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Expression, Detergent Solubilization, and Purification of a Membrane Transporter, the MexB Multidrug Resistance Protein
10:43

Expression, Detergent Solubilization, and Purification of a Membrane Transporter, the MexB Multidrug Resistance Protein

Published on: December 3, 2010

Molecular analysis of the multidrug transporter, P-glycoprotein

U A Germann1, T C Chambers

  • 1Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA, 02139-4242, U.S.A., Germann@macnet.vpharm.com.

Cytotechnology
|November 13, 2008
PubMed

Insights

Tumor cells can resist chemotherapy due to multidrug resistance (MDR), often involving P-glycoprotein. This protein acts as an ATP-dependent efflux pump, reducing drug accumulation and limiting cancer treatment success.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Background:

  • Acquired or inherent resistance in tumor cells to cytotoxic drugs hinders effective cancer chemotherapy.
  • Multidrug resistance (MDR) is a significant challenge, characterized by simultaneous resistance to various anti-cancer drugs.
  • The human MDR1 gene product, P-glycoprotein, has been identified as a key mechanism contributing to MDR.

Purpose of the Study:

  • To review the current understanding of P-glycoprotein's structure and function in multidrug resistance.
  • To elucidate the molecular mechanisms underlying P-glycoprotein's role as an ATP-dependent drug efflux pump.
  • To explore P-glycoprotein's potential roles beyond drug transport, including ion and lipid transport and cholesterol biosynthesis.

Main Methods:

  • Analysis of drug-selected tumor cells to identify resistance mechanisms.
  • Structure-function studies utilizing cell biological, molecular genetic, and biochemical approaches.
  • Review of existing literature on P-glycoprotein's domain organization, topology, and activity.

Main Results:

  • P-glycoprotein, a 170 kDa N-glycosylated plasma membrane protein, is overexpressed in resistant cells, leading to reduced drug accumulation.
  • P-glycoprotein functions as an ATP-dependent efflux pump, characteristic of the ATP-binding cassette (ABC) transporter superfamily.
  • Studies have investigated drug and ATP binding sites, ATPase and transport activities, and potential roles in ion/lipid transport and phosphorylation effects.

Conclusions:

  • P-glycoprotein is a critical factor in multidrug resistance, significantly impacting cancer chemotherapy outcomes.
  • Understanding P-glycoprotein's structure and function is essential for developing strategies to overcome drug resistance.
  • Further research into P-glycoprotein's diverse functions may reveal new therapeutic targets for cancer treatment.

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