Cellular potassium ion deprivation enhances apoptosis induced by cisplatin.
The anticancer drug cisplatin induces cell death by apoptosis. Apoptosis is dependent on cellular loss of potassium ions (K+). We have recently shown that the antifungal drug amphotericin B (enhancing K+ efflux), combined with the Na+, K+, 2Cl(-)-cotransport blocker bumetanide (decreasing K+ influx), augmented cisplatin-induced apoptosis in vitro. We therefore quantified K+ fluxes with the K+ analogue rubidium (86Rb+) in cisplatin-induced apoptosis of mesothelioma cells treated with bumetanide and amphotericin B. Bumetanide combined with amphotericin B enhanced cisplatin-induced apoptosis by a pronounced initial reduction of K+ influx due (in addition to Na+, K+, 2Cl(-)-cotransport inhibition) also to Na+, K+, ATPase pump inhibition. As 86Rb+ efflux was initially preserved, combination of the drugs would lead to net K+ loss. Combinations of K+ flux modulators leading to cellular potassium ion deprivation thus augments cisplatin-induced apoptosis and could therefore possibly be used to enhance the antitumour efficacy of cisplatin treatment.
Marklund
Linda
L
Department of Medical Biosciences, Clinical Chemistry, Umeå University, S-901 85 Umeå, Sweden.
Andersson
Britta
B
Behnam-Motlagh
Parviz
P
Sandström
Per-Erik
PE
Henriksson
Roger
R
Grankvist
Kjell
K
D000666:Amphotericin B / Q000494:pharmacology; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D002034:Bumetanide / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin; D053938:DNA Fragmentation; D004357:Drug Synergism; D004791:Enzyme Inhibitors; D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D010042:Ouabain; D011188:Potassium / Q000032:analysis / Q000378:metabolism*; D012414:Rubidium Radioisotopes; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D012414:Rubidium Radioisotopes; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D002034:Bumetanide; D010042:Ouabain; D000666:Amphotericin B; D000254:Sodium-Potassium-Exchanging ATPase; D002945:Cisplatin; D011188:Potassium