کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9012781 | 1125016 | 2005 | 15 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
کاردیولوژی و پزشکی قلب و عروق
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![عکس صفحه اول مقاله: Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide](/preview/png/9012781.png)
چکیده انگلیسی
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 H2O2 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 H2O2-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 H2O2-mediated pathways in apoptosis. Flow cytometry revealed that H2O2 formation preceded the increase in ÎΨm 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-2â²-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 H2O2 generation, although DOX-induced apoptosis may involve topoisomerase II inhibition. This oxidative DNA damage causes indirect H2O2 generation through PARP and NAD(P)H oxidase activation, leading to the ÎΨm increase and subsequent caspase-3 activation in DOX-induced apoptosis.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Life Sciences - Volume 76, Issue 13, 11 February 2005, Pages 1439-1453
Journal: Life Sciences - Volume 76, Issue 13, 11 February 2005, Pages 1439-1453
نویسندگان
Hideki Mizutani, Saeko Tada-Oikawa, Yusuke Hiraku, Michio Kojima, Shosuke Kawanishi,