کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2513630 1118426 2010 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
New caspase-independent but ROS-dependent apoptosis pathways are targeted in melanoma cells by an iron-containing cytosine analogue
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی داروشناسی
پیش نمایش صفحه اول مقاله
New caspase-independent but ROS-dependent apoptosis pathways are targeted in melanoma cells by an iron-containing cytosine analogue
چکیده انگلیسی

Chemotherapy resistance and related defects in apoptotic signaling are crucial for the high mortality of melanoma. Effective drugs are lacking, also due to the fact that apoptosis regulation in this tumor is essentially not understood. The cytosine analogue ferropoptoside (N69), which contains an iron carbonyl complex, resulted in strong induction of apoptosis in melanoma cells starting already after 2 h, whereas cytotoxicity remained at a low level. Surprisingly, there was no indication for any caspase activation at early times, although cytochrome c was released from mitochondria. Indicative for new proapoptotic pathways was the production of reactive oxygen species (ROS) as an early effect, and the inhibition of apoptosis by the antioxidant vitamin E. Apoptosis was also blocked by exogenous Bcl-2 overexpression and by the pan-protease inhibitor zVAD. However, only zVAD also prevented ROS production, for which Bcl-2 remained without an effect. Thus, new proapoptotic pathways are described here for melanoma cells clearly related to ROS production. A cascade enclosing enhanced levels of intracellular iron, which lead to enhanced ROS production in a Fenton reaction, appears as suggestive. Whereas off-target effects of zVAD appear as upstream, Bcl-2 may exert its inhibitory activity downstream of ROS. New proapoptotic pathways are of particular interest for melanoma as they may open new options for targeting this highly therapy-refractory tumor.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 79, Issue 4, 15 February 2010, Pages 575–586
نویسندگان
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