Aurintricarboxylic acid, a putative inhibitor of apoptosis, is a potent inhibitor of DNA topoisomerase II in vitro and in Chinese hamster fibrosarcoma cells

Benchokroun, Youssef; Couprie, Jeannine; Larsen, Annette K.

doi:10.1016/0006-2952(94)00465-x

Cited by 59 publications

(40 citation statements)

References 25 publications

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“…The nuclease activity, measured by 32 P release, was also stimulated by Mn 2+ , Mg 2+ and Ca 2+ and completely circumvented at 4°C or after heat treatment of the cytosol (Figure 7c, d and data not shown). Aurintricarboxylic acid and Zn 2+ , non-specific inhibitors of DNases 32,39,40 obliterated the enzyme activity with a K i of 2.5 and 0.2 m, respectively, implying that the affinity of the cytosolic nuclease toward these inhibitors is 20-to 50-fold higher than that of pancreatic DNase …”

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confidence: 99%

Metabolic instability of plasmid DNA in the cytosol: a potential barrier to gene transfer

et al. 1999

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Inefficient nuclear delivery of plasmid DNA is thought to activity of apoptotic and lysosomal nucleases; (2) disposal be one of the daunting hurdles to gene transfer, utilizing a of microinjected plasmid DNA was inhibited in cytosolnonviral delivery system such as polycation-DNA complex.depleted cells or following the encapsulation of DNA in Following its internalization by endocytosis, plasmid DNA phospholipid vesicles; (3) generation and subsequent elimhas to be released into the cytosol before its nuclear entry ination of free 3Ј-OH ends could be detected by the tercan occur. However, the stability of plasmid DNA in the minal deoxynucleotidyl transferase-mediated dUTP nick cytoplasm, that may play a determinant role in the transfecend-labeling assay (TUNEL), reflecting the fragmentation tion efficiency, is not known. The turnover of plasmid DNA, of the injected DNA; and finally (4) isolated cytosol, delivered by microinjection into the cytosol, was deterobtained by selective permeabilization of the plasma memmined by fluorescence in situ hybridization (FISH) and brane, exhibits divalent cation-dependent, thermolabile quantitative single-cell fluorescence video-image analysis. nuclease activity, determined by Southern blotting and 32 PBoth single-and double-stranded circular plasmid DNA disrelease from end-labeled DNA. Collectively, these findings appeared with an apparent half-life of 50-90 min from the suggest that the metabolic instability of plasmid DNA, cytoplasm of HeLa and COS cells, while the amount of cocaused by cytosolic nuclease, may constitute a previously injected dextran (MW 70 000) remained unaltered. We prounrecognized impediment for DNA translocation into the pose that cytosolic nuclease(s) are responsible for the nucleus and a possible target to enhance the efficiency of rapid degradation of plasmid DNA, since (1) elimination of gene delivery. plasmid DNA cannot be attributed to cell division or to the Keywords: gene transfer; plasmid DNA; turnover; degradation; DNase; microinjection Introduction Liposome-mediated cellular transfer of plasmid DNA is a promising approach for gene therapy. However, despite the significant amount of lipid/DNA complexes internalized by the target cells, transgene expression remains undesirably low.1 Obstacles to nuclear accumulation of plasmid DNA include: the slow internalization process of the lipid/DNA complex in certain cells; 2 the entrapment of DNA in the endolysosomal compartment; 1,3,4 and the diffusional barrier of the nuclear envelope. 5The underlying mechanism of escape of internalized plasmid DNA from the endo-lysosomes is not fully understood. This process involves the destabilization of the limiting membrane of the endolysosomal compartment, the dissociation of the lipid/DNA complex and the release of plasmid DNA into the cytosol.6-8 Penetration of naked plasmid DNA into the cytosol was verified by using the T7 polymerase transfection system, which Correspondence: GL Lukacs, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canad...

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Metabolic instability of plasmid DNA in the cytosol: a potential barrier to gene transfer

et al. 1999

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“…Type II inhibitors include amsacrine, etoposide phosphate and teniposide, aurintricarboxylic acid 48 . These are semisynthetic derivatives of epipodophyllotoxins, alkaloids naturally occurring in the root of American Mayapple (Podophyllum peltatum), doxorubicin, idarubicin, epirubicin and mitoxantrone 49,50 .…”

Section: Drug-targeted Chemotherapy: Topoisomerases As Drug Targetsmentioning

confidence: 99%

“…Etoposide being a typical topo II inhibitor stabilizes the cleavable complex formation with DNA topo II without an intercalating action. Etoposide with cisplatin exhibits a synergistic effect against lung cancer both in vitro and in vivo, and the modulatory effect of cisplatin on topo II activity is indicated to be the reason for the synergistic antitumour effect 45,48,[93][94][95] .…”

Section: Nonintercalating Topoisomerase-targeting Drugs 1 Epipodomentioning

confidence: 99%

“…A brief study of the different steps in the catalytic cycle shows that merbarone has no effect on either DNA binding or ATP hydrolysis but it is a potent inhibitor of enzyme mediated DNA cleavage. More recently, colony formation assays show that both inhibitors, merbarone and ICRF-187 are able to significantly potentiate the cytotoxicity of the alkylating agent melphalan 48,82 .…”

Section: Merbaronementioning

confidence: 99%

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Topoisomerase as target for antibacterial and anticancer drug discovery

Kathiravan

Khilare

Nikoomanesh

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…[3][4][5][6][7][8][9][10] ATA is also known to inhibit enzymes that do not bind to nucleic acids, such as Phe:tRNA ligase, aminopropyltransferase, phosphofructokinase and several enzymes required by NAD(H)/NADP(H). [11][12][13][14] More recently, a study conducted by our group as well as a study conducted by Liang et al reported that ATA inhibits protein tyrosine phosphatases (PTPs).…”

Section: Introductionmentioning

confidence: 99%

Antiapoptotic Effect of Aurintricarboxylic Acid; Extracellular Action versus Inhibition of Cytosolic Protein Tyrosine Phosphatases

2008

Bulletin of the Korean Chemical Society

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Aurintricarboxylic acid (ATA) prevents apoptosis in a wide range of cell types, including PC12 cells. ATA is known to increase the phosphorylation level of IGF-1 receptor (IGF-1R) and downstream signaling proteins. ATA can translocate across the plasma membrane of PC12 cells and inhibit protein tyrosine phosphatases (PTPs) and, therefore, it is not clear whether ATA exerted its antiapoptotic effect through activation of IGF-1R or by inhibition of cytosolic PTPs. When PC12 cells, deprived of serum, were treated with Fab fragment of anti-IGF-1R antibody to prevent the binding of ATA to the extracellular domain of IGF-1R, ATA was found to penetrate into the cytosolic space of the cells. Under these conditions, the survival-promoting effects of ATA were abolished, and the increase of phosphorylation and characteristic cleavage of IGF-1R were not observed. These results indicate that the antiapoptotic effect of ATA in PC12 cells is due to the binding of ATA to the extracellular domain of IGF-1R and subsequent activation of the IGF-1R, not inhibition of cytosolic PTP(s).

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Aurintricarboxylic acid, a putative inhibitor of apoptosis, is a potent inhibitor of DNA topoisomerase II in vitro and in Chinese hamster fibrosarcoma cells

Cited by 59 publications

References 25 publications

Metabolic instability of plasmid DNA in the cytosol: a potential barrier to gene transfer

Metabolic instability of plasmid DNA in the cytosol: a potential barrier to gene transfer

Topoisomerase as target for antibacterial and anticancer drug discovery

Antiapoptotic Effect of Aurintricarboxylic Acid; Extracellular Action versus Inhibition of Cytosolic Protein Tyrosine Phosphatases

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