title: ATR-Chk1 signaling inhibition as a therapeutic strategy to enhance cisplatin chemosensitivity in urothelial bladder cancer.
abstract: 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.
authors.affiliation: Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.|Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ching-Chia
authors.initials: CC
authors.lastname: Li
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.|Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Juan-Cheng
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung , Taiwan.
authors.forename: Mei-Chin
authors.initials: MC
authors.lastname: Lu
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.|Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Lee
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.|Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chieh-Yu
authors.initials: CY
authors.lastname: Peng
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.|Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Hsu
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.|Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Yun-Hao
authors.initials: YH
authors.lastname: Dai
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Fang-Rong
authors.initials: FR
authors.lastname: Chang
authors.affiliation: Center of Drug Discovery ,College of Pharmacy, China Pharmaceutical University, Nanjing, China.
authors.forename: Da-Yong
authors.initials: DY
authors.lastname: Zhang
authors.affiliation: Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan.
authors.forename: Wen-Jeng
authors.initials: WJ
authors.lastname: Wu
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.|Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center of Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Yang-Chang
authors.initials: YC
authors.lastname: Wu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D018736:DNA Adducts; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D060787:Neoplasm Grading; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D018736:DNA Adducts; D012333:RNA, Messenger; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D002945:Cisplatin
keywords: ATR-Chk1; bladder cancer; natural products