts were treated with vehicle, atrasentan, paclitaxel, and paclitaxel+atrasentan. RESULTS: Saturation binding assays demonstrated endothelin receptor density of MLL and AT-1 cells seven- and threefold higher than G cells, respectively. Q-PCR showed 9- and 4.5-fold greater ET(A) mRNA expression in MLL and AT-1 than G cells, respectively and no endothelin receptor B (ET(B)) expression. Combination therapy had significant effect on reduction of tumor volume than paclitaxel or atrasentan alone. CONCLUSIONS: ET(A) expression increases in aggressive prostate carcinoma. ET(A) blockade combined with paclitaxel may reduce tumor growth in advanced prostate carcinoma.
BACKGROUND: Mitogenic and anti-apoptotic actions of endothelin-1 (ET-1) are mediated through endothelin A (ET(A)) receptors. We investigated endothelin receptor expression in increasingly aggressive phenotype and in vivo effects of combination therapy using ET(A) antagonist with paclitaxel. METHODS: Dunning prostate cancer cells ranged in aggressiveness from non-tumorigenic G, to tumorigenic, non-metastatic AT-1, and to tumorigenic and metastatic MLL. Binding assays were performed alongside Q-PCR to assess receptor density. MLL xenografts were treated with vehicle, atrasentan, paclitaxel, and paclitaxel+atrasentan. RESULTS: Saturation binding assays demonstrated endothelin receptor density of MLL and AT-1 cells seven- and threefold higher than G cells, respectively. Q-PCR showed 9- and 4.5-fold greater ET(A) mRNA expression in MLL and AT-1 than G cells, respectively and no endothelin receptor B (ET(B)) expression. Combination therapy had significant effect on reduction of tumor volume than paclitaxel or atrasentan alone. CONCLUSIONS:ET(A) expression increases in aggressive prostate carcinoma. ET(A) blockade combined with paclitaxel may reduce tumor growth in advanced prostate carcinoma.
Authors: Ardavan Akhavan; Kevin H McHugh; Georgi Guruli; Robert R Bies; William C Zamboni; Sandra A Strychor; Joel B Nelson; Beth R Pflug Journal: Neoplasia Date: 2006-09 Impact factor: 5.715