Systematic chemical screening identifies disulfiram as a repurposed drug that enhances sensitivity to cisplatin in bladder cancer: a summary of preclinical studies
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Published:2019-11-01
Issue:12
Volume:121
Page:1027-1038
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ISSN:0007-0920
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Container-title:British Journal of Cancer
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language:en
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Short-container-title:Br J Cancer
Author:
Kita Yuki,Hamada Akihiro,Saito Ryoichi,Teramoto Yuki,Tanaka Ryusuke,Takano Keishi,Nakayama Kenji,Murakami Kaoru,Matsumoto Keiyu,Akamatsu Shusuke,Yamasaki Toshinari,Inoue Takahiro,Tabata Yasuhiko,Okuno Yasushi,Ogawa Osamu,Kobayashi Takashi
Abstract
Abstract
Background
Since the standard gemcitabine and cisplatin (GC) chemotherapy for advanced bladder cancer yields limited therapeutic effect due to chemoresistance, it is a clinical challenge to enhance sensitivity to GC.
Methods
We performed high-throughput screening by using a library of known chemicals and repositionable drugs. A total of 2098 compounds were administered alone or with GC to human bladder cancer cells, and chemicals that enhanced GC effects were screened.
Results
Disulfiram (DSF), an anti-alcoholism drug, was identified as a candidate showing synergistic effects with cisplatin but not with gemcitabine in multiple cell lines. Co-administration of DSF with GC affected cellular localisation of a cisplatin efflux transporter ATP7A, increased DNA–platinum adducts and promoted apoptosis. Micellar DSF nanoparticles (DSF-NP) that stabilised DSF in vivo, enhanced the inhibitory effect of cisplatin in patient-derived and cell-based xenograft models without severe adverse effects. A drug susceptibility evaluation system by using cancer tissue-originated spheroid culture showed promise in identifying cases who would benefit from DSF with cisplatin.
Conclusions
The present study highlighted the advantage of drug repurposing to enhance the efficacy of anticancer chemotherapy. Repurposing of DSF to a chemotherapy sensitiser may provide additional efficacy with less expense by using an available drug with a well-characterised safety profile.
Funder
MEXT | Japan Society for the Promotion of Science
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
Reference52 articles.
1. The Global Cancer Observatory: International Agency for Research on Cancer, World Health Organization; 2018. [Available from:
https://gco.iarc.fr/
]. 2. Stenzl, A., Cowan, N. C., De Santis, M., Kuczyk, M. A., Merseburger, A. S., Ribal, M. J. et al. Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Eur. Urol. 59, 1009–1018 (2011). 3. Bellmunt, J., de Wit, R., Vaughn, D. J., Fradet, Y., Lee, J. L., Fong, L. et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. New Engl. J. Med. 376, 1015–1026 (2017). 4. von der Maase, H., Sengelov, L., Roberts, J. T., Ricci, S., Dogliotti, L., Oliver, T. et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J. Clin. Oncol. 23, 4602–4608 (2005). 5. Corbett, A., Pickett, J., Burns, A., Corcoran, J., Dunnett, S. B., Edison, P. et al. Drug repositioning for Alzheimer's disease. Nat. Rev. Drug Discov. 11, 833–846 (2012).
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