کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
8434260 1546637 2018 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Pharmacologic inhibition of AKT leads to cell death in relapsed multiple myeloma
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
Pharmacologic inhibition of AKT leads to cell death in relapsed multiple myeloma
چکیده انگلیسی
Multiple myeloma (MM) is a neoplastic plasma cell disorder with high disease recurrence rates. Novel therapeutic approaches capable of improving outcomes in patients with MM are urgently required. The AKT signalling plays a critical regulatory role in MM pathophysiology, including survival, proliferation, metabolism, and has emerged as a key therapeutic target. Here, we identified a novel AKT inhibitor, HS1793, and defined its mechanism of action and clinical significance in MM. HS1793 disrupted the interaction between AKT and heat shock protein 90, resulting in protein phosphatase 2A-modulated phosphorylated-AKT (p-AKT) reduction. Moreover, we observed reductions in the kinase activity of the AKT downstream target, IκB kinase alpha, and the transcriptional activity of nuclear factor kappa B, which induced mitochondria-mediated cell death in MM cells exclusively. We confirmed the cytotoxicity and specificity of HS1793 via PET-CT imaging of a metastatic mouse model generated using human MM cells. We also evaluated the cytotoxic effects of HS1793 in primary and relapsed MM cells isolated from patients. Thus, HS1793 offers great promise in eliminating MM cells and improving therapeutic responses in primary and relapsed/refractory MM patients.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cancer Letters - Volume 432, 28 September 2018, Pages 205-215
نویسندگان
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