کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5552348 1557887 2017 17 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Targeting of multiple senescence-promoting genes and signaling pathways by triptonide induces complete senescence of acute myeloid leukemia cells
ترجمه فارسی عنوان
هدف قرار دادن ژن های پیشرفته چند ساله و مسیرهای سیگنالینگ توسط ترپتونید القاء کامل پیری سلول های لوسمی میلوئید حاد
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی داروشناسی
چکیده انگلیسی

Leukemia cells aberrantly overexpress senescence-suppression telomerase reverse transcriptase (TERT) and down-regulate key senescence-promoting genes to escape complete senescence, resulting in immortalization and malignant progression. Accordingly, induction of complete senescence is a sensible strategy for anti-leukemia therapy. However, effective senescence-based anti-leukemia drugs with low toxicity are currently lacking. In this study, we found that triptonide (chemical name diterpene triepoxide), a small molecule derived from the herb Tripterygium wilfordii Hook, strongly induced complete senescence in cultured acute myeloid leukemia (AML) cell lines, and potently inhibited growth and colony formation of U937 and HL-60 AML cell line with IC50 values of 7.5 and 12 nM, respectively. Strikingly, triptonide (4 mg/kg) nearly completely suppressed human leukemia cell tumorigenicity (>99%) without obvious toxicity in a mouse xenograft model. Mechanistic studies showed that triptonide induced senescence followed by apoptosis mainly by suppressing transcription of TERT and oncogenic c-Myc, while concomitantly promoting transcription of senescence-promoting genes p16 and p21 and the pro-apoptotic gene encoding DNA damage-inducible transcript 3. These effects of triptonide are mediated by selective mitogen-activated protein kinase kinase-3/p38 signaling pathway activation. Our study provides a conceptual framework for inducing complete senescence as an effective anti-leukemia therapeutic strategy through a “multiple-hits” model and supports further development of triptonide as an anti-cancer agent.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 126, 15 February 2017, Pages 34-50
نویسندگان
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