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Intracellular pH does not affect drug extrusion by P-glycoprotein
1Department of Biophysics, University Medical School of Debrecen, Hungary.
Summary
Alkaline intracellular pH (pH(i)) in multidrug resistance (MDR) cells does not significantly impact P-glycoprotein (Pgp) drug efflux. However, MDR cells uniquely acidify their external environment when treated with verapamil, suggesting an indirect link to MDR.
Area of Science:
- Cell Biology
- Pharmacology
- Biochemistry
Background:
- Multidrug resistance (MDR) in cancer cells often involves P-glycoprotein (Pgp) expression.
- Cells with Pgp-mediated MDR frequently exhibit an elevated intracellular pH (alkalinity) compared to sensitive cells.
Purpose of the Study:
- To investigate the role of elevated intracellular pH in Pgp-mediated multidrug resistance.
- To determine if altering intracellular pH affects the drug accumulation in MDR cells.
Main Methods:
- Utilized the carbonylcyanide m-chlorophenylhydrazone (CCCP) ionophore to decrease intracellular pH in MDR cells.
- Employed flow cytometry and radioactive drug accumulation assays to measure daunorubicin (DNR) uptake.
- Monitored extracellular medium acidification in the presence of verapamil using a flow-through system.
Main Results:
- CCC-induced changes in intracellular pH did not significantly alter daunorubicin accumulation in either Pgp-positive or Pgp-negative cell lines.
- The efficiency of P-glycoprotein drug pumping appears unaffected by significant shifts in intracellular pH.
- MDR cells, but not parental cells, showed external medium acidification when treated with verapamil.
Conclusions:
- Intracellular pH does not appear to be a major determinant of P-glycoprotein pumping efficiency in MDR.
- An indirect relationship between pH regulation and the MDR phenotype is suggested by verapamil-induced extracellular acidification in MDR cells.