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Comparative study on ABCB1-dependent efflux of anthracyclines and their metabolites: consequences for cancer

Kamil Piska1, Paulina Koczurkiewicz-Adamczyk1, Marek Jamrozik2

  • 1Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|September 27, 2023
PubMed

Insights

ABCB1 transporter effluxes anthracyclines and their metabolites, like daunorubicinol. This efflux impacts drug accumulation in resistant cancer cells, potentially explaining reduced anticancer efficacy.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Molecular Biology

Background:

  • ABCB1 (P-glycoprotein, MDR1) is crucial in cancer multidrug resistance, particularly against anthracyclines like doxorubicin.
  • Intracellular metabolism of anthracyclines yields less active metabolites, but their efflux by ABCB1 is poorly understood.

Purpose of the Study:

  • To investigate the susceptibility of anthracyclines (doxorubicin, daunorubicin) and their metabolites (doxorubicinol, daunorubicinol) to ABCB1-dependent efflux.
  • To elucidate the role of ABCB1 in the accumulation and activity of these compounds in resistant cancer cells.

Main Methods:

  • Recombinant ABCB1 ATPase transporter assays.
  • Anthracycline accumulation assays in ABCB1-overexpressing resistant cells.
  • Molecular modeling studies.

Main Results:

  • Daunorubicinol showed a high potential for ABCB1-mediated efflux.
  • ABCB1 activity significantly altered the accumulation of doxorubicin and daunorubicinol in resistant cells.
  • Valspodar, an ABCB1 modulator, influenced the accumulation of doxorubicin and daunorubicinol.

Conclusions:

  • ABCB1-mediated efflux affects both anthracyclines and their metabolites.
  • The interplay between anthracycline metabolism and metabolite efflux by ABCB1 may diminish their anticancer properties.
Keywords:
ABCB1Anthracyclinescancer resistancemetabolitesvalspodar

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