Tumour cell proliferation is abolished by inhibitors of Na+/H+ and HCO3-/Cl- exchange.
Cell membrane-associated ion transporters, Na+/H+ exchanger and Na(+)-dependent HCO3-/Cl- antiport, were shown to be important in the regulation of acidic intracellular pH in different cell types. This study investigated the role of the ion exchangers and their inhibitors in the serum-induced proliferation of two murine tumour cell lines, P815 and L929. The presence of Na+/H+ exchanger [inhibited by amiloride and 5-(N-ethyl-N-isopropyl)amiloride (EIPA)] and Na(+)-dependent HCO3-/Cl- antiport [inhibited by 4,4'-diisothiocyanostilbene-2,2-disulphonic acid (DIDS)] was shown on the tumour cell line tested. EIPA suppressed tumour cell proliferation more strongly than amiloride, and its effect was further increased after intracellular acidification by nigericin. DIDS slightly inhibited proliferation of L929 cell line and did not influence proliferation of P815 cells. However, in nigericin acidified cells DIDS had a dose dependent antiproliferative effect. Furthermore, DIDS significantly increased antiproliferative effects of amiloride and EIPA, suggesting the activity of Na(+)-dependent HCO3-/Cl- antiport in tumour cell proliferation. These results demonstrate the importance of Na(+)-dependent HCO3-/Cl- exchange in addition to Na+/H+ antiport, in tumour cell proliferation and indicate the possibility that ion exchange inhibitors could act as antitumour reagents.
Horvat
B
B
Centre d'immunologie de Marseille-Luminy Parc Scientifique de Luminy-Case 906, France.
Taheri
S
S
Salihagić
A
A
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D027963:Chloride-Bicarbonate Antiporters; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism*
D002352:Carrier Proteins; D027963:Chloride-Bicarbonate Antiporters; D017923:Sodium-Hydrogen Exchangers; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D000584:Amiloride; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; C039614:ethylisopropylamiloride