کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1397256 1501114 2015 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics
چکیده انگلیسی


• We report on the identification of novel compounds with inhibitory activity on SIRT6.
• The new compounds reduce TNF-α production and increase glucose uptake in cells.
• SIRT6 inhibitors can be used to sensitize tumor cells to anticancer agents.

The NAD+-dependent sirtuin SIRT6 is highly expressed in human breast, prostate, and skin cancer where it mediates resistance to cytotoxic agents and prevents differentiation. Thus, SIRT6 is an attractive target for the development of new anticancer agents to be used alone or in combination with chemo- or radiotherapy. Here we report on the identification of novel quinazolinedione compounds with inhibitory activity on SIRT6. As predicted based on SIRT6's biological functions, the identified new SIRT6 inhibitors increase histone H3 lysine 9 acetylation, reduce TNF-α production and increase glucose uptake in cultured cells. In addition, these compounds exacerbate DNA damage and cell death in response to the PARP inhibitor olaparib in BRCA2-deficient Capan-1 cells and cooperate with gemcitabine to the killing of pancreatic cancer cells. In conclusion, new SIRT6 inhibitors with a quinazolinedione-based structure have been identified which are active in cells and could potentially find applications in cancer treatment.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Medicinal Chemistry - Volume 102, 18 September 2015, Pages 530–539
نویسندگان
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