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Molecular Pharmacology

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Research ArticleArticle

Overexpression of Mcl-1 Confers Multidrug Resistance, Whereas Topoisomerase IIβ Downregulation Introduces Mitoxantrone-Specific Drug Resistance in Acute Myeloid Leukemia

David L. Hermanson, Sonia G. Das, Yunfang Li and Chengguo Xing
Molecular Pharmacology August 2013, 84 (2) 236-243; DOI: https://doi.org/10.1124/mol.113.086140
David L. Hermanson
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (D.L.H., S.G.D., Y.L., C.X.); and Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts (S.G.D.)
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Sonia G. Das
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (D.L.H., S.G.D., Y.L., C.X.); and Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts (S.G.D.)
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Yunfang Li
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (D.L.H., S.G.D., Y.L., C.X.); and Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts (S.G.D.)
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Chengguo Xing
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (D.L.H., S.G.D., Y.L., C.X.); and Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts (S.G.D.)
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Abstract

Drug resistance is a serious challenge in cancer treatment and can be acquired through multiple mechanisms. These molecular changes may introduce varied extents of resistance to different therapies and need to be characterized for optimal therapy choice. A recently discovered small molecule, ethyl-2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate) (CXL017), reveals selective cytotoxicity toward drug-resistant leukemia. A drug-resistant acute myeloid leukemia cell line, HL60/MX2, also failed to acquire resistance to CXL017 upon chronic exposure and regained sensitivity toward standard therapies. In this study, we investigated the mechanisms responsible for HL60/MX2 cells’ drug resistance and the molecular basis for its resensitization. Results show that the HL60/MX2 cell line has an elevated level of Mcl-1 protein relative to the parental cell line, HL60, and its resensitized cell line, HL60/MX2/CXL017, whereas it has a reduced level of topoisomerase IIβ. Mcl-1 overexpression in HL60/MX2 cells is mainly regulated through phospho-extracellular signal-regulated protein kinases 1 and 2–mediated Mcl-1 stabilization, whereas the reduction of topoisomerase IIβ in HL60/MX2 cells is controlled through genetic downregulation. Upregulating Mcl-1 introduces multidrug resistance to standard therapies, whereas its downregulation results in significant cell death. Downregulating topoisomerase IIβ confers resistance specifically to mitoxantrone, not to other topoisomerase II inhibitors. Overall, these data suggest that Mcl-1 overexpression is a critical determinant for cross-resistance to standard therapies, whereas topoisomerase IIβ downregulation is specific to mitoxantrone resistance.

Footnotes

    • Received March 12, 2013.
    • Accepted May 21, 2013.
  • This research was supported by the National Institutes of Health National Cancer Institute [Grant R01-CA163864]; Leukemia Research Fund [Seed Grant]; Academic Health Center [Faculty Research Development Grant]; and University of Minnesota [Graduate School of the University of Minnesota Ph.D. Dissertation Fellowships].

  • dx.doi.org/10.1124/mol.113.086140.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (2)
Molecular Pharmacology
Vol. 84, Issue 2
1 Aug 2013
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Research ArticleArticle

Drug-Resistant Mechanisms in AML

David L. Hermanson, Sonia G. Das, Yunfang Li and Chengguo Xing
Molecular Pharmacology August 1, 2013, 84 (2) 236-243; DOI: https://doi.org/10.1124/mol.113.086140

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Research ArticleArticle

Drug-Resistant Mechanisms in AML

David L. Hermanson, Sonia G. Das, Yunfang Li and Chengguo Xing
Molecular Pharmacology August 1, 2013, 84 (2) 236-243; DOI: https://doi.org/10.1124/mol.113.086140
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