Abstract
Infections with soil-transmitted helminths (STHs) are considered among the most persistent global health problems. The few available drugs have limitations including low efficacy against Trichuris trichiura infections. As a starting point toward drug repositioning, we studied a set of FDA-approved oncology drugs for activity against Trichuris muris since targets relevant to cancer therapy might have a function in helminth biology. Drugs were tested in vitro on the larval and adult stage of T. muris. Compounds active in vitro were tested in the T. muris mouse model at single oral dosages of 200–400 mg/kg. Of the 114 drugs tested in vitro, 12 showed activity against T. muris larvae (>80 % drug effect at 50 μM). Ten of these drugs were also active on the adult worm stage (>80 % drug effect at 50 μM), of which six revealed IC50 values between 1.8 and 5.0 μM. Except for tamoxifen citrate, all in vitro active drugs were protein kinase inhibitors. None of the drugs tested in vivo showed efficacy, revealing worm burden reductions of 0–24 % and worm expulsion rates of 0–7.9 %. The promising in vitro activities of protein kinases could not be confirmed in vivo. Drug discovery against STH should be strengthened including the definition of compound progression criteria. Follow-up structure-activity relationship studies with modified compounds might be considered.
References
Alvarez LI, Mottier ML, Lanusse CE (2007) Drug transfer into target helminth parasites. Trends Parasitol 23:97–104. doi:10.1016/j.pt.2007.01.003
Bethony J, Brooker S, Albonico M et al (2006) Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet 367:1521–1532. doi:10.1016/S0140-6736(06)68653-4
Cowan N, Keiser J (2015) Repurposing of anticancer drugs: in vitro and in vivo activities against Schistosoma mansoni. Parasit Vectors 8:417. doi:10.1186/s13071-015-1023-y
Dissous C, Grevelding CG (2011) Piggy-backing the concept of cancer drugs for schistosomiasis treatment: a tangible perspective? Trends Parasitol 27:59–66. doi:10.1016/j.pt.2010.09.001
European Medicines Agency (EMA) CHMP assessment report for GIOTRIF® (afatinib). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002280/WC500152394.pdf.
Hansen TVA, Friis C, Nejsum P et al (2014) Uptake of benzimidazoles by Trichuris suis in vivo in pigs. Int J Parasitol Drugs Drug Resist 4:112–117. doi:10.1016/j.ijpddr.2014.03.003
Keiser J, Utzinger J (2008) Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis. JAMA 299:1937–1948. doi:10.1001/jama.299.16.1937
Panic G, Duthaler U, Speich B, Keiser J (2014) Repurposing drugs for the treatment and control of helminth infections. Int J Parasitol Drugs Drug Resist 4:185–200. doi:10.1016/j.ijpddr.2014.07.002
Pubchem open chemistry database. Tamoxifen citrate |C32H37NO8]. [Accessed 22 Jul 2016]. https://pubchem.ncbi.nlm.nih.gov/compound/2733525#section=Top.
Schmidt C (2015) Cancer: reshaping the cancer clinic. Nature 527:S10–S11. doi:10.1038/527S10a
Speich B, Ali SM, Ame SM et al (2015) Efficacy and safety of albendazole plus ivermectin, albendazole plus mebendazole, albendazole plus oxantel pamoate, and mebendazole alone against Trichuris trichiura and concomitant soil-transmitted helminth infections: a four-arm, randomised controlled trial. Lancet Infect Dis 15:277–284. doi:10.1016/S1473-3099(14)71050-3
Tilney LG, Connelly PS, Guild GM et al (2005) Adaptation of a nematode parasite to living within the mammalian epithelium. J Exp Zoolog A Comp Exp Biol 303:927–945. doi:10.1002/jez.a.214
Wimmersberger D, Tritten L, Keiser J (2013) Development of an in vitro drug sensitivity assay for Trichuris muris first-stage larvae. Parasit Vectors 6:42. doi:10.1186/1756-3305-6-42
Acknowledgments
We are grateful for the donation of the oncology cancer drugs by the DTP/NCI. JK is grateful to the European Research Council (ERC-2013-CoG 614739-A_HERO) for financial support.
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Noemi Cowan and Alessia Raimondo contributed equally to this work.
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Cowan, N., Raimondo, A. & Keiser, J. Approved oncology drugs lack in vivo activity against Trichuris muris despite in vitro activity. Parasitol Res 115, 4443–4446 (2016). https://doi.org/10.1007/s00436-016-5225-9
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DOI: https://doi.org/10.1007/s00436-016-5225-9