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Tytuł pozycji:

Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide.

Tytuł:
Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide.
Autorzy:
Mizutani H; Department of Environmental and Molecular Medicine, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
Tada-Oikawa S
Hiraku Y
Kojima M
Kawanishi S
Źródło:
Life sciences [Life Sci] 2005 Feb 11; Vol. 76 (13), pp. 1439-53. Date of Electronic Publication: 2005 Jan 20.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Publication: <2008->: Amsterdam : Elsevier
Original Publication: Oxford; Elmsford, N. Y. [etc.] Pergamon Press.
MeSH Terms:
Antibiotics, Antineoplastic/*pharmacology
Apoptosis/*drug effects
Deoxyguanosine/*analogs & derivatives
Doxorubicin/*pharmacology
Hydrogen Peroxide/*metabolism
8-Hydroxy-2'-Deoxyguanosine ; Aminoquinolines/pharmacology ; Anthracyclines/pharmacology ; Caspase 3 ; Caspases/metabolism ; Chromatography, High Pressure Liquid ; DNA/biosynthesis ; DNA/genetics ; DNA Damage/drug effects ; Deoxyguanosine/pharmacology ; Electrochemistry ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; HL-60 Cells ; Humans ; Indenes/pharmacology ; Membrane Potentials/drug effects ; NADPH Oxidases/antagonists & inhibitors ; Poly(ADP-ribose) Polymerase Inhibitors ; Topoisomerase I Inhibitors
Substance Nomenclature:
0 (Aminoquinolines)
0 (Anthracyclines)
0 (Antibiotics, Antineoplastic)
0 (Enzyme Inhibitors)
0 (Indenes)
0 (Poly(ADP-ribose) Polymerase Inhibitors)
0 (Topoisomerase I Inhibitors)
80168379AG (Doxorubicin)
88847-89-6 (8-Hydroxy-2'-Deoxyguanosine)
9007-49-2 (DNA)
93N13LB4Z2 (amrubicin)
BBX060AN9V (Hydrogen Peroxide)
EC 1.6.3.- (NADPH Oxidases)
EC 3.4.22.- (CASP3 protein, human)
EC 3.4.22.- (Caspase 3)
EC 3.4.22.- (Caspases)
G9481N71RO (Deoxyguanosine)
YVC96489QV (6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one)
Entry Date(s):
Date Created: 20050201 Date Completed: 20050301 Latest Revision: 20220409
Update Code:
20240104
DOI:
10.1016/j.lfs.2004.05.040
PMID:
15680309
Czasopismo naukowe
The main anticancer action of doxorubicin (DOX) is believed to be due to topoisomerase II inhibition and free radical generation. Our previous study has demonstrated that TAS-103, a topoisomerase inhibitor, induces apoptosis through DNA cleavage and subsequent H(2)O(2) generation mediated by NAD(P)H oxidase activation [H. Mizutani et al. J. Biol. Chem. 277 (2002) 30684-30689]. Therefore, to clarify whether DOX functions as an anticancer drug through the same mechanism or not, we investigated the mechanism of apoptosis induced by DOX in the human leukemia cell line HL-60 and the H(2)O(2)-resistant sub-clone, HP100. DOX-induced DNA ladder formation could be detected in HL-60 cells after a 7 h incubation, whereas it could not be detected under the same condition in HP100 cells, suggesting the involvement of H(2)O(2)-mediated pathways in apoptosis. Flow cytometry revealed that H(2)O(2) formation preceded the increase in Delta Psi m and caspase-3 activation. Poly(ADP-ribose) polymerase (PARP) and NAD(P)H oxidase inhibitors prevented DOX-induced DNA ladder formation in HL-60 cells. Moreover, DOX significantly induced formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine, an indicator of oxidative DNA damage, in HL-60 cells at 1 h, but not in HP100 cells. DOX-induced apoptosis was mainly initiated by oxidative DNA damage in comparison with the ability of other topoisomerase inhibitors (TAS-103, amrubicin and amrubicinol) to cause DNA cleavage and apoptosis. These results suggest that the critical apoptotic trigger of DOX is considered to be oxidative DNA damage by the DOX-induced direct H(2)O(2) generation, although DOX-induced apoptosis may involve topoisomerase II inhibition. This oxidative DNA damage causes indirect H(2)O(2) generation through PARP and NAD(P)H oxidase activation, leading to the Delta Psi m increase and subsequent caspase-3 activation in DOX-induced apoptosis.

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