Abstract
BackgroundSince 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.MethodsWe 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.ResultsDisulfiram (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.ConclusionsThe 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.
Highlights
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
CP compound, GC gemcitabine + cisplatin Data for CP alone indicate the ratio of OD450 for CP alone to OD450 for vehicle Data for GC (IC20) + CP indicate the ratio of OD450 for GC + CP to OD450 for GC
NAC partly reversed the inhibition of colony-forming ability in cells treated with GC + DSF (Fig. 2e). These results indicate that co-administration of DSF enhances apoptosis induced by GC, which is partly attributed to reactive oxygen species (ROS) accumulation
Summary
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. 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. Despite the current trends for the increasing use of immune checkpoint inhibitors, the response rates are far from sufficient.[3] platinum-based cytotoxic chemotherapy is still the treatment of choice for advanced bladder cancer in many contexts. The initial response rate for gemcitabine (GEM) and cisplatin (CDDP), one of the standard systemic chemotherapies for advanced bladder cancer, is ~50–70% due to intrinsic resistance.[4] Even in responders, many tumours develop acquired resistance and regrow after a short time. The development of a novel method to enhance the efficacy of cytotoxic chemotherapy for advanced bladder cancer without compromising tolerability is critical
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