Abstract
BackgroundDrug 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.MethodsIn 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.ResultsEleven 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.ConclusionOur 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.
Highlights
Drug discovery for the neglected tropical disease schistosomiasis has a high priority
Drugs and media The cancer drug library used for schistosome in vitro assays was gratefully received in June 2014 from the Developmental Therapeutics Program (DTP)/National Cancer Institute (NCI) as 10 mM stock solutions (20 μl) in dimethyl sulfoxide (DMSO) in 96-well plates
Idarubicin hydrochloride, regorafenib, sorafenib, and temsirolimus were lethal to newly transformed schistosomula (NTS) within 24 h, everolimus and sirolimus within 48 h, and bosutinib, daunorubicin, and vandetanib within 72 h (Table 1)
Summary
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. The Schistosoma mansoni genome encodes several genes for targets of drugs marketed for human use, including several anticancer drugs. Schistosomiasis is a neglected tropical disease caused by the blood-dwelling fluke of the genus Schistosoma. The clinically relevant species are S. mansoni, S. haematobium, and S. japonicum. Praziquantel is the sole treatment against all three species. The lack of drugs in the discovery pipeline highly encourages efforts to identify an alternative treatment of schistosomiasis, in anticipation of praziquantel resistance [3, 4]. Drug repurposing is an efficient tool to find new drugs against helminthiases, reducing time and costs of drug research and development [5]
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