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.
引用
收藏
页数:12
相关论文
共 43 条
[41]   PARP-1 Regulates Resistance of Pancreatic Cancer to TRAIL Therapy [J].
Yuan, Kaiyu ;
Sun, Yong ;
Zhou, Tong ;
McDonald, Jay ;
Chen, Yabing .
CLINICAL CANCER RESEARCH, 2013, 19 (17) :4750-4759
[42]   Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development [J].
Zhou, Shu-Feng ;
Wang, Lin-Lin ;
Di, Yuan Ming ;
Xue, Charlie Changli ;
Duan, Wei ;
Li, Chun Guang ;
Li, Yong .
CURRENT MEDICINAL CHEMISTRY, 2008, 15 (20) :1981-2039
[43]   Reversal of P-gp and MRP1-mediated multidrug resistance by H6, a gypenoside aglycon from Gynostemma pentaphyllum, in vincristine-resistant human oral cancer (KB/VCR) cells [J].
Zhu, Hengrui ;
Liu, Zulong ;
Tang, Lisha ;
Liu, Junhua ;
Zhou, Mei ;
Xie, Fang ;
Wang, Zheng ;
Wang, Yuqi ;
Shen, Sida ;
Hu, Lihong ;
Yu, Long .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2012, 696 (1-3) :43-53