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


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Lambert
P A
PA
Department of Surgery, Eastern Virginia Medical School, Norfolk 23507, USA.
Somers
K D
KD
Kohn
E C
EC
Perry
R R
RR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000970:Antineoplastic Agents / Q000633:toxicity*; D001943:Breast Neoplasms / Q000473:pathology*; D002121:Calcium Channel Blockers / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D017364:Collagenases / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D011960:Receptors, Estrogen / Q000032:analysis; D014230:Triazoles / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D011960:Receptors, Estrogen; D014230:Triazoles; C062058:carboxyamido-triazole; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9