Systematic chemical screening identifies disulfiram as a repurposed drug that enhances sensitivity to cisplatin in bladder cancer: a summary of preclinical studies.

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.

Infection of humans and animals with Echinococcus granulosus (G1 and G3 strains) and E. ortleppi in Southern Brazil.

The Rio Grande do Sul state, in Southern Brazil, is one of the foci of human cystic echinococcosis (CE). The sheep strain (G1) of Echinococcus granulosus and Echinococcus ortleppi (also known as cattle strain G5) have been reported before to infect livestock. However, up to the present, no molecular data are available on isolates of the E. granulosus complex from humans and dogs. The present study analyzed hydatid cysts from 6 CE patients and adult worms from 12 dogs. Sequencing of the mitochondrial cox1 and 12S rRNA genes detected the E. granulosus G1 genotype from four human cases, the G3 genotype (or buffalo strain) from one human case and E. ortleppi from another human case, respectively. Ten of the twelve dogs were found infected with the G1 genotype, and one dog each harbored worms of the G3 genotype and E. ortleppi. Obvious morphological differences were recognized between the G1 and E. ortleppi adult worms from dogs in this region. The buffalo strain (G3) is for the first time reported from South America.

Removal of Mn(II) ions from aqueous neutral media by manganese-oxidizing fungus in the presence of carbon fiber.

A manganese-oxidizing fungus was isolated from a hot spring in Japan. The fungus was increasingly effective at oxidizing Mn(II) ions as the concentration of organic carbon sources in the growth medium was decreased. The fungus oxidized 50 ppm of Mn(II) ions within 160 h in a pH 7.3 medium at 25 degrees C. The presence of carbon fiber shortened the time to 80 h, and promoted steady oxidation. The oxidation products were identified by XPS and XRD to be poorly crystallized and amorphous MnO(2), both with and without the fiber. These results suggest that the fiber participates in kinetically limited oxidation. The fungus was entangled with and clung to the fibers, and the oxidized Mn species accumulated on the fungus. Similarly shaped polyethylene telephthalate fiber did not enhance the oxidation, nor was adhesion of the fungus observed. Although the mechanism is still unknown, the present work shows that removal of Mn from solution through the precipitation and accumulation of Mn-oxides on the fungus in the presence of carbon fiber is a promising improvement for water treatment.