Antiproliferative and antiinvasive effects of carboxyamido-triazole on breast cancer cell lines.

Abstract

Basement membrane invasion is one of the critical components of the metastatic cascade. The antiproliferative and antiinvasive activity of carboxyamido-triazole (CAI), a calcium influx inhibitor, was studied in five human breast cancer cell lines (MCF-7, MCF-7/ADRR, MDA-231, MDA-231R44, and BT-474). Sensitivity of the cell lines to CAI was measured with a microculture tetrazolium assay. The Boyden chamber Matrigel chemoinvasion assay was used to measure the antiinvasive activity of CAI. Matrix metalloproteinase activity was analyzed by gelatin zymography. The 50% inhibitory concentrations of CAI were cell line dependent and ranged from 7.49 +/- 4.05 mumol/L to 46.1 +/- 8.6 mumol/L. CAI at a low, minimally toxic concentration (5 mumol/L) inhibited invasion by greater than 75% in the four invasive cell lines (MCF-7/ADRR, MDA-231, MDA-231R44, and BT-474) regardless of estrogen receptor or p-glycoprotein status (p < 0.01). CAI treatment also reduced matrix metalloproteinase activity in conditioned media from three of the four invasive lines (p < 0.05). CAI at clinically achievable concentrations is an effective antiproliferative and antiinvasive agent against human breast cancer cell lines regardless of estrogen receptor or p-glycoprotein status. Reduction in matrix metalloproteinase activity may be partially responsible for CAI inhibition of invasion.