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.
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.
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.
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.
British journal of cancer. 2019 Nov 01 [Epub ahead of print]
Yuki Kita, Akihiro Hamada, Ryoichi Saito, Yuki Teramoto, Ryusuke Tanaka, Keishi Takano, Kenji Nakayama, Kaoru Murakami, Keiyu Matsumoto, Shusuke Akamatsu, Toshinari Yamasaki, Takahiro Inoue, Yasuhiko Tabata, Yasushi Okuno, Osamu Ogawa, Takashi Kobayashi
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan., Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan., Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan., Department of Environmental and Health Sciences, Hokkaido Institute of Public Health, Sapporo, Japan., Department of Clinical System Onco-Informatics, Kyoto University Graduate School of Medicine, Kyoto, Japan., Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan. .