P-gp localization in mitochondria and its functional characterization in multiple drug-resistant cell lines

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Multidrug resistance (MDR) is linked to P-glycoprotein (P-gp) efflux pumps.
• MDR cells resist apoptosis and anticancer drugs.
• The role of P-gp in mitochondria is not fully understood.

Purpose of the Study:

• To investigate P-gp presence and function within mitochondria.
• To determine P-gp's role in drug-sensitive and MDR cancer cell lines.

Main Methods:

• Western blot analysis
• Confocal laser microscopy
• Rhodamine 123 transport assays
• MDR1 small interfering RNA
• Flow cytometry

Main Results:

• P-gp is expressed and functionally active in mitochondria of MDR cells (P1(0.5), PN1A).
• Mitochondrial Rhodamine 123 accumulation is reduced in MDR cells due to P-gp efflux.
• P-gp actively transports drugs out of mitochondria.

Conclusions:

• Functionally active P-gp is present in the mitochondrial membrane of MDR cells.
• Mitochondrial P-gp effluxes anticancer drugs into the cytosol.
• P-gp may protect mitochondrial DNA from drug-induced damage.