Inhibition of Na+/H+ exchanger activity by an alkyl-lysophospholipid analogue in a human breast cancer cell line.
The mechanisms by which ET-18-OCH3 (1-O-octadecyl-2-O-methyl-sn-glycero-3 -phosphocholine) and other analogues of alkyl-lysophospholipids exert their antineoplastic effects are not yet fully elucidated. Possible interference with mechanisms involving intracellular pH (pHi) regulation was examined by measuring the effect of ET-18-OCH3 on the activity of the Na+/H+ exchanger in the breast cancer-derived cell line MCF-7. When ET-18-OCH3 was added to culture medium at 10 muM (determined as a noncytotoxic but cytostatic concentration), it led to an intracellular acidification (0.15 pH unit). It also decreased the rate of pHi recovery by Na+/H+ exchange following artificial acidification. Kinetic parameters of the exchange indicated that this was due to a decrease in the affinity of the exchanger for both transported ions, rather than to a decrease in the number of exchanger proteins in the membrane (same maximal efflux rate for treated and untreated cells). These results suggest that Na+/H+ exchanger inhibition and subsequent cytoplasmic acidification participate in the mode of action of ET-18-OCH3, and could be used for modulation of tumor-cell chemosensitivity or their subsequent commitment into programmed cell death.
Besson
P
P
Laboratoire de Physiologie et Biophysique Cellulaires, Faculté de Pharmacie, Université de Tours, France.
Goré
J
J
Vincent
E
E
Hoinard
C
C
Bougnoux
P
P
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002021:Buffers; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D010742:Phospholipid Ethers / Q000494:pharmacology*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002021:Buffers; D010742:Phospholipid Ethers; D017923:Sodium-Hydrogen Exchangers; C026659:edelfosine