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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

The Chemotherapeutic Agents XK469 (2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 (2-{4-[(7-Bromo-2-quinolinyl)oxy]phenoxy}propionic acid) Inhibit Cytokinesis and Promote Polyploidy and Induce Senescence

John J. Reiners Jr., Miriam Kleinman, Aby Joiakim and Patricia A. Mathieu
Journal of Pharmacology and Experimental Therapeutics March 2009, 328 (3) 796-806; DOI: https://doi.org/10.1124/jpet.108.144808
John J. Reiners Jr.
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Miriam Kleinman
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Aby Joiakim
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Patricia A. Mathieu
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Abstract

The therapeutic usefulness of the quinoxaline derivatives XK469 (2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 (2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid) has been attributed to their abilities to induce G2/M arrest and apoptotic or autophagic cell death. Concentrations of XK469 or SH80 ≥ 5 μM were cytostatic to cultures of the normal murine melanocyte cell line Melan-a. Higher concentrations caused dose-dependent cytotoxicity. Concentrations ≥10 μM provoked dramatic morphological changes typified by marked increases in cell size and granularity. XK469/SH80-treated cultures accumulated tetraploid (4N) DNA-containing cells within 24 h of treatment, an 8N population within 3 days, and a 16N population within 5 days. Increases in ploidy correlated with the appearance of multinucleated cells. Under no circumstances did cells exhibit evidence of furrow formation. Both drugs suppressed cytokinesis in additional mammalian cell lines. Cytotoxic concentrations of XK469 elevated DEVDase activities (a measure of procaspase-3/7 activation) and enhanced cellular staining by a fluorescent analog of the pan caspase inhibitor valine-alanine-aspartic acid-fluoromethyl ketone within 48 to 96 h of treatment. Within 48 h of treatment, cytostatic and cytotoxic concentrations of XK469 elevated p21 contents, reduced Bcl-2 and Bcl-XL contents, and induced autophagy, as monitored by the accumulaton of phosphatidylethanolamine-modified cleavage product of microtubule-associated protein light chain 3 (LC3-II). Cultures treated with ≥10 μM XK469 or SH80 for 5 days could not be induced to divide upon removal of drugs. Such cultures maintained high LC3-II contents, exhibited reduced cyclin E and D1 contents, and extensively expressed senescence-associated β-galactosidase within 14 to 17 days of cessation of drug treatment. Hence, XK469 and SH80 inhibit cytokinesis, promote polyploidy, and induce senescence in Melan-a cells.

Footnotes

  • M.K. was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grant T32-ES012163]. This project used the services of the Imaging and Cytometry Facility Core, supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grant P30-ES06639].

  • doi:10.1124/jpet.108.144808.

  • ABBREVIATIONS: XK469, 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid; SH80, 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}-propionic acid; XK472, ethyl 2-{4-[(6-chloro-2-quinoxalinyl)oxy]phenoxy}propionate; HO33342, Höechst dye HO33342; HA14-1, ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; AMC, 7-amino-4-methylcoumarin; PBS, phosphate-buffered saline; SSC, side light scatter; FSC, forward light scatter; FAM-VAD-FMK, carboxyfluorescein derivative of valine-alanine-aspartic acid-fluoromethyl ketone; FACS, fluorescence-activated cell sorting; LC3-II, phosphatidylethanolamine-modified LC3-I.

    • Received August 13, 2008.
    • Accepted December 5, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 382 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 382, Issue 2
1 Aug 2022
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

The Chemotherapeutic Agents XK469 (2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 (2-{4-[(7-Bromo-2-quinolinyl)oxy]phenoxy}propionic acid) Inhibit Cytokinesis and Promote Polyploidy and Induce Senescence

John J. Reiners, Miriam Kleinman, Aby Joiakim and Patricia A. Mathieu
Journal of Pharmacology and Experimental Therapeutics March 1, 2009, 328 (3) 796-806; DOI: https://doi.org/10.1124/jpet.108.144808

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

The Chemotherapeutic Agents XK469 (2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 (2-{4-[(7-Bromo-2-quinolinyl)oxy]phenoxy}propionic acid) Inhibit Cytokinesis and Promote Polyploidy and Induce Senescence

John J. Reiners, Miriam Kleinman, Aby Joiakim and Patricia A. Mathieu
Journal of Pharmacology and Experimental Therapeutics March 1, 2009, 328 (3) 796-806; DOI: https://doi.org/10.1124/jpet.108.144808
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