OBJECTIVE: The CXCR4/CXCL12 axis appears crucial in the metastasis of bladder cancer. Our aim was to evaluate the potency of the CXCR4 antagonist, 4F-benzoyl-TE14011 (4F-bTE), as an anti-metastatic drug in this disease. In this study, we assessed the ability of 4F-bTE to inhibit tumor cell motility, invasion through extracellular matrix (ECM), matrix metalloproteinase (MMP) secretion and cytoskeletal responses to chemokine. METHODS: To assess the degree to which cells could migrate and invade ECM under various conditions, we used TCCSUP bladder cancer cells in a Boyden chamber system. To monitor actin polymerization, we stained cells on chamber slides with AlexaFluor 594 phalloidin. To measure matrix-metalloproteinase-2 and -9 (MMP) activity, we used gelatin zymography. To assess the effects of the CXCR4 antagonist 4F-bTE on each of the above parameters, we exposed bladder cancer cells either to chemokine CXCL12, alone, or to both CXCL12 and 4F-bTE. We also monitored cells for apoptotic and necrotic changes during drug treatment. RESULTS: The CXCR4 antagonist 4F-bTE markedly decreased CXCL12-induced bladder cancer cell migration and ECM invasion in Boyden chamber assays. The antagonist also blocked chemokine-induced actin polymerization as well as the induction of MMP-2 and MMP-9 in these cells. CONCLUSION: The CXCR4 antagonist 4F-bTE has the potential to inhibit expression of the metastatic phenotype and may provide therapeutic value to patients.
OBJECTIVE: The CXCR4/CXCL12 axis appears crucial in the metastasis of bladder cancer. Our aim was to evaluate the potency of the CXCR4 antagonist, 4F-benzoyl-TE14011 (4F-bTE), as an anti-metastatic drug in this disease. In this study, we assessed the ability of 4F-bTE to inhibit tumor cell motility, invasion through extracellular matrix (ECM), matrix metalloproteinase (MMP) secretion and cytoskeletal responses to chemokine. METHODS: To assess the degree to which cells could migrate and invade ECM under various conditions, we used TCCSUP bladder cancer cells in a Boyden chamber system. To monitor actin polymerization, we stained cells on chamber slides with AlexaFluor 594 phalloidin. To measure matrix-metalloproteinase-2 and -9 (MMP) activity, we used gelatin zymography. To assess the effects of the CXCR4 antagonist 4F-bTE on each of the above parameters, we exposed bladder cancer cells either to chemokine CXCL12, alone, or to both CXCL12 and 4F-bTE. We also monitored cells for apoptotic and necrotic changes during drug treatment. RESULTS: The CXCR4 antagonist 4F-bTE markedly decreased CXCL12-induced bladder cancer cell migration and ECM invasion in Boyden chamber assays. The antagonist also blocked chemokine-induced actin polymerization as well as the induction of MMP-2 and MMP-9 in these cells. CONCLUSION: The CXCR4 antagonist 4F-bTE has the potential to inhibit expression of the metastatic phenotype and may provide therapeutic value to patients.
Authors: Elizabeth M Gaughan; Bruce J Dezube; Mark Bower; David M Aboulafia; Gerry Bohac; Timothy P Cooley; Liron Pantanowitz Journal: BMC Urol Date: 2009-08-31 Impact factor: 2.264