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Proteasomal inhibition potentiates drugs targeting DNA topoisomerase II

Ka C Lee1, Rebecca L Bramley1, Ian G Cowell1

  • 1Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.

Biochemical Pharmacology
|January 23, 2016
PubMed

Insights

Proteasome inhibition enhances the efficacy of DNA topoisomerase II (TOP2) poisons. Blocking proteasome activity stabilizes TOP2-DNA complexes, increasing growth inhibition by drugs like mitoxantrone.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • DNA topoisomerase II (TOP2) creates transient double-strand breaks during DNA replication and repair.
  • TOP2 poisons stabilize these breaks, leading to cell death.
  • Proteasome-mediated removal is a key mechanism for repairing TOP2-induced DNA damage.

Purpose of the Study:

  • To investigate the effect of proteasome inhibition on the efficacy of TOP2 poisons.
  • To explore the mechanism by which proteasome inhibitors potentiate TOP2-targeting drugs.

Main Methods:

  • Utilized K562 and Nalm 6 cell lines.
  • Treated cells with various TOP2 poisons (mitoxantrone, mAMSA, etoposide, doxorubicin, epirubicin, idarubicin).
  • Inhibited proteasome activity using MG132 and PS341 (Velcade).
  • Assessed cell growth inhibition and TOP2-DNA complex stability.

Main Results:

  • Proteasome inhibition with MG132 significantly potentiated growth inhibition by all tested TOP2 poisons.
  • Mitoxantrone exhibited the highest potentiation by MG132 across different cell lines.
  • Proteasome inhibition reduced the removal rate of stabilized TOP2-DNA complexes.

Conclusions:

  • Proteasome inhibition enhances the cytotoxic effects of TOP2 poisons.
  • This potentiation may occur by reducing the repair rate of TOP2-DNA lesions.
  • Combining proteasome inhibitors with TOP2 poisons represents a potential therapeutic strategy.
Keywords:
DNA topoisomerase IIMG132MitoxantroneProteasomeVelcade

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