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ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer

 Eun Young Kim  ;  Ji Ye Jung  ;  Arum Kim  ;  Yoon Soo Chang  ;  Se Kyu Kim 
 Neoplasia, Vol.19(4) : 354-363, 2017 
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Aged ; Animals ; Apoptosis/drug effects* ; Apoptosis/genetics ; Biomarkers ; Biphenyl Compounds/pharmacology* ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cisplatin/pharmacology* ; Disease Models, Animal ; Drug Synergism ; Female ; Gene Expression ; Humans ; Immunohistochemistry ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism* ; Lung Neoplasms/pathology ; Male ; Mice ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Nitrophenols/pharmacology* ; Piperazines/pharmacology ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects* ; Sulfonamides/pharmacology* ; Tumor Burden ; Xenograft Model Antitumor Assays
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
김세규(Kim, Se Kyu)
김아름(Kim, Arum)
김은영(Kim, Eun Young) ORCID logo https://orcid.org/0000-0002-3281-5744
장윤수(Chang, Yoon Soo) ORCID logo https://orcid.org/0000-0003-3340-4223
정지예(Jung, Ji Ye) ORCID logo https://orcid.org/0000-0003-1589-4142
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