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.
Bergmann
J
J
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. jbergma@mdc-berlin.de
Langen
P
P
Thomas
Y
Y
Brachwitz
H
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001940:Breast / Q000166:cytology; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008246:Lysophospholipids / Q000494:pharmacology*; D008345:Manganese / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010768:Phosphoserine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship
C090562:2-chloro-2-deoxy-1-O-hexadecylglycero-3-phosphocholine; D000970:Antineoplastic Agents; D008246:Lysophospholipids; C111025:aracytidine-5'-hexadecylphosphonophosphate; D003561:Cytarabine; D010767:Phosphorylcholine; C090561:hexadecylphosphoserine; D010768:Phosphoserine; D008345:Manganese; C039128:miltefosine; D000252:Calcium-Transporting ATPases; D002118:Calcium