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XK469, a selective topoisomerase IIbeta poison
H Gao1, K C Huang, E F Yamasaki
1Department of Radiology, Colleges of Pharmacy and Medicine, The Ohio State University, Columbus, OH 43210, USA.
Abstract:
XK469 (NSC 697887) is a synthetic quinoxaline phenoxypropionic acid derivative that possesses unusual solid tumor selectivity and activity against multidrug-resistant cancer cells. We report here that XK469 and its S(-) and R(+)-isomers induce reversible protein-DNA crosslinks in mammalian cells. Under protein denaturing conditions, the protein-DNA crosslinks are rendered irreversible and stable to DNA banding by CsCl gradient ultracentrifugation. Several lines of evidence indicate that the primary target of XK469 is topoisomerase IIbeta. Preferential targeting of topoisomerase IIbeta may explain the solid tumor selectivity of XK469 and its analogs because solid tumors, unlike leukemias, often have large populations of cells in the G(1)/G(0) phases of the cell cycle in which topoisomerase IIbeta is high whereas topoisomerase IIalpha, the primary target of many leukemia selective drugs, is low.
Insights
XK469, a novel quinoxaline derivative, creates protein-DNA crosslinks in cancer cells. Its selective targeting of topoisomerase IIbeta may explain its effectiveness against solid tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- XK469 is a synthetic quinoxaline phenoxypropionic acid derivative.
- It exhibits selective activity against solid tumors and multidrug-resistant cancer cells.
Purpose of the Study:
- To investigate the mechanism of action of XK469.
- To determine the molecular target of XK469 and its isomers.
Main Methods:
- Treatment of mammalian cells with XK469 and its isomers.
- Analysis of protein-DNA crosslinks under various conditions.
- Assessment of topoisomerase IIbeta as the primary target.
Main Results:
- XK469 and its isomers induce reversible protein-DNA crosslinks.
- These crosslinks become irreversible under denaturing conditions.
- Evidence strongly suggests topoisomerase IIbeta is the primary molecular target.
Conclusions:
- XK469's mechanism involves inducing protein-DNA crosslinks.
- Preferential targeting of topoisomerase IIbeta may underlie its solid tumor selectivity.
- This selectivity is potentially due to higher topoisomerase IIbeta levels in G(1)/G(0) phase solid tumor cells.