Diverging effects of 5-HT3 receptor antagonists ondansetron and granisetron on estramustine-inhibited cellular potassium transport.
We used 86Rb+ (K+ analogue) to study potassium influx during the interaction of highly specific 5-HT3-receptor antagonists, ondansetron and granisetron, with the effects of the anticancer drug, estramustine phosphate, on P31 mesothelioma cells. Estramustine phosphate (80 mg/l, 142 micromol/l) for 120 min. reduced 86Rb+ influx by 18.7%. The reduction was inhibited by ondansetron (0.1 micromol/l), but augmented by granisetron (0.1 micromol/l). Serotonin (1.0 micromol/l) antagonized ondansetron inhibition and restored granisetron-augmented reduction of estramustine phosphate-induced 86Rb+ influx to the level of the drug itself. Estramustine phosphate inhibited cellular Na+, K+, 2Cl- -cotransport activity whereas Na+, K+, ATPase activity was unaffected. Ondansetron blockade of estramustine phosphate-induced reduction of 86Rb+ influx was due to increased Na+, K+, ATPase and Na+, K+, 2Cl- -cotransport whereas augmentation of estramustine phosphate-induced reduction of 86Rb+ influx by granisetron, or combination of 5-HT3 receptor antagonists with serotonin was due mainly to inhibition of cellular Na+, K+, ATPase activity Thus, ondansetron possesses a distinct ability to reverse K+ influx of tumour cells exposed to estramustine phosphate whereas granisetron does not, due to different effect on cellular Na+, K+, ATPase and Na+, K+, 2Cl- -cotransport activity. Highly 5-HT3 receptor-specific antiemetic agents may have different effects on ion transport of tumour cells during treatment with cytotoxic drugs.
Behnam-Motlagh
P
P
Department of Clinical Chemistry, Umeå University, Sweden.
Sandström
P E
PE
Henriksson
R
R
Grankvist
K
K
D000932:Antiemetics / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002034:Bumetanide / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D004347:Drug Interactions; D004961:Estramustine / Q000494:pharmacology*; D017829:Granisetron / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms; D008654:Mesothelioma; D017294:Ondansetron / Q000494:pharmacology*; D010042:Ouabain / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D027981:Symporters; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000096922:K Cl- Cotransporters
D000932:Antiemetics; D000970:Antineoplastic Agents; D002034:Bumetanide; D002712:Chlorides; D004961:Estramustine; D017829:Granisetron; D017294:Ondansetron; D010042:Ouabain; D011188:Potassium; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D027981:Symporters; D000096922:K Cl- Cotransporters