کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2512864 1118380 2012 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Increased expression of VDAC1 sensitizes carcinoma cells to apoptosis induced by DNA cross-linking agents
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی داروشناسی
پیش نمایش صفحه اول مقاله
Increased expression of VDAC1 sensitizes carcinoma cells to apoptosis induced by DNA cross-linking agents
چکیده انگلیسی

A major clinical problem regarding antitumoral treatment with DNA cross-linking agents such as cisplatin (Cisp), mechlorethamine (HN2) or its derivative melphalan (MLP) is intrinsic or acquired resistance to therapy, which frequently results from a resistance to apoptosis induction. In this study, aimed to identify novel sensitizing targets to DNA cross-linker-induced cell death, we demonstrated that MLP, Cisp and HN2 induce mitochondrial permeability transition pore (PTP)-mediated apoptosis in cervical and colon carcinoma cells. This apoptotic pathway is characterized by dissipation of the mitochondrial membrane potential, production of ROS, mitochondrial translocation of Bax, release of apoptogenic factors, caspase activation and nuclear alterations. The opening of PTP and subsequent apoptosis was reduced in Bax deficient cells and in cells with elevated Bcl-2 level, but not in cells invalidated for Bak. We further showed that, among the pro-apoptotic PTP regulators tested (VDAC1, creatine kinase, ANT1 and ANT3), exogenous overexpression of VDAC1 was the most effective in enhancing Cisp- and MLP-induced apoptosis. In addition, pharmacologically induced up-regulation of VDAC1 by the chemotherapeutic agent arsenic trioxide (As2O3) greatly sensitized HeLa cells to Cisp and MLP treatment. These data indicate that increased expression of VDAC1 appears as a promising strategy to improve DNA cross-linker-induced chemotherapy.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 83, Issue 9, 1 May 2012, Pages 1172–1182
نویسندگان
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