Opposite effects on cytosolic Ca2+ of antitumor phospholipids by induction of calcium influx and activation of endoplasmic reticulum Ca(2+)-ATPase.

The ability of four different antitumor phospholipids, 1-O-hexadecyl-2-chloro-2-deoxyglycero-3-phosphocholine (ET16CIPC), hexadecylphosphocholine (C16OPC), hexadecylphospho-L-serine analogs (C16OPS, C16OPS-N-Ac) and cytidine-5'-hexadecylphosphonophosphate (C16PCMP) to modulate the cytosolic Ca2+ concentration [Ca2+]i was studied in an immortalized human mammary epithelial cell line H184 A1N4. The compounds induced different modes of activity depending on their structure and concentration. ET16CIPC induced between 0.31 and 5 microM a concentration dependent transient increase which was followed by a sustained increase at 10 microM. Studies using LaCl3 and Mn2+ quench of the Fura-2 fluorescence indicated that both effects are the result of an extracellular Ca2+ influx. Low concentrations of C16OPC, C16OPS and C16OPS-N-Ac induced no, or only a small, transient increase, whereas C16PCMP caused a decrease in [Ca2+]i. Thapsigargin and cyclopiazonic acid, specific inhibitors of the endoplasmic reticulum Ca(2+)-ATPase, prolonged the transient [Ca2+]i increase following ET16CIPC concentration dependently, increased markedly the small transient increase following C16OPC and the C16-phosphoserine analogs and converted the decrease in the basal [Ca2+]i level induced by C16PCMP to an increase. The identical effects with thapsigargin and cyclopiazonic acid provide evidence that the [Ca2+]i response observed is an expression of the balance between the ability of an analog to raise [Ca2+]i and to remove Ca2+ by activation of the endoplasmic reticulum Ca(2+)-ATPase. This behaviour might contribute to the antiproliferative effectiveness of antitumor phospholipids.