Open AccessATR-Chk1 signaling inhibition as a therapeutic strategy to enhance cisplatin chemosensitivity in urothelial bladder cancer
Author(s) -
Ching Chia Li,
Juan Yang,
MeiChin Lu,
Chia-Lin Lee,
Chieh Yu Peng,
Wei-Feng Hsu,
Yun Dai,
Fang Rong Chang,
Da Yong Zhang,
Wen Jeng Wu,
Yang Chang Wu
Publication year - 2015
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.6482
Subject(s) - cisplatin , bladder cancer , cancer research , medicine , chemotherapy , dna damage , cancer , pharmacology , biology , dna , genetics
DNA damage responses contribute to cisplatin resistance; however, therapeutic strategies to overcome cisplatin resistance have not yet been established. Here, we demonstrate that inhibition of ATR-Chk1 pathway with the potent inhibitor WYC0209 sensitizes bladder cancer cells to cisplatin. In the clinical microarray profile, high ATR expression is associated with poor prognosis in bladder cancer patients who receive chemotherapy. We show that pharmacological and genetic suppressing of ATR sensitized cells to cisplatin. Treatment with WYC0209 or siATR increased levels of cisplatin-DNA adducts, concomitant with decreased levels of p-glycoprotein expression. Additionally, Combinations of cisplatin and WYC0209 show synergistic activity against bladder cancer. Ultimately, WYC0209 enhanced the anti-tumor effects of cisplatin and suppressed p-glycoprotein expression in bladder cancer xenografts. These results indicate that inhibiting ATR-Chk1 activation with WYC0209 suppresses p-glycoprotein expression and increases cisplatin activity in bladder cancer. Our findings collectively suggest that ATR-Chk1 is a target for improving the efficacy of cisplatin in bladder cancer.