Repurposing of anticancer drugs: in vitro and in vivo activities against Schistosoma mansoni.
BACKGROUND
Drug discovery for the neglected tropical disease schistosomiasis has a high priority. Anticancer drugs, especially protein kinase inhibitors, might serve as a starting point for drug discovery owing to the importance of protein kinases in helminth growth and development. Furthermore, the Schistosoma mansoni genome encodes several genes for targets of drugs marketed for human use, including several anticancer drugs.


METHODS
In this study, we screened the approved oncology drug set of the National Cancer Institute's Developmental Therapeutic Program for antischistosomal activity. Drugs were tested in vitro against the larval and adult stage of S. mansoni. IC50 values and albumin binding were determined for active compounds. Lead compounds were tested in the chronic S. mansoni mouse model.


RESULTS
Eleven of the 114 compounds tested revealed IC50 values ≤ 10 μM against both S. mansoni stages. Five of these lost activity against adult S. mansoni in the presence of serum albumin. Of 6 compounds studied in vivo, the highest activity was observed from two kinase inhibitors trametinib, and vandetanib, which reduced worm burden by 63.6 and 48.1% respectively, after a single oral dose of 400 mg/kg body weight.


CONCLUSIONS
Our study has confirmed that oncology drugs possess antischistosomal activity. There is space for further investigation, including elucidation of the mechanisms of action of schistosome-active cancer drugs, application of different treatment courses, and structure-activity relationship studies for improving drug potency.
Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, P.O. Box, CH-4002, Basel, Switzerland. noemi.cowan@unibas.ch.|University of Basel, P.O. Box, CH-4003, Basel, Switzerland. noemi.cowan@unibas.ch.
Noemi
N
Cowan
Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, P.O. Box, CH-4002, Basel, Switzerland. jennifer.keiser@unibas.ch.|University of Basel, P.O. Box, CH-4003, Basel, Switzerland. jennifer.keiser@unibas.ch.
Jennifer
J
Keiser
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D058492:Drug Repositioning; D020128:Inhibitory Concentration 50; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D012550:Schistosoma mansoni / Q000187:drug effects*; D012555:Schistosomiasis mansoni / Q000188:drug therapy; D012556:Schistosomicides / Q000494:pharmacology*
D000970:Antineoplastic Agents; D010880:Piperidines; D011728:Pyridones; D011744:Pyrimidinones; D011799:Quinazolines; D012556:Schistosomicides; C560077:trametinib; C452423:vandetanib