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Reduced ouabain-sensitive potassium entry as a possible mechanism of multidrug-resistance in P388 cells
1Department of Oncology, Hadassah University Hospital, Jerusalem, Israel.
Abstract:
Multidrug-resistant P388 cells were found to be resistant also to a variety of ammonium, phosphonium and arsonium compounds. As previously shown for anthracyclines and vinca alkaloids, the resistance to the permanently charged lipophilic cationic compounds could be circumvented by verapamil. Relative to drug-sensitive cells, K+ uptake and plasma membrane Mg-ATPase activity in multidrug-resistant cells are ouabain resistant. The intracellular K+ concentration in drug-resistant cells is maintained at a normal level by increased activity of the furosemide sensitive transport system. It is suggested that the reduced activity of the electrogenic Na(+)-K+ pump in multidrug-resistant, cells could result in a lower transmembrane potential and therefore reduced accumulation of cationic lipophilic compounds.
Insights
Multidrug-resistant cells exhibit resistance to various cationic compounds. Verapamil can overcome this resistance, suggesting altered ion transport mechanisms contribute to multidrug resistance.
Area of Science:
- Cell Biology
- Pharmacology
- Biochemistry
Background:
- Multidrug resistance (MDR) is a significant challenge in cancer therapy.
- P388 cells exhibit resistance to anthracyclines and vinca alkaloids.
- Cationic lipophilic compounds are also affected by multidrug resistance.
Purpose of the Study:
- To investigate the resistance mechanisms of multidrug-resistant P388 cells to cationic compounds.
- To explore the role of ion transport in multidrug resistance.
- To determine if verapamil can circumvent resistance to these compounds.
Main Methods:
- Testing resistance of multidrug-resistant P388 cells to ammonium, phosphonium, and arsonium compounds.
- Assessing the effect of verapamil on drug resistance.
- Measuring K+ uptake and Mg-ATPase activity in drug-sensitive and resistant cells.
- Investigating the furosemide-sensitive transport system and Na(+)-K+ pump activity.
Main Results:
- Multidrug-resistant P388 cells showed resistance to various cationic compounds.
- Verapamil successfully circumvented this resistance, similar to its effect on anthracyclines and vinca alkaloids.
- Drug-resistant cells displayed ouabain-resistant K+ uptake and Mg-ATPase activity.
- Intracellular K+ levels were maintained by increased furosemide-sensitive transport.
- Reduced electrogenic Na(+)-K+ pump activity correlated with lower transmembrane potential.
Conclusions:
- Altered ion transport, specifically reduced Na(+)-K+ pump activity, contributes to multidrug resistance in P388 cells.
- The decreased transmembrane potential in resistant cells may lead to reduced accumulation of cationic lipophilic drugs.
- Verapamil's ability to overcome resistance highlights the potential of targeting ion transport in MDR therapies.