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Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide.
Life Sci. 2005 Feb 11; 76(13):1439-53.LS

Abstract

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.

Authors+Show Affiliations

Department of Environmental and Molecular Medicine, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15680309

Citation

Mizutani, Hideki, et al. "Mechanism of Apoptosis Induced By Doxorubicin Through the Generation of Hydrogen Peroxide." Life Sciences, vol. 76, no. 13, 2005, pp. 1439-53.
Mizutani H, Tada-Oikawa S, Hiraku Y, et al. Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide. Life Sci. 2005;76(13):1439-53.
Mizutani, H., Tada-Oikawa, S., Hiraku, Y., Kojima, M., & Kawanishi, S. (2005). Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide. Life Sciences, 76(13), 1439-53.
Mizutani H, et al. Mechanism of Apoptosis Induced By Doxorubicin Through the Generation of Hydrogen Peroxide. Life Sci. 2005 Feb 11;76(13):1439-53. PubMed PMID: 15680309.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide. AU - Mizutani,Hideki, AU - Tada-Oikawa,Saeko, AU - Hiraku,Yusuke, AU - Kojima,Michio, AU - Kawanishi,Shosuke, Y1 - 2005/01/20/ PY - 2004/02/29/received PY - 2004/05/18/accepted PY - 2005/2/1/pubmed PY - 2005/3/2/medline PY - 2005/2/1/entrez SP - 1439 EP - 53 JF - Life sciences JO - Life Sci VL - 76 IS - 13 N2 - 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. SN - 0024-3205 UR - https://www.unboundmedicine.com/medline/citation/15680309/Mechanism_of_apoptosis_induced_by_doxorubicin_through_the_generation_of_hydrogen_peroxide_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0024-3205(04)00987-7 DB - PRIME DP - Unbound Medicine ER -