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Use of kinase inhibitors against schistosomes to improve and broaden praziquantel efficacy

Published online by Cambridge University Press:  03 August 2020

Sujeevi S. K. Nawaratna ,
Donald P. McManus Open the ORCID record for Donald P. McManus [Opens in a new window] ,
Robin B. Gasser ,
Paul J. Brindley ,
Glen M. Boyle ,
Vanessa Rivera ,
Shiwanthi L. Ranasinghe ,
Malcolm K. Jones Open the ORCID record for Malcolm K. Jones [Opens in a new window] ,
Hong You Open the ORCID record for Hong You [Opens in a new window]  and
Geoffrey N. Gobert
Sujeevi S. K. Nawaratna
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia School of Medicine, Griffith University, Gold Coast, Australia
Donald P. McManus
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia
Robin B. Gasser
Affiliation:
Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, Australia
Paul J. Brindley
Affiliation:
School of Medicine and Health Sciences, George Washington University, WashingtonDC, USA
Glen M. Boyle
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia
Vanessa Rivera
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia School of Medicine, Deakin University, Geelong, Australia
Shiwanthi L. Ranasinghe
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia
Malcolm K. Jones
Affiliation:
School of Veterinary Science, The University of Queensland, Gatton, Australia
Hong You*
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia
Geoffrey N. Gobert*
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia School of Biological Sciences, Queen's University Belfast, Belfast, UK
*
Author for correspondence: Geoffrey N. Gobert, E-mail: G.Gobert@qub.ac.uk; Hong You, E-mail: Hong.You@qimrberghofer.edu.au
Author for correspondence: Geoffrey N. Gobert, E-mail: G.Gobert@qub.ac.uk; Hong You, E-mail: Hong.You@qimrberghofer.edu.au
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Abstract

Praziquantel (PZQ) is the drug of choice for schistosomiasis. The potential drug resistance necessitates the search for adjunct or alternative therapies to PZQ. Previous functional genomics has shown that RNAi inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) gene in Schistosoma adult worms significantly improved the effectiveness of PZQ. Here we tested the in vitro efficacy of 15 selective and non-selective CaMK inhibitors against Schistosoma mansoni and showed that PZQ efficacy was improved against refractory juvenile parasites when combined with these CaMK inhibitors. By measuring CaMK activity and the mobility of adult S. mansoni, we identified two non-selective CaMK inhibitors, Staurosporine (STSP) and 1Naphthyl PP1 (1NAPP1), as promising candidates for further study. The impact of STSP and 1NAPP1 was investigated in mice infected with S. mansoni in the presence or absence of a sub-lethal dose of PZQ against 2- and 7-day-old schistosomula and adults. Treatment with STSP/PZQ induced a significant (47–68%) liver egg burden reduction compared with mice treated with PZQ alone. The findings indicate that the combination of STSP and PZQ dosages significantly improved anti-schistosomal activity compared to PZQ alone, demonstrating the potential of selective and non-selective CaMK/kinase inhibitors as a combination therapy with PZQ in treating schistosomiasis.

Keywords

1Naphthyl PP1adjunct therapyCaMKCaMKIIkinase inhibitorspraziquantelSchistosoma mansonischistosomulaStaurosporineSTSP
Type
Research Article
Information
Parasitology , Volume 147 , Issue 13 , November 2020 , pp. 1488 - 1498
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Copyright
Copyright © The Author(s) 2020. Published by Cambridge University Press

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Footnotes

*

These authors contributed equally.

References

Abe, S, Kubota, T, Otani, Y, Furukawa, T, Watanabe, M, Kumai, K, Akiyama, T, Akinaga, S and Kitajima, M (2001) UCN-01 (7-hydoxystaurosporine) inhibits in vivo growth of human cancer cells through selective perturbation of G1 phase checkpoint machinery. Japanese Journal of Cancer Research 92, 537–545.CrossRefGoogle ScholarPubMed
Abla, N, Keiser, J, Vargas, M, Reimers, N, Haas, H and Spangenberg, T (2017) Evaluation of the pharmacokinetic-pharmacodynamic relationship of praziquantel in the Schistosoma mansoni mouse model. PLoS Neglected Tropical Diseases 11, e0005942.CrossRefGoogle ScholarPubMed
Allison, DC and Ridolpho, P (1980) Use of a trypan blue assay to measure the deoxyribonucleic acid content and radioactive labeling of viable cells. Journal of Histochemistry and Cytochemistry 28, 700–703.CrossRefGoogle ScholarPubMed
Andrews, P, Thomas, H, Pohlke, R and Seubert, J (1983) Praziquantel. Medicinal Research Reviews 3, 147–200.CrossRefGoogle ScholarPubMed
Araujo-Montoya, BO, Rofatto, HK, Tararam, CA, Farias, LP, Oliveira, KC, Verjovski-Almeida, S, Wilson, RA and Leite, LC (2011) Schistosoma mansoni: molecular characterization of Alkaline Phosphatase and expression patterns across life cycle stages. Experimental Parasitology 129, 284–291.CrossRefGoogle ScholarPubMed
Basch, PF (1981) Cultivation of Schistosoma mansoni in vitro. I. Establishment of cultures from cercariae and development until pairing. Journal of Parasitology 67, 179–185.Google ScholarPubMed
Boyle, GM, D'Souza, MM, Pierce, CJ, Adams, RA, Cantor, AS, Johns, JP, Maslovskaya, L, Gordon, VA, Reddell, PW and Parsons, PG (2014) Intra-lesional injection of the novel PKC activator EBC-46 rapidly ablates tumors in mouse models. PLoS ONE 9, e108887.CrossRefGoogle ScholarPubMed
Chai, JY (2013) Praziquantel treatment in trematode and cestode infections: an update. Infection & Chemotherapy 45, 32–43.CrossRefGoogle ScholarPubMed
Chuah, C, Jones, MK, McManus, DP, Nawaratna, SK, Burke, ML, Owen, HC, Ramm, GA and Gobert, GN (2016) Characterising granuloma regression and liver recovery in a murine model of Schistosomiasis japonica. International Journal for Parasitology 46, 239–252.CrossRefGoogle Scholar
Cioli, D and Pica-Mattoccia, L (2003) Praziquantel. Parasitology Research 90(Supp 1), S3–S9.CrossRefGoogle ScholarPubMed
Day, TA, Bennett, JL and Pax, RA (1992) Praziquantel: the enigmatic antiparasitic. Parasitology Today 8, 342–344.CrossRefGoogle ScholarPubMed
de Moraes, J, Nascimento, C, Yamaguchi, LF, Kato, MJ and Nakano, E (2012) Schistosoma mansoni: in vitro schistosomicidal activity and tegumental alterations induced by piplartine on schistosomula. Experimental Parasitology 132, 222–227.CrossRefGoogle ScholarPubMed
Doenhoff, MJ, Cioli, D and Utzinger, J (2008) Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Current Opinion in Infectious Diseases 21, 659–667.CrossRefGoogle ScholarPubMed
Eder, JP Jr, Garcia-Carbonero, R, Clark, JW, Supko, JG, Puchalski, TA, Ryan, DP, Deluca, P, Wozniak, A, Campbell, A, Rothermel, J and LoRusso, P (2004) A phase I trial of daily oral 4′-N-benzoyl-staurosporine in combination with protracted continuous infusion 5-fluorouracil in patients with advanced solid malignancies. Investigational New Drugs 22, 139–150.CrossRefGoogle ScholarPubMed
Gobert, GN, McManus, DP, Nawaratna, S, Moertel, L, Mulvenna, J and Jones, MK (2009) Tissue specific profiling of females of Schistosoma japonicum by integrated laser microdissection microscopy and microarray analysis. PLoS Neglected Tropical Diseases 3, e469.CrossRefGoogle ScholarPubMed
Greenberg, RM (2005) Ca2+ signalling, voltage-gated Ca2+ channels and praziquantel in flatworm neuromusculature. Parasitology 131(Suppl), S97–S108.CrossRefGoogle ScholarPubMed
Hill, DL, Tillery, KF, Rose, LM and Posey, CF (1994) Disposition in mice of 7-hydroxystaurosporine, a protein kinase inhibitor with antitumor activity. Cancer Chemotherapy and Pharmacology 35, 89–92.CrossRefGoogle ScholarPubMed
Hoffmann, KF, Johnston, DA and Dunne, DW (2002) Identification of Schistosoma mansoni gender-associated gene transcripts by cDNA microarray profiling. Genome Biology 3, 0041.1–0041.12.Google ScholarPubMed
Hotez, PJ and Fenwick, A (2009) Schistosomiasis in Africa: an emerging tragedy in our new global health decade. PLoS Neglected Tropical Diseases 3, e485.CrossRefGoogle ScholarPubMed
Jones, MK, McManus, DP, Sivadorai, P, Glanfield, A, Moertel, L, Belli, SI and Gobert, GN (2007) Tracking the fate of iron in early development of human blood flukes. International Journal of Biochemistry & Cell Biology 39, 1646–1658.CrossRefGoogle ScholarPubMed
Lo, NC, Addiss, DG, Hotez, PJ, King, CH, Stothard, JR, Evans, DS, Colley, DG, Lin, W, Coulibaly, JT, Bustinduy, AL, Raso, G, Bendavid, E, Bogoch, II, Fenwick, A, Savioli, L, Molyneux, D, Utzinger, J and Andrews, JR (2017) A call to strengthen the global strategy against schistosomiasis and soil-transmitted helminthiasis: the time is now. The Lancet. Infectious Diseases 17, e64–e69.CrossRefGoogle Scholar
Marxer, M, Ingram, K and Keiser, J (2012) Development of an in vitro drug screening assay using Schistosoma haematobium schistosomula. Parasites & Vectors 5, 165.CrossRefGoogle Scholar
McManus, DP, Dunne, DW, Sacko, M, Utzinger, J, Vennervald, BJ and Zhou, XN (2018) Schistosomiasis. Nature Reviews Disease Primers 4, 13.CrossRefGoogle ScholarPubMed
Milligan, JN and Jolly, ER (2011) Cercarial transformation and in vitro cultivation of Schistosoma mansoni schistosomules. Journal of Visualized Experiments 54, e3191.Google Scholar
Mizukami, J, Sato, T, Camps, M, Ji, H, Rueckle, T, Swinnen, D, Tsuboi, R, Takeda, K and Ichijo, H (2014) ASK1 Promotes the contact hypersensitivity response through IL-17 production. Scientific Reports 4, 4714.CrossRefGoogle ScholarPubMed
Moertel, L, Gobert, GN and McManus, DP (2008) Comparative real-time PCR and enzyme analysis of selected gender-associated molecules in Schistosoma japonicum. Parasitology 135, 575–583.CrossRefGoogle ScholarPubMed
Monnerat, C, Henriksson, R, Le Chevalier, T, Novello, S, Berthaud, P, Faivre, S and Raymond, E (2004) Phase I study of PKC412 (N-benzoyl-staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer. Annals of Oncology 15, 316–323.CrossRefGoogle Scholar
Nawaratna, SSK, You, H, Jones, MK, McManus, DP and Gobert, GN (2018) Calcium and Ca(2+)/calmodulin-dependent kinase II as targets for helminth parasite control. Biochemical Society Transactions. doi:10.1042/BST20180480.CrossRefGoogle Scholar
Park, BS, Abdel-Azeem, AZ, Al-Sanea, MM, Yoo, KH, Tae, JS and Lee, SH (2013) Staurosporine analogues from microbial and synthetic sources and their biological activities. Current Medicinal Chemistry 20, 3872–3902.CrossRefGoogle ScholarPubMed
Pica-Mattoccia, L and Cioli, D (2004) Sex- and stage-related sensitivity of Schistosoma mansoni to in vivo and in vitro praziquantel treatment. International Journal for Parasitology 34, 527–533.CrossRefGoogle ScholarPubMed
Pica-Mattoccia, L, Doenhoff, MJ, Valle, C, Basso, A, Troiani, AR, Liberti, P, Festucci, A, Guidi, A and Cioli, D (2009) Genetic analysis of decreased praziquantel sensitivity in a laboratory strain of Schistosoma mansoni. Acta Tropica 111, 82–85.CrossRefGoogle Scholar
Pinto, JG, Soares, CP and Mittmann, J (2011) Assessment of Leishmania major and Leishmania braziliensis promastigote viability after photodynamic treatment with aluminum phthalocyanine tetrasulfonate (AlPcS4). Journal of Venomous Animals and Toxins including Tropical Diseases 17, 300–307.Google Scholar
Robichaux, MA, Chenaux, G, Ho, HY, Soskis, MJ, Dravis, C, Kwan, KY, Sestan, N, Greenberg, ME, Henkemeyer, M and Cowan, CW (2014) Ephb receptor forward signaling regulates area-specific reciprocal thalamic and cortical axon pathfinding. Proceedings of the National Academy of Sciences of the USA 111, 2188–2193.CrossRefGoogle ScholarPubMed
Schwarz, R, Kaspar, A, Seelig, J and Kunnecke, B (2002) Gastrointestinal transit times in mice and humans measured with 27Al and 19F nuclear magnetic resonance. Magnetic Resonance in Medicine 48, 255–261.CrossRefGoogle ScholarPubMed
Serfilippi, LM, Pallman, DR and Russell, B (2003) Serum clinical chemistry and hematology reference values in outbred stocks of albino mice from three commonly used vendors and two inbred strains of albino mice. Contemporary Topics in Laboratory Animal Science 42, 46–52.Google ScholarPubMed
Smout, MJ, Kotze, AC, McCarthy, JS and Loukas, A (2010) A novel high throughput assay for anthelmintic drug screening and resistance diagnosis by real-time monitoring of parasite motility. PLoS Neglected Tropical Diseases 4, e885.CrossRefGoogle ScholarPubMed
Soskis, MJ, Ho, HY, Bloodgood, BL, Robichaux, MA, Malik, AN, Ataman, B, Rubin, AA, Zieg, J, Zhang, C, Shokat, KM, Sharma, N, Cowan, CW and Greenberg, ME (2012) A chemical genetic approach reveals distinct EphB signaling mechanisms during brain development. Nature Neuroscience 15, 1645–1654.CrossRefGoogle ScholarPubMed
Tekwu, EM, Anyan, WK, Boamah, D, Baffour-Awuah, KO, Keyetat Tekwu, S, Penlap Beng, V, Nyarko, AK and Bosompem, KM (2016) Mechanically produced schistosomula as a higher-throughput tools for phenotypic pre-screening in drug sensitivity assays: current research and future trends. Biomarker Research 4, 21.CrossRefGoogle ScholarPubMed
Tran, MH, Freitas, TC, Cooper, L, Gaze, S, Gatton, ML, Jones, MK, Lovas, E, Pearce, EJ and Loukas, A (2010) Suppression of mRNAs encoding tegument tetraspanins from Schistosoma mansoni results in impaired tegument turnover. PLoS Pathogens 6, e1000840.CrossRefGoogle ScholarPubMed
Xiao, SH, Keiser, J, Chen, MG, Tanner, M and Utzinger, J (2010) Research and development of antischistosomal drugs in the People's Republic of China a 60-year review. Advances in Parasitology 73, 231–295.CrossRefGoogle ScholarPubMed
Xiao, SH, Sun, J and Chen, MG (2018) Pharmacological and immunological effects of praziquantel against Schistosoma japonicum: a scoping review of experimental studies. Infectious Diseases of Poverty 7, 9.CrossRefGoogle ScholarPubMed
You, H, Zhang, W, Moertel, L, McManus, DP and Gobert, GN (2009) Transcriptional profiles of adult male and female Schistosoma japonicum in response to insulin reveal increased expression of genes involved in growth and development. International Journal for Parasitology 39, 1551–1559.CrossRefGoogle ScholarPubMed
You, H, Zhang, W, Jones, MK, Gobert, GN, Mulvenna, J, Rees, G, Spanevello, M, Blair, D, Duke, M, Brehm, K and McManus, DP (2010) Cloning and characterisation of Schistosoma japonicum insulin receptors. PLoS ONE 5, e9868.CrossRefGoogle ScholarPubMed
You, H, McManus, DP, Hu, W, Smout, MJ, Brindley, PJ and Gobert, GN (2013) Transcriptional responses of in vivo praziquantel exposure in schistosomes identifies a functional role for calcium signalling pathway member CamKII. PLoS Pathogens 9, e1003254.CrossRefGoogle ScholarPubMed
You, H, McManus, DP and Gobert, GN (2015) Current and prospective chemotherapy options for schistosomiasis. Expert Opinion on Orphan Drugs 3, 195–205.CrossRefGoogle Scholar
Zhang, W, Li, J, Duke, M, Jones, MK, Kuang, L, Zhang, J, Blair, D, Li, Y and McManus, DP (2011) Inconsistent protective efficacy and marked polymorphism limits the value of Schistosoma japonicum tetraspanin-2 as a vaccine target. PLoS Neglected Tropical Diseases 5, e1166.CrossRefGoogle ScholarPubMed
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