Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Lauren M. Congdon, Alan Pourpak, Aluvia M. Escalante, Robert T Dorr, Terry H Landowski

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Although multiple myeloma patients often respond to initial therapy, the majority of patients will relapse with disease that is refractory to further drug treatment. Thus, new therapeutic strategies are needed. One common mechanism of acquired drug resistance involves a reduction in the expression or function of the drug target. We hypothesized that the cytotoxic activity of topoisomerase II (topo II) poisons could be enhanced, and drug resistance overcome, by increasing the expression and activity of the drug target, topo II in myeloma cells. To test this hypothesis, we evaluated the cytotoxicity of the anthracene-containing topo II poison, ethonafide (AMP-53/6-ethoxyazonafide), in combination with the proteasome inhibitor bortezomib (PS-341/Velcade). Combination drug activity studies were done in 8226/S myeloma cells and its drug resistant subclone, 8226/Dox1V. We found that a 24-h treatment of cells with bortezomib maximally increased topo IIα protein expression and activity, and consistently increased the cytotoxicity of ethonafide in the 8226/S and 8226/Dox1V cell lines. This increase in cytotoxicity corresponded to an increase in DNA double-strand breaks, as measured by the neutral comet assay. Therefore, increasing topo IIα expression through inhibition of proteasomal degradation increased DNA double-strand breaks and enhanced the cytotoxicity of the topo II poison ethonafide. These data suggest that bortezomib-mediated stabilization of topo IIα expression may potentiate the cytotoxic activity of topo II poisons and thereby, provide a strategy to circumvent drug resistance.

Original languageEnglish (US)
Pages (from-to)883-890
Number of pages8
JournalBiochemical Pharmacology
Volume75
Issue number4
DOIs
StatePublished - Feb 15 2008

Fingerprint

Type II DNA Topoisomerase
Poisons
Cytotoxicity
Proteins
Drug Resistance
Pharmaceutical Preparations
Double-Stranded DNA Breaks
Multiple Myeloma
Cells
Drug therapy
Proteasome Inhibitors
Comet Assay
2-(2'-(dimethylamino)ethyl)-1,2-dihydro-7-ethoxydibenz(de,h)isoquinoline-1,3-dione
DNA
Drug Combinations
Therapeutics
Plasma Cells
Refractory materials
Assays
Stabilization

Keywords

  • Combination therapy
  • Multiple myeloma
  • Proteasome inhibition
  • Topoisomerase IIα

ASJC Scopus subject areas

  • Pharmacology

Cite this

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide). / Congdon, Lauren M.; Pourpak, Alan; Escalante, Aluvia M.; Dorr, Robert T; Landowski, Terry H.

In: Biochemical Pharmacology, Vol. 75, No. 4, 15.02.2008, p. 883-890.

Research output: Contribution to journalArticle

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abstract = "Multiple myeloma (MM) is an incurable malignancy of plasma cells. Although multiple myeloma patients often respond to initial therapy, the majority of patients will relapse with disease that is refractory to further drug treatment. Thus, new therapeutic strategies are needed. One common mechanism of acquired drug resistance involves a reduction in the expression or function of the drug target. We hypothesized that the cytotoxic activity of topoisomerase II (topo II) poisons could be enhanced, and drug resistance overcome, by increasing the expression and activity of the drug target, topo II in myeloma cells. To test this hypothesis, we evaluated the cytotoxicity of the anthracene-containing topo II poison, ethonafide (AMP-53/6-ethoxyazonafide), in combination with the proteasome inhibitor bortezomib (PS-341/Velcade). Combination drug activity studies were done in 8226/S myeloma cells and its drug resistant subclone, 8226/Dox1V. We found that a 24-h treatment of cells with bortezomib maximally increased topo IIα protein expression and activity, and consistently increased the cytotoxicity of ethonafide in the 8226/S and 8226/Dox1V cell lines. This increase in cytotoxicity corresponded to an increase in DNA double-strand breaks, as measured by the neutral comet assay. Therefore, increasing topo IIα expression through inhibition of proteasomal degradation increased DNA double-strand breaks and enhanced the cytotoxicity of the topo II poison ethonafide. These data suggest that bortezomib-mediated stabilization of topo IIα expression may potentiate the cytotoxic activity of topo II poisons and thereby, provide a strategy to circumvent drug resistance.",
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