کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2112956 1084431 2013 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Pulling the plug on a cancer cell by eliminating XIAP with AEG35156
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
Pulling the plug on a cancer cell by eliminating XIAP with AEG35156
چکیده انگلیسی

XIAP, the X-linked inhibitor of apoptosis, is the best example of an endogenous cellular suppressor of apoptosis. XIAP is effective because it directly limits the activity of several critical death-inducing caspases, notably caspase-3, -7 and -9, either by direct enzyme inhibition or through ubiquitin-mediated proteasomal degradation. Furthermore, XIAP acts simultaneously at several nodes in the apoptotic cascade, blocking both the intrinsic and extrinsic death pathways, and thereby preventing feed-forward amplification loops that would otherwise lead to cell death. XIAP over-expression, or increased activity, is associated with cancer progression, resistance to therapy and poor prognosis. Targeting XIAP gene expression by antisense oligonucleotides, or other approaches, demonstrates anti-cancer effects with XIAP down-regulation. These early preclinical studies led to the development of a clinical candidate mixed-backbone antisense oligonucleotide, AEG35156, against XIAP for the treatment of cancer. Published clinical results for the first-in-class and first-in-human trials of AEG35156 are summarized herein, including single agent and combination chemotherapy phase-I or -II trials for solid tumors, lymphoma, and acute myeloid leukemia. These trials demonstrate the safety of AEG35156, as well as some initial promising signs of anti-cancer activity.


► XIAP is a potent suppressor of cell death and is a validated drug target.
► XIAP loss results in an immunodeficiency and anti-lymphoma effects.
► Antisense AEG35156 causes XIAP downregulation in circulating cancer cells and PBMCs.
► AEG35156 alone shows some anti-lymphoma and anti-tumor effects in clinical trials.
► AEG35156 has been given to 135 cancer patients and is well tolerated.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cancer Letters - Volume 332, Issue 2, 28 May 2013, Pages 215–224
نویسندگان
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