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Inhibition of topoisomerase II by 8-chloro-adenosine triphosphate induces DNA double-stranded breaks in 8-chloro-adenosine-exposed human myelocytic leukemia K562 cells.

Abstract：

:8-Chloro-cAMP and 8-chloro-adenosine (8-Cl-Ado) are known to inhibit proliferation of cancer cells by converting 8-Cl-Ado into an ATP analog, 8-chloro-ATP (8-Cl-ATP). Because type II topoisomerases (Topo II) are ATP-dependent, we infer that 8-Cl-Ado exposure might interfere with Topo II activities and DNA metabolism in cells. We found that 8-Cl-Ado exposure inhibited Topo II-catalytic activities in K562 cells, as revealed by decreased relaxation of the supercoiled pUC19 DNA and inhibited decatenation of the kinetoplast DNA (kDNA). In vitro assays showed that 8-Cl-ATP, but not 8-Cl-Ado, could directly inhibit Topo IIalpha-catalyzed relaxation and decatenation of substrate DNA. Furthermore, 8-Cl-ATP inhibited Topo II-catalyzed ATP hydrolysis and increased salt-stabilized closed clamp. In addition, 8-Cl-Ado exposure decreased bromo-deoxyuridine (BrdU) incorporation into DNA and led to enhanced DNA double-stranded breaks (DSBs) and to increased formation of gamma-H2AX nuclear foci in exposed K562 cells. Together, 8-Cl-Ado/8-Cl-ATP can inhibit Topo II activities in cells, thereby inhibiting DNA synthesis and inducing DNA DSBs, which may contribute to 8-Cl-Ado-inhibited proliferation of cancers.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Yang SY,Jia XZ,Feng LY,Li SY,An GS,Ni JH,Jia HT

doi

10.1016/j.bcp.2008.10.022

subject

Has Abstract

pub_date

2009-02-01 00:00:00

pages

433-43

issue

3

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(08)00775-2

journal_volume

77

pub_type

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