Quercetin: synergistic action with carboxyamidotriazole in human breast carcinoma cells

Quercetin, a plant flavonoid, blocks signal transduction pathways by inhibiting 1-phosphatidylinositol 4-kinase (EC 2.7.1.67, PI kinase) and 1-phosphatidylinositol 4-phosphate 5-kinase (EC 2.7.1.68, PIP kinase), resulting in a reduction of inositol 1,4,5-trisphosphate (IP3) concentration which decreases the release of calcium from intracellular sources. Carboxyamidotriazole (CAI), a novel anticancer agent, inhibits calcium entry into cells. Because both drugs reduce cytosolic calcium levels, we tested the action of quercetin and CAI in human carcinoma cells. Human breast carcinoma MDA-MB-435 cells were grown in minimum essential medium with 10% fetal bovine serum. In growth inhibition assay the IC50s for quercetin and CAI were 55 and 4.8 microM, respectively; in clonogenic assay, 28 and 1.4 microM, respectively. When quercetin and CAI were added to the cultures, synergism was observed in isobolograms in growth inhibition and clonogenic assays. In growth inhibition assay, the best combination was 20 microM quercetin with 4 microM CAI; in clonogenic assay, 30 microM quercetin with 1.2 microM CAI. Since these drugs are in phase I trials the synergistic action of quercetin and CAI may be of interest in clinical trials for breast carcinoma.