کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2136530 1087794 2015 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Metformin synergistically sensitizes FLT3-ITD-positive acute myeloid leukemia to sorafenib by promoting mTOR-mediated apoptosis and autophagy
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
Metformin synergistically sensitizes FLT3-ITD-positive acute myeloid leukemia to sorafenib by promoting mTOR-mediated apoptosis and autophagy
چکیده انگلیسی


• Metformin and sorafenib synergistically inhibit the proliferation of FLT3-ITD mutated leukemic cells.
• Metformin synergistically sensitize FLT3-ITD-positive acute myeloid leukemia to sorafenib by inducing cell apoptosis and autophagy.
• The anti-leukemic effect of metformin and sorafenib is, to some extent, mediated by the mTOR/p70S6K/4EBP1 pathway.

Mutations of Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD), accounting for approximately 30% of patients with acute myeloid leukemia (AML), results in poor therapeutic efficacy and short survival. Sorafenib, an oral multikinase inhibitor, can inhibit FLT3 and improve clinical outcome of FLT3 mutated leukemia. Our current studies have shown that, the antidiabetic drug metformin also exerts anti-leukemic effect by activating p-AMPK and synergistically sensitizes FLT3 mutated AML to sorafenib. Both agents suppress cell proliferation in a dose-dependent manner and induce apoptosis via cell cycle arrest, but does not obviously modulate autophagy marker, light chain 3 (LC3). Mechanistically, in the presence of metformin, the anticancer potential of sorafenib, accompanying with increased LC3 levels, is found to be synergistically enhanced with the remarkably reduced protein expression of the mTOR/p70S6K/4EBP1 pathway, while not appreciably altering cell cycle. Overall, these results show metformin in aid of sorafenib may represent a promising and attractive strategy for the treatment of FLT3-ITD mutated AML.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Leukemia Research - Volume 39, Issue 12, December 2015, Pages 1421–1427
نویسندگان
, , , , , , , , , , , ,