The Novel Triazolonaphthalimide Derivative LSS-11 Synergizes the Anti-Proliferative Effect of Paclitaxel via STAT3-Dependent MDR1 and MRP1 Downregulation in Chemoresistant Lung Cancer Cells

被引:21
作者
Ji, Liyan [1 ,2 ,3 ]
Liu, Xi [1 ]
Zhang, Shuwei [1 ]
Tang, Shunan [3 ]
Yang, Simin [3 ]
Li, Shasha [3 ]
Qi, Xiaoxiao [1 ]
Yu, Siwang [3 ]
Lu, Linlin [1 ]
Meng, Xiangbao [3 ]
Liu, Zhongqiu [1 ]
机构
[1] Guangzhou Univ Chinese Med, Int Inst Translat Chinese Med, Guangzhou 510006, Guangdong, Peoples R China
[2] Guangzhou Univ Chinese Med, Postdoctoral Res Stn, Guangzhou 510006, Guangdong, Peoples R China
[3] Peking Univ, Sch Pharmaceut Sci, Dept Chem Biol, Beijing 100191, Peoples R China
来源
MOLECULES | 2017年 / 22卷 / 11期
关键词
triazolonaphthalimide derivative; paclitaxel resistance; lung cancer; STAT3; inhibition; MULTIDRUG-RESISTANCE; DRUG-RESISTANCE; P-GLYCOPROTEIN; TOPOISOMERASE-II; ACTIVATION; APOPTOSIS; PATHWAY; EXPRESSION; PROTEINS; MARKERS;
D O I
10.3390/molecules22111822
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Multidrug resistance (MDR) is a major cause of the inefficacy and poor response to paclitaxel-based chemotherapy. The combination of conventional cytotoxic drugs has been a plausible strategy for overcoming paclitaxel resistance. Herein, we investigated the cytotoxic effects and underlying mechanism of LSS-11, a novel naphthalimide derivative-based topoisomerase inhibitor, in paclitaxel-resistant A549 (A549/T) lung cancer cells. LSS-11 enhanced cell death in A549/T cells by inducing apoptosis through increasing the DR5 protein level and PARP1 cleavage. Importantly, LSS-11 dose-dependently reduced STAT3 phosphorylation and downregulated its target genes MDR1 and MRP1, without affecting P-gp transport function. Chromatin coimmunoprecipitation (ChIP) assay further revealed that LSS-11 hindered the binding of STAT3 to the MDR1 and MRP1 promoters. Additionally, pharmacological inhibition of p-STAT3 by sulforaphane downregulated MDR1 and MRP1, resulting in A549/T cell death by triggering apoptosis. Collectively, our data show that LSS-11 is a potent naphthalimide-based chemosensitizer that could enhance cell death in paclitaxel-resistant lung cancer cells through the DR5/PARP1 pathway and STAT3/MDR1/MRP1 STAT3 inhibition.
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页数:12
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