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Research ArticleArticle

Metabolic Transformation of Antitumor Acridinone C-1305 but Not C-1311 via Selective Cellular Expression of UGT1A10 Increases Cytotoxic Response: Implications for Clinical Use

Monika Pawlowska, Rong Chu, Barbara Fedejko-Kap, Ewa Augustin, Zofia Mazerska, Anna Radominska-Pandya and Timothy C. Chambers
Drug Metabolism and Disposition February 2013, 41 (2) 414-421; DOI: https://doi.org/10.1124/dmd.112.047811
Monika Pawlowska
Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, Gdańsk, Poland (M.P., B.F.-K., E.A., Z.M.); and Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (R.C., A.R.-P., T.C.C.)
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Rong Chu
Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, Gdańsk, Poland (M.P., B.F.-K., E.A., Z.M.); and Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (R.C., A.R.-P., T.C.C.)
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Barbara Fedejko-Kap
Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, Gdańsk, Poland (M.P., B.F.-K., E.A., Z.M.); and Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (R.C., A.R.-P., T.C.C.)
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Ewa Augustin
Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, Gdańsk, Poland (M.P., B.F.-K., E.A., Z.M.); and Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (R.C., A.R.-P., T.C.C.)
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Zofia Mazerska
Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, Gdańsk, Poland (M.P., B.F.-K., E.A., Z.M.); and Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (R.C., A.R.-P., T.C.C.)
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Anna Radominska-Pandya
Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, Gdańsk, Poland (M.P., B.F.-K., E.A., Z.M.); and Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (R.C., A.R.-P., T.C.C.)
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Timothy C. Chambers
Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, Gdańsk, Poland (M.P., B.F.-K., E.A., Z.M.); and Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (R.C., A.R.-P., T.C.C.)
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Abstract

The acridinone derivates 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone (C-1305) and 5-diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) are promising antitumor agents with high activity against several experimental cellular and tumor models and are under evaluation in preclinical and early phase clinical trials. Recent evidence from our laboratories has indicated that both compounds were conjugated by several uridine diphosphate-glucuronyltransferase (UGT) isoforms, the most active being extrahepatic UGT1A10. The present studies were designed to test the ability and selectivity of UGT1A10 in the glucuronidation of acridinone antitumor agents in a cellular context. We show that in KB-3 cells, a HeLa subline lacking expression of any UGT isoforms, both C-1305 and C-1311 undergo metabolic transformation to the glucuronidated forms on overexpression of UGT1A10. Furthermore, UGT1A10 overexpression significantly increased the cytotoxicity of C-1305, but not C-1311, suggesting that the glucuronide was more potent than the C-1305 parent compound. These responses were selective for UGT1A10 because documented overexpression of UGT2B4 failed to produce glucuronide products and failed to alter the cytotoxicity for both compounds. These findings contribute to our understanding of the mechanisms of action of these agents and are of particular significance because data for C-1305 contradict the dogma that glucuronidation typically plays a role in detoxification or deactivation. In summary, these studies suggest that extrahepatic UGT1A10 plays an important role in the metabolism and the bioactivation of C-1305 and constitutes the basis for further mechanistic studies on the mode of action of this drug, as well as translational studies on the role of this enzyme in regulation of C-1305 toxicity in cancer.

Footnotes

  • This work was supported by grants from the National Institutes of Health National Cancer Institute [Grant CA109821] (to T.C.C.); the National Institutes of Health National Institute of General Medical Sciences [Grant GM075893] to A.R.-P.; and the Department of Defense [Grant X81XWH-11-1-0795] funded by U.S. Army Medical Research and Materiel Command to A.R.-P. M.P. was supported in part by the Development of Interdisciplinary Doctoral Studies at Gdansk University of Technology project in the Area of Novel Technologies, supported by the European Union within European Social Fund and by a Research and Development grant from Chemical Faculty of Gdansk University of Technology [Grant 019432/009]. R.C. was supported in part by funds from the Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences.

  • dx.doi.org/10.1124/dmd.112.047811.

  • Received July 16, 2012.
  • Accepted November 16, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (2)
Drug Metabolism and Disposition
Vol. 41, Issue 2
1 Feb 2013
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Research ArticleArticle

Glucuronidation of Acridinones Increases Cytotoxic Response

Monika Pawlowska, Rong Chu, Barbara Fedejko-Kap, Ewa Augustin, Zofia Mazerska, Anna Radominska-Pandya and Timothy C. Chambers
Drug Metabolism and Disposition February 1, 2013, 41 (2) 414-421; DOI: https://doi.org/10.1124/dmd.112.047811

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Research ArticleArticle

Glucuronidation of Acridinones Increases Cytotoxic Response

Monika Pawlowska, Rong Chu, Barbara Fedejko-Kap, Ewa Augustin, Zofia Mazerska, Anna Radominska-Pandya and Timothy C. Chambers
Drug Metabolism and Disposition February 1, 2013, 41 (2) 414-421; DOI: https://doi.org/10.1124/dmd.112.047811
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