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Research ArticleArticle

Triapine and a More Potent Dimethyl Derivative Induce Endoplasmic Reticulum Stress in Cancer Cells

Robert Trondl, Lea S. Flocke, Christian R. Kowol, Petra Heffeter, Ute Jungwirth, Georg E. Mair, Ralf Steinborn, Éva A. Enyedy, Michael A. Jakupec, Walter Berger and Bernhard K. Keppler
Molecular Pharmacology March 2014, 85 (3) 451-459; DOI: https://doi.org/10.1124/mol.113.090605
Robert Trondl
Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria (R.T., L.S.F., C.R.K., M.A.J., B.K.K.); Research Platform “Translational Cancer Therapy Research” (R.T., C.R.K., P.H., U.J., M.A.J., W.B., B.K.K.), Institute of Cancer Research (P.H., U.J., W.B.), and Comprehensive Cancer Centre (P.H., U.J., W.B.), Medical University of Vienna, Vienna, Austria; Genomics Core Facility, VetCore, University of Veterinary Medicine, Vienna, Austria (G.E.M., R.S.); Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged, Hungary (E.A.E.); and Hungarian Academy of Science-USZ Bioinorganic Chemistry Research Group, Szeged, Hungary (E.A.E.)
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Lea S. Flocke
Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria (R.T., L.S.F., C.R.K., M.A.J., B.K.K.); Research Platform “Translational Cancer Therapy Research” (R.T., C.R.K., P.H., U.J., M.A.J., W.B., B.K.K.), Institute of Cancer Research (P.H., U.J., W.B.), and Comprehensive Cancer Centre (P.H., U.J., W.B.), Medical University of Vienna, Vienna, Austria; Genomics Core Facility, VetCore, University of Veterinary Medicine, Vienna, Austria (G.E.M., R.S.); Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged, Hungary (E.A.E.); and Hungarian Academy of Science-USZ Bioinorganic Chemistry Research Group, Szeged, Hungary (E.A.E.)
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Christian R. Kowol
Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria (R.T., L.S.F., C.R.K., M.A.J., B.K.K.); Research Platform “Translational Cancer Therapy Research” (R.T., C.R.K., P.H., U.J., M.A.J., W.B., B.K.K.), Institute of Cancer Research (P.H., U.J., W.B.), and Comprehensive Cancer Centre (P.H., U.J., W.B.), Medical University of Vienna, Vienna, Austria; Genomics Core Facility, VetCore, University of Veterinary Medicine, Vienna, Austria (G.E.M., R.S.); Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged, Hungary (E.A.E.); and Hungarian Academy of Science-USZ Bioinorganic Chemistry Research Group, Szeged, Hungary (E.A.E.)
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Petra Heffeter
Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria (R.T., L.S.F., C.R.K., M.A.J., B.K.K.); Research Platform “Translational Cancer Therapy Research” (R.T., C.R.K., P.H., U.J., M.A.J., W.B., B.K.K.), Institute of Cancer Research (P.H., U.J., W.B.), and Comprehensive Cancer Centre (P.H., U.J., W.B.), Medical University of Vienna, Vienna, Austria; Genomics Core Facility, VetCore, University of Veterinary Medicine, Vienna, Austria (G.E.M., R.S.); Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged, Hungary (E.A.E.); and Hungarian Academy of Science-USZ Bioinorganic Chemistry Research Group, Szeged, Hungary (E.A.E.)
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Ute Jungwirth
Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria (R.T., L.S.F., C.R.K., M.A.J., B.K.K.); Research Platform “Translational Cancer Therapy Research” (R.T., C.R.K., P.H., U.J., M.A.J., W.B., B.K.K.), Institute of Cancer Research (P.H., U.J., W.B.), and Comprehensive Cancer Centre (P.H., U.J., W.B.), Medical University of Vienna, Vienna, Austria; Genomics Core Facility, VetCore, University of Veterinary Medicine, Vienna, Austria (G.E.M., R.S.); Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged, Hungary (E.A.E.); and Hungarian Academy of Science-USZ Bioinorganic Chemistry Research Group, Szeged, Hungary (E.A.E.)
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Georg E. Mair
Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria (R.T., L.S.F., C.R.K., M.A.J., B.K.K.); Research Platform “Translational Cancer Therapy Research” (R.T., C.R.K., P.H., U.J., M.A.J., W.B., B.K.K.), Institute of Cancer Research (P.H., U.J., W.B.), and Comprehensive Cancer Centre (P.H., U.J., W.B.), Medical University of Vienna, Vienna, Austria; Genomics Core Facility, VetCore, University of Veterinary Medicine, Vienna, Austria (G.E.M., R.S.); Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged, Hungary (E.A.E.); and Hungarian Academy of Science-USZ Bioinorganic Chemistry Research Group, Szeged, Hungary (E.A.E.)
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Ralf Steinborn
Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria (R.T., L.S.F., C.R.K., M.A.J., B.K.K.); Research Platform “Translational Cancer Therapy Research” (R.T., C.R.K., P.H., U.J., M.A.J., W.B., B.K.K.), Institute of Cancer Research (P.H., U.J., W.B.), and Comprehensive Cancer Centre (P.H., U.J., W.B.), Medical University of Vienna, Vienna, Austria; Genomics Core Facility, VetCore, University of Veterinary Medicine, Vienna, Austria (G.E.M., R.S.); Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged, Hungary (E.A.E.); and Hungarian Academy of Science-USZ Bioinorganic Chemistry Research Group, Szeged, Hungary (E.A.E.)
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Éva A. Enyedy
Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria (R.T., L.S.F., C.R.K., M.A.J., B.K.K.); Research Platform “Translational Cancer Therapy Research” (R.T., C.R.K., P.H., U.J., M.A.J., W.B., B.K.K.), Institute of Cancer Research (P.H., U.J., W.B.), and Comprehensive Cancer Centre (P.H., U.J., W.B.), Medical University of Vienna, Vienna, Austria; Genomics Core Facility, VetCore, University of Veterinary Medicine, Vienna, Austria (G.E.M., R.S.); Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged, Hungary (E.A.E.); and Hungarian Academy of Science-USZ Bioinorganic Chemistry Research Group, Szeged, Hungary (E.A.E.)
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Michael A. Jakupec
Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria (R.T., L.S.F., C.R.K., M.A.J., B.K.K.); Research Platform “Translational Cancer Therapy Research” (R.T., C.R.K., P.H., U.J., M.A.J., W.B., B.K.K.), Institute of Cancer Research (P.H., U.J., W.B.), and Comprehensive Cancer Centre (P.H., U.J., W.B.), Medical University of Vienna, Vienna, Austria; Genomics Core Facility, VetCore, University of Veterinary Medicine, Vienna, Austria (G.E.M., R.S.); Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged, Hungary (E.A.E.); and Hungarian Academy of Science-USZ Bioinorganic Chemistry Research Group, Szeged, Hungary (E.A.E.)
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Walter Berger
Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria (R.T., L.S.F., C.R.K., M.A.J., B.K.K.); Research Platform “Translational Cancer Therapy Research” (R.T., C.R.K., P.H., U.J., M.A.J., W.B., B.K.K.), Institute of Cancer Research (P.H., U.J., W.B.), and Comprehensive Cancer Centre (P.H., U.J., W.B.), Medical University of Vienna, Vienna, Austria; Genomics Core Facility, VetCore, University of Veterinary Medicine, Vienna, Austria (G.E.M., R.S.); Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged, Hungary (E.A.E.); and Hungarian Academy of Science-USZ Bioinorganic Chemistry Research Group, Szeged, Hungary (E.A.E.)
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Bernhard K. Keppler
Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria (R.T., L.S.F., C.R.K., M.A.J., B.K.K.); Research Platform “Translational Cancer Therapy Research” (R.T., C.R.K., P.H., U.J., M.A.J., W.B., B.K.K.), Institute of Cancer Research (P.H., U.J., W.B.), and Comprehensive Cancer Centre (P.H., U.J., W.B.), Medical University of Vienna, Vienna, Austria; Genomics Core Facility, VetCore, University of Veterinary Medicine, Vienna, Austria (G.E.M., R.S.); Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged, Hungary (E.A.E.); and Hungarian Academy of Science-USZ Bioinorganic Chemistry Research Group, Szeged, Hungary (E.A.E.)
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Abstract

Triapine (3-AP; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a ribonucleotide reductase inhibitor, has been extensively evaluated in clinical trials in the last decade. This study addresses the role of endoplasmic reticulum (ER) stress in the anticancer activity of 3-AP and the derivative N4,N4-dimethyl-triapine (3-AP-Me), differing from 3-AP only by dimethylation of the terminal nitrogen. Treatment of colon cancer cells with 3-AP or 3-AP-Me activated all three ER stress pathways (PERK, IRE1a, ATF6) by phosphorylation of eIF2α and upregulation of gene expression of activating transcription factors ATF4 and ATF6. In particular, 3-AP-Me led to an upregulation of the alternatively spliced mRNA variant XBP1 (16-fold). Moreover, 3-AP and 3-AP-Me activated the cellular stress kinases c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases, and inhibition of JNK activity antagonized the cytotoxic effect of both compounds. Subsequent to induction of the unfolded protein response, a significant upregulation of proapoptotic proteins was detected, including the transcription factor CHOP and Bim, an essential factor for ER stress–related apoptosis. In correlation with the higher degree of ER stress after 3-AP-Me treatment, also a more potent depolarization of mitochondrial membranes was found. These data suggest that 3-AP and 3-AP-Me induce apoptosis via ER stress. This was further corroborated by showing that inhibition of protein biosynthesis with cycloheximide prior to 3-AP and 3-AP-Me treatment leads to a significant reduction of the antiproliferative properties of both compounds. Taken together, this study demonstrates that induction of ER stress contributes to the mode of action of 3-AP and that terminal dimethylation leads to an even more pronounced manifestation of this effect.

Footnotes

    • Received November 5, 2013.
    • Accepted December 23, 2013.
  • This work was supported by the Johanna Mahlke née Obermann Foundation for Cancer Research and the Austrian Science Fund [Grant P22072-B11].

  • Part of this work was previously presented at the following conference: Trondl R, Jungwirth U, Heffeter P, Kowol CR, Arion VB, Jakupec MA, Keppler BK (2011) Terminal dimethyl substitution of triapine leads to activation of CHOP and induction of apoptosis via ER stress in human colon cancer cells. Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2–6; Orlando, FL.

  • dx.doi.org/10.1124/mol.113.090605.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 85 (3)
Molecular Pharmacology
Vol. 85, Issue 3
1 Mar 2014
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Research ArticleArticle

ER Stress Induction by Triapine and Its Dimethyl Derivative

Robert Trondl, Lea S. Flocke, Christian R. Kowol, Petra Heffeter, Ute Jungwirth, Georg E. Mair, Ralf Steinborn, Éva A. Enyedy, Michael A. Jakupec, Walter Berger and Bernhard K. Keppler
Molecular Pharmacology March 1, 2014, 85 (3) 451-459; DOI: https://doi.org/10.1124/mol.113.090605

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Research ArticleArticle

ER Stress Induction by Triapine and Its Dimethyl Derivative

Robert Trondl, Lea S. Flocke, Christian R. Kowol, Petra Heffeter, Ute Jungwirth, Georg E. Mair, Ralf Steinborn, Éva A. Enyedy, Michael A. Jakupec, Walter Berger and Bernhard K. Keppler
Molecular Pharmacology March 1, 2014, 85 (3) 451-459; DOI: https://doi.org/10.1124/mol.113.090605
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