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Cytotoxic Mechanism of XK469: Resistance of Topoisomerase IIβ Knockout Cells and Inhibition of Topoisomerase I

https://doi.org/10.1006/bbrc.2001.4249Get rights and content

Abstract

Topoisomerase IIβ knockout mouse cells (β−/−) were found to have only slight resistance to m-AMSA, a dual topoisomerase IIα-IIβ poison, as compared to wild-type cells (β+/+) during 1 h or 3 day exposures to the drug. In contrast, the β−/− cells were greater than threefold resistant to XK469, a selective topoisomerase IIβ poison during three day drug exposures (β+/+ IC50 = 175 μM, β−/− IC50 = 581 μM). Short term (1 h) exposure to XK469 was not cytotoxic to either β−/− or β+/+ cells, suggesting that anticancer therapy with XK469 may be more efficacious if systemic levels can be prolonged. During studies on topoisomerase activity in nuclear extracts of the β+/+ and β−/− cells, we found evidence that XK469 is a weak topoisomerase I catalytic inhibitor. The high IC50 for topoisomerase I inhibition (2 mM) suggests that topoisomerase I is not a significant target for XK469 cytotoxicity.

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Cited by (21)

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    COMPARE analysis of cytotoxicity data from the NCI-60 cell line screen showed that its mechanism of action is unique in that it was not similar to that of any known cytotoxic agent in the NCI database. Whilst not definitive, the available data suggest that XK469 acts as a selective topoisomerase IIβ inhibitor.5–9 Other proposed mechanisms include XK469-induced inhibition of cyclin B1 ubiquitination10 and apoptosis via binding of the peripheral benzodiazepine receptor.11

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