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2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic acid (XK469), an inhibitor of topoisomerase (Topo) IIbeta, up-regulates Topo IIalpha and enhances Topo IIalpha-mediated cytotoxicity.

Abstract
Topoisomerase (Topo) IIalpha has proven to be an adequate anticancer target for tumors expressing this enzyme. In this study, we elucidated the effect of 2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic acid (XK469; a new Topo IIbeta inhibitor) in the modulation of Topo IIalpha levels and sensitivity to Topo IIalpha poisons. We demonstrate by Western blot analysis that indolent B-cell tumors express undetectable levels of this enzyme and are refractory to the effects of Topo IIalpha poisons such as VP16. Using the Waldenstrom's macroglobulinemia (WM) cell line WSU-WM, we show that XK469 induced the expression of Topo IIalpha protein by 24 h compared with control. Immunofluorescence studies by confocal microscopy using a specific monoclonal antibody against Topo IIalpha supported the immunoblot findings with high intensity staining in XK469-exposed cells. To determine the effect of up-regulating Topo IIalpha on sensitivity of Topo IIalpha-directed inhibitors, WSU-WM cells were exposed to simultaneous, sequential, and reverse order XK469 and VP16. We demonstrate that 24 h of exposure to XK469 before VP16 resulted in a maximum synergistic response. In contrast, simultaneous or reverse order exposure resulted in an antagonistic effect. A similar trend was observed with cells obtained from chronic lymphocytic leukemia patients, but not in normal lymphocytes. This increase in VP16 sensitivity after 24 h of XK469 exposure was associated with VP16-dependent DNA cleavage, as demonstrated by formation of a smeared DNA band in a SDS-KCL DNA cleavage assay. From this study, we concluded that XK469 up-regulates Topo IIalpha levels and consequently sensitizes indolent malignant B cells to the cytotoxic effect of VP16 in a schedule-dependent manner.
AuthorsEdith J Mensah-Osman, Ayad M Al-Katib, Hai-Young Wu, Nadir I Osman, Ramzi M Mohammad
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 1 Issue 14 Pg. 1321-6 (Dec 2002) ISSN: 1535-7163 [Print] United States
PMID12516965 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antigens, Neoplasm
  • Culture Media, Serum-Free
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Protein Isoforms
  • Quinoxalines
  • XK 469
  • Etoposide
  • DNA
  • DNA Topoisomerases, Type II
Topics
  • Antigens, Neoplasm
  • Blotting, Western
  • Culture Media, Serum-Free
  • DNA (metabolism)
  • DNA Topoisomerases, Type II (metabolism)
  • DNA-Binding Proteins
  • Enzyme Inhibitors (pharmacology)
  • Etoposide (pharmacology)
  • Humans
  • Immunohistochemistry
  • Leukemia, Lymphocytic, Chronic, B-Cell (blood)
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Neoplasm Transplantation
  • Protein Isoforms
  • Quinoxalines (pharmacology)
  • Time Factors
  • Tumor Cells, Cultured
  • Up-Regulation
  • Waldenstrom Macroglobulinemia (drug therapy, metabolism)

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