کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8456991 | 1548789 | 2017 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer
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کلمات کلیدی
RT-PCRDFS3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide - 3- (4،5-dimethylthiazol-2-yl) -2،5-difenyltetrazolium bromideFFPE - MEPMTT - MTTImmunohistochemistry - ایمونوهیستوشیمیIHC - ایمونوهیستوشیمیdisease-free survival - بقاء بدون بیماریoverall survival - بقای کلNSCLC - سرطان ریوی غیر سلول کوچکNon-small cell lung cancer - سرطان غیر سلول کوچک ریهcombination index - شاخص ترکیبیformalin-fixed paraffin embedded - پارافین ثابت فرمالین تعبیه شده است
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer](/preview/png/8456991.png)
چکیده انگلیسی
A subset of non-small cell lung cancer (NSCLC), which does not have a druggable driver mutation, is treated with platinum-based cytotoxic chemotherapy, but it develops resistance triggered by DNA damage responses. Here, we investigated the effect of activation of STAT3 by cisplatin on anti-apoptotic proteins and the effectiveness of a co-treatment with cisplatin and a BH3 mimetic, ABT-737. We analyzed the relationship between cisplatin and STAT3 pathway and effect of ABT-737, when combined with cisplatin in NSCLC cells and K-ras mutant mouse models. The synergism of this combination was evaluated by the Chou-Talalay Combination Index method. In vivo activity was evaluated by micro-CT. In NSCLC cells, there was a time and dose-dependent phosphorylation of SRC-JAK2-STAT3 by cisplatin, followed by increased expression of anti-apoptotic molecules. When the expression of the BCL-2 protein family members was evaluated in clinical samples, BCL-xL was most frequently overexpressed. Dominant negative STAT3 suppressed their expression, suggesting that STAT3 mediates cisplatin mediated overexpression of the anti-apoptotic molecules. ABT-737 displaced BCL-xL from mitochondria and induced oligomerization of BAK. ABT-737 itself showed cytotoxic effects and a combination of ABT-737 with cisplatin showed strong synergistic cytotoxicity. In a murine lung cancer model, co-treatment with ABT-737 and cisplatin induced significant tumor regression. These findings reveal a synergistic cytotoxic and anti-tumor activity of ABT-737 and cisplatin co-treatment in preclinical models, and suggest that clinical trials using this strategy may be beneficial in advanced NSCLC.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neoplasia - Volume 19, Issue 4, April 2017, Pages 354-363
Journal: Neoplasia - Volume 19, Issue 4, April 2017, Pages 354-363
نویسندگان
Eun Young Kim, Ji Ye Jung, Arum Kim, Yoon Soo Chang, Se Kyu Kim,