In archaebacteria, there is a doxorubicin efflux pump similar to mammalian P-glycoprotein

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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

S Miyauchi1, M Komatsubara, N Kamo

  • 1Department of Biophysics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.

Biochimica Et Biophysica Acta
|October 5, 1992
PubMed

Insights

Archaebacteria Haloferax volcanii exhibits anthracycline resistance, potentially mediated by a P-glycoprotein (Pgp)-like efflux pump. This resistance was reversed by nifedipine (NDP), suggesting a conserved mechanism across evolution.

Area of Science:

  • Microbiology
  • Biochemistry
  • Molecular Biology

Background:

  • Anticancer drug resistance is a significant challenge in chemotherapy.
  • P-glycoprotein (Pgp) is a key mediator of multidrug resistance in eukaryotes.
  • The presence and function of Pgp-like proteins in archaea are not well understood.

Purpose of the Study:

  • To investigate the mechanism of anthracycline resistance in the archaebacterium Haloferax volcanii.
  • To determine if a Pgp-like efflux pump is responsible for this resistance.
  • To explore the potential for conserved drug resistance mechanisms between archaea and mammals.

Main Methods:

  • Selection of an anthracycline-resistant Haloferax volcanii mutant.
  • Assessment of rhodamine 123 (RH123) accumulation using flow cytometry.
  • Evaluation of the effects of Pgp modulators (nifedipine, diltiazem, verapamil) and an uncoupler (FCCP) on RH123 transport.
  • Analysis of RH123 efflux kinetics in resistant and wild-type cells.

Main Results:

  • The resistant mutant showed significantly reduced RH123 accumulation compared to wild-type cells.
  • Nifedipine (NDP), diltiazem, and verapamil enhanced RH123 accumulation in resistant cells.
  • The uncoupler FCCP fully restored RH123 accumulation and inhibited RH123 efflux in resistant cells.
  • Resistant cells exhibited a higher rate of RH123 efflux, indicative of an active efflux mechanism.

Conclusions:

  • Haloferax volcanii possesses an active efflux mechanism for RH123, similar to Pgp-mediated efflux.
  • A Pgp-like protein likely contributes to anthracycline resistance in this archaeon.
  • These findings suggest that Pgp-like efflux pumps may be conserved across a wide evolutionary range, from archaea to mammals.

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