Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Ji, Liyan, Liu, Xi, Zhang, Shuwei, Tang, Shunan, Yang, Simin, Li, Shasha, Qi, Xiaoxiao, Yu, Siwang, Lu, Linlin, Meng, Xiangbao, Liu, Zhongqiu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150343/
https://www.ncbi.nlm.nih.gov/pubmed/29072615
http://dx.doi.org/10.3390/molecules22111822
_version_ 1783356972312035328
author Ji, Liyan
Liu, Xi
Zhang, Shuwei
Tang, Shunan
Yang, Simin
Li, Shasha
Qi, Xiaoxiao
Yu, Siwang
Lu, Linlin
Meng, Xiangbao
Liu, Zhongqiu
author_facet Ji, Liyan
Liu, Xi
Zhang, Shuwei
Tang, Shunan
Yang, Simin
Li, Shasha
Qi, Xiaoxiao
Yu, Siwang
Lu, Linlin
Meng, Xiangbao
Liu, Zhongqiu
author_sort Ji, Liyan
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6150343
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-61503432018-11-13 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 Ji, Liyan Liu, Xi Zhang, Shuwei Tang, Shunan Yang, Simin Li, Shasha Qi, Xiaoxiao Yu, Siwang Lu, Linlin Meng, Xiangbao Liu, Zhongqiu Molecules Article 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. MDPI 2017-10-26 /pmc/articles/PMC6150343/ /pubmed/29072615 http://dx.doi.org/10.3390/molecules22111822 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ji, Liyan
Liu, Xi
Zhang, Shuwei
Tang, Shunan
Yang, Simin
Li, Shasha
Qi, Xiaoxiao
Yu, Siwang
Lu, Linlin
Meng, Xiangbao
Liu, Zhongqiu
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort novel triazolonaphthalimide derivative lss-11 synergizes the anti-proliferative effect of paclitaxel via stat3-dependent mdr1 and mrp1 downregulation in chemoresistant lung cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150343/
https://www.ncbi.nlm.nih.gov/pubmed/29072615
http://dx.doi.org/10.3390/molecules22111822
work_keys_str_mv AT jiliyan thenoveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT liuxi thenoveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT zhangshuwei thenoveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT tangshunan thenoveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT yangsimin thenoveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT lishasha thenoveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT qixiaoxiao thenoveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT yusiwang thenoveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT lulinlin thenoveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT mengxiangbao thenoveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT liuzhongqiu thenoveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT jiliyan noveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT liuxi noveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT zhangshuwei noveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT tangshunan noveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT yangsimin noveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT lishasha noveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT qixiaoxiao noveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT yusiwang noveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT lulinlin noveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT mengxiangbao noveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells
AT liuzhongqiu noveltriazolonaphthalimidederivativelss11synergizestheantiproliferativeeffectofpaclitaxelviastat3dependentmdr1andmrp1downregulationinchemoresistantlungcancercells