ATR-Chk1 signaling inhibition as a therapeutic strategy to enhance cisplatin chemosensitivity in urothelial bladder cancer
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Ching-Chia Li1,2,3,*, Juan-Cheng Yang4,5,*, Mei-Chin Lu6, Chia-Lin Lee4,5, Chieh-Yu Peng4,5, Wei-Yu Hsu4,5, Yun-Hao Dai4,5, Fang-Rong Chang7, Da-Yong Zhang8, Wen-Jeng Wu2,3,9 and Yang-Chang Wu4,5,7,10
1 Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
2 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
3 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
4 School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan
5 Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
6 Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung , Taiwan
7 Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan
8 Center of Drug Discovery ,College of Pharmacy, China Pharmaceutical University, Nanjing, China
9 Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan
10 Center of Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
* These authors have contributed equally to this work
Yang-Chang Wu, email:
Wen-Jeng Wu, email:
Keywords: bladder cancer, ATR-Chk1, natural products
Received: March 11, 2015 Accepted: November 21, 2015 Published: December 05, 2015
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.
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