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P-glycoproteins: mediators of multidrug resistance
U A Germann1, I Pastan, M M Gottesman
1Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Abstract:
Multidrug resistance represents a major obstacle to successful chemotherapy of metastatic disease. Elevated levels in cancer cells of the product of the multidrug resistance gene, P-glycoprotein or the multidrug transporter, have been associated with the development of simultaneous resistance to a great variety of amphiphilic cytotoxic drugs. P-glycoprotein is an integral plasma membrane protein which contains 12 putative transmembrane regions and two ATP binding sites. It confers multidrug resistance by functioning as an energy-dependent drug efflux pump. Here we describe recent studies on the biosynthesis, structure, function, and mechanism of action of P-glycoprotein which have provided insights into the complexity of this multifunctional transport system and revealed an additional chloride channel activity. The physiological role of P-glycoprotein, however, still remains to be elucidated.
Insights
Multidrug resistance in cancer is often caused by P-glycoprotein, an efflux pump that removes chemotherapy drugs. Recent studies explore its biosynthesis, structure, function, and a newly found chloride channel activity.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Multidrug resistance (MDR) is a significant challenge in cancer chemotherapy, particularly for metastatic cancers.
- Elevated P-glycoprotein (P-gp) levels in cancer cells correlate with resistance to numerous amphiphilic cytotoxic drugs.
- P-glycoprotein is a plasma membrane protein functioning as an ATP-dependent drug efflux pump.
Purpose of the Study:
- To review recent research on P-glycoprotein (P-gp).
- To elucidate the biosynthesis, structure, function, and mechanism of action of P-gp.
- To investigate the implications of P-gp's multifunctional transport system, including its chloride channel activity.
Main Methods:
- Review of recent scientific literature on P-glycoprotein.
- Analysis of studies detailing P-gp biosynthesis and structure.
- Examination of functional and mechanistic studies of P-gp's drug efflux and channel activities.
Main Results:
- P-glycoprotein confers multidrug resistance by acting as an energy-dependent drug efflux pump.
- Recent studies have provided deeper insights into the complex nature of this multifunctional transport system.
- An additional chloride channel activity associated with P-glycoprotein has been identified.
Conclusions:
- P-glycoprotein is a key factor in multidrug resistance, acting as a drug efflux pump.
- Understanding P-gp's complex structure and function, including its chloride channel activity, is crucial for developing new cancer therapies.
- The precise physiological role of P-glycoprotein requires further investigation.