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P-glycoprotein and multidrug resistance
M M Gottesman1, I Pastan, S V Ambudkar
1Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. gottesman@od1em1.od.nih.gov
Abstract:
Although the phenomenon of simultaneous resistance to multiple cytotoxic drugs (multidrug resistance) in cancer cells has been discussed for more than two decades, and the human and mouse genes encoding an energy-dependent transporter (the multidrug transporter or P-glycoprotein) responsible for multidrug resistance were cloned 10 years ago, there is still considerable controversy about the mechanism of action of this efflux pump and its true biological function. This review summarizes the current research on the mechanism of action of the multidrug transporter, including the hydrophobic cleaner and altered partitioning models, the possible function of P-glycoprotein as a chloride and/or ATP channel, the role of phosphorylation in its function and fact and speculation about its physiological role.
Insights
Multidrug resistance in cancer involves P-glycoprotein, an efflux pump. This review explores its controversial mechanisms and physiological roles, clarifying its function in cancer multidrug resistance.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Multidrug resistance (MDR) in cancer is a long-standing challenge.
- P-glycoprotein, an energy-dependent transporter, is a key mediator of MDR.
- Despite decades of research and gene cloning, its precise mechanism and biological function remain debated.
Purpose of the Study:
- To review current research on the mechanism of action of the multidrug transporter (P-glycoprotein).
- To discuss proposed models, such as the hydrophobic cleaner and altered partitioning models.
- To examine the potential function of P-glycoprotein as a chloride and/or ATP channel and the role of phosphorylation.
Main Methods:
- Literature review of existing research on P-glycoprotein.
- Analysis of proposed models for P-glycoprotein's mechanism of action.
- Synthesis of findings regarding its function, phosphorylation, and physiological role.
Main Results:
- Controversy persists regarding the exact mechanism of P-glycoprotein's drug efflux.
- P-glycoprotein may function as a chloride and/or ATP channel.
- Phosphorylation plays a role in modulating P-glycoprotein activity.
Conclusions:
- The precise mechanism and physiological role of P-glycoprotein require further elucidation.
- Understanding P-glycoprotein is crucial for overcoming cancer multidrug resistance.
- Continued research is needed to resolve the controversies surrounding this important transporter.