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Molecular Pharmacology

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Research ArticleArticle

Context-Dependent Antagonism between Akt Inhibitors and Topoisomerase Poisons

Marina Gálvez-Peralta, Karen S. Flatten, David A. Loegering, Kevin L. Peterson, Paula A. Schneider, Charles Erlichman and Scott H. Kaufmann
Molecular Pharmacology May 2014, 85 (5) 723-734; DOI: https://doi.org/10.1124/mol.113.088674
Marina Gálvez-Peralta
Divisions of Oncology Research (M.G.-P., K.S.F., D.A.L., K.L.P., P.A.S., S.H.K.) and Medical Oncology (C.E.), Department of Oncology and Department of Molecular Pharmacology & Experimental Therapeutics (S.H.K.), Mayo Clinic College of Medicine, Rochester, Minnesota
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Karen S. Flatten
Divisions of Oncology Research (M.G.-P., K.S.F., D.A.L., K.L.P., P.A.S., S.H.K.) and Medical Oncology (C.E.), Department of Oncology and Department of Molecular Pharmacology & Experimental Therapeutics (S.H.K.), Mayo Clinic College of Medicine, Rochester, Minnesota
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David A. Loegering
Divisions of Oncology Research (M.G.-P., K.S.F., D.A.L., K.L.P., P.A.S., S.H.K.) and Medical Oncology (C.E.), Department of Oncology and Department of Molecular Pharmacology & Experimental Therapeutics (S.H.K.), Mayo Clinic College of Medicine, Rochester, Minnesota
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Kevin L. Peterson
Divisions of Oncology Research (M.G.-P., K.S.F., D.A.L., K.L.P., P.A.S., S.H.K.) and Medical Oncology (C.E.), Department of Oncology and Department of Molecular Pharmacology & Experimental Therapeutics (S.H.K.), Mayo Clinic College of Medicine, Rochester, Minnesota
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Paula A. Schneider
Divisions of Oncology Research (M.G.-P., K.S.F., D.A.L., K.L.P., P.A.S., S.H.K.) and Medical Oncology (C.E.), Department of Oncology and Department of Molecular Pharmacology & Experimental Therapeutics (S.H.K.), Mayo Clinic College of Medicine, Rochester, Minnesota
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Charles Erlichman
Divisions of Oncology Research (M.G.-P., K.S.F., D.A.L., K.L.P., P.A.S., S.H.K.) and Medical Oncology (C.E.), Department of Oncology and Department of Molecular Pharmacology & Experimental Therapeutics (S.H.K.), Mayo Clinic College of Medicine, Rochester, Minnesota
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Scott H. Kaufmann
Divisions of Oncology Research (M.G.-P., K.S.F., D.A.L., K.L.P., P.A.S., S.H.K.) and Medical Oncology (C.E.), Department of Oncology and Department of Molecular Pharmacology & Experimental Therapeutics (S.H.K.), Mayo Clinic College of Medicine, Rochester, Minnesota
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Abstract

Signaling through the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, which is aberrantly activated in >50% of carcinomas, inhibits apoptosis and contributes to drug resistance. Accordingly, several Akt inhibitors are currently undergoing preclinical or early clinical testing. To examine the effect of Akt inhibition on the activity of multiple widely used classes of antineoplastic agents, human cancer cell lines were treated with the Akt inhibitor A-443654 [(2S)-1-(1H-indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan-2-amine; ATP-competitive] or MK-2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one;dihydrochloride; allosteric inhibitor) or with small interfering RNA (siRNA) targeting phosphoinositide-dependent kinase 1 (PDK1) along with cisplatin, melphalan, camptothecin, or etoposide and assayed for colony formation. Surprisingly different results were observed when Akt inhibitors were combined with different drugs. Synergistic effects were observed in multiple cell lines independent of PI3K pathway status when A-443654 or MK-2206 was combined with the DNA cross-linking agents cisplatin or melphalan. In contrast, effects of the Akt inhibitors in combination with camptothecin or etoposide were more complicated. In HCT116 and DLD1 cells, which harbor activating PI3KCA mutations, A-443654 over a broad concentration range enhanced the effects of camptothecin or etoposide. In contrast, in cell lines lacking activating PI3KCA mutations, partial inhibition of Akt signaling synergized with camptothecin or etoposide, but higher A-443654 or MK-2206 concentrations (>80% inhibition of Akt signaling) or PDK1 siRNA antagonized the topoisomerase poisons by diminishing DNA synthesis, a process that contributes to effective DNA damage and killing by these agents. These results indicate that the effects of combining inhibitors of the PI3K/Akt pathway with certain classes of chemotherapeutic agents might be more complicated than previously recognized.

Footnotes

    • Received July 22, 2013.
    • Accepted February 25, 2014.
  • M.G.-P. and K.S.F. contributed equally to this work.

  • This work was supported, in part, by the National Institutes of Health National Cancer Institute [Grant R01-CA73709]; and by funds from the Commonwealth Foundation.

  • dx.doi.org/10.1124/mol.113.088674.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 85 (5)
Molecular Pharmacology
Vol. 85, Issue 5
1 May 2014
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Research ArticleArticle

Effect of Akt Inhibition on Action of Topoisomerase Poisons

Marina Gálvez-Peralta, Karen S. Flatten, David A. Loegering, Kevin L. Peterson, Paula A. Schneider, Charles Erlichman and Scott H. Kaufmann
Molecular Pharmacology May 1, 2014, 85 (5) 723-734; DOI: https://doi.org/10.1124/mol.113.088674

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Research ArticleArticle

Effect of Akt Inhibition on Action of Topoisomerase Poisons

Marina Gálvez-Peralta, Karen S. Flatten, David A. Loegering, Kevin L. Peterson, Paula A. Schneider, Charles Erlichman and Scott H. Kaufmann
Molecular Pharmacology May 1, 2014, 85 (5) 723-734; DOI: https://doi.org/10.1124/mol.113.088674
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