The Role of Alternative Toxicological Trials in Drug Discovery Programs.
The Case of Caenorhabditis elegans and Other Methods

Gabriela      Göethel; Lucas   Volnei   Augsten; Gustavo   Machado   das Neves; Itamar   Luís   Gonçalves; João   Pedro Silveira   de Souza; Solange   Cristina   Garcia; Vera   Lucia   Eifler-Lima
doi:10.2174/0929867329666220329190825
Abstract

The discovery of a new drug requires over a billion dollars and around 12 years of research efforts, and toxicity is the leading reason for the failure to approve candidate drugs. Many alternative methods have been validated to detect toxicity as early as possible to diminish the waste of resources and efforts in medicinal chemistry research, and in vivo alternative methods are especially valuable for the amount of information they can provide at little cost and in a short time. In this work, we present a review of the literature published between the years 2000 and 2021 on in vivo alternative methods of toxicity screening employed in medicinal chemistry, which we believe will be useful because, in addition to shortening the research time, these studies provide much additional information aside from the toxicity of drug candidate compounds. These in vivo models include zebrafish, Artemia salina, Galleria mellonella, Drosophila melanogaster, planarians, and Caenorhabditis elegans. The most published ones in the last decade were zebrafish, D. melanogaster, and C. elegans due to their reliability, ease, and cost-effectiveness in implementation and flexibility. Special attention is given to C. elegans because of its rising popularity, a wide range of uses, including toxicity screening, and active effects measurement, from antioxidant effects to anthelmintic and antimicrobial activities, and its fast and reliable results. Over time, C. elegans also became a viable high-throughput (HTS) automated drug screening option. Additionally, this manuscript lists briefly the other screening methods used for the initial toxicological analyses and the role of alternative in vivo methods in these scenarios, classifying them as in silico, in vitro and alternative in vivo models that have been receiving a growing increase in interest in recent years.
Keywords: Medicinal chemistry, drug development, toxicity screening, alternative models, toxicology trials, drug discovery, Caenorhabditis elegans.
« Previous Next »
[1] 
Buckle, D.R.; Erhardt, P.W.; Ganellin, C.R.; Kobayashi, T.; Perun, T.J.; Proudfoot, J.; Senn-Bilfinger, J. Glossary of terms used in medicinal chemistry Part II (IUPAC recommendations 2013). Annu. Rep. Med. Chem.,  2013, 48(8), 387-418.
[http://dx.doi.org/10.1016/B978-0-12-417150-3.00024-7] 
[2] 
McKim, J.M., Jr. Building a tiered approach to in vitro predictive toxicity screening: A focus on assays with in vivo relevance. Comb. Chem. High Throughput Screen.,  2010, 13(2), 188-206.
[http://dx.doi.org/10.2174/138620710790596736] [PMID: 20053163] 
[3] 
Hevener, K.E. Computational toxicology methods in chemical library design and high-throughput screening hit validation. Methods Mol. Biol.,  2018, 1800, 275-285.
[http://dx.doi.org/10.1007/978-1-4939-7899-1_13] [PMID: 29934898] 
[4] 
Jaroch, K.; Jaroch, A.; Bojko, B. Cell cultures in drug discovery and development: The need of reliable in vitro in vivo extrapolation for pharmacodynamics and pharmacokinetics assessment. J. Pharm. Biomed. Anal.,  2018, 147, 297-312.
[http://dx.doi.org/10.1016/j.jpba.2017.07.023] [PMID: 28811111] 
[5] 
Hubrecht, R.C.; Carter, E. The 3Rs and humane experimental technique: Implementing change. Animals (Basel),  2019, 9(10), 754.
[http://dx.doi.org/10.3390/ani9100754] [PMID: 31575048] 
[6] 
Freires, I.A.; Sardi, J.C.; de Castro, R.D.; Rosalen, P.L. Alternative animal and non-animal models for drug discovery and development: Bonus or burden? Pharm. Res.,  2017, 34(4), 681-686.
[http://dx.doi.org/10.1007/s11095-016-2069-z] [PMID: 27858217] 
[7] 
Marvadi, S.K.; Krishna, V.S.; Surineni, G.; Srilakshmi Reshma, R.; Sridhar, B.; Sriram, D.; Kantevari, S. Synthesis, in vitro, and in vivo (Zebra fish) antitubercular activity of 7,8-dihydroquinolin-5(6H)-ylidenehydrazinecarbothioa- mides. Bioorg. Chem.,  2020, 96, 103626.
[http://dx.doi.org/10.1016/j.bioorg.2020.103626] [PMID: 32007719] 
[8] 
Kay, S.; Edwards, J.; Brown, J.; Dixon, R. Galleria mellonella infection model identifies both high and low lethality of Clostridium perfringens toxigenic strains and their response to antimicrobials. Front. Microbiol.,  2019, 10, 1281.
[http://dx.doi.org/10.3389/fmicb.2019.01281] [PMID: 31333591] 
[9] 
Pandey, U.B.; Nichols, C.D. Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol. Rev.,  2011, 63(2), 411-436.
[http://dx.doi.org/10.1124/pr.110.003293] [PMID: 21415126] 
[10] 
Kimura, H.; Sakai, Y.; Fujii, T. Organ/body-on-a-chip based on microfluidic technology for drug discovery. Drug Metab. Pharmacokinet.,  2018, 33(1), 43-48.
[http://dx.doi.org/10.1016/j.dmpk.2017.11.003] [PMID: 29175062] 
[11] 
Hunt, P.R. The C. elegans model in toxicity testing. J. Appl. Toxicol.,  2017, 37(1), 50-59.
[http://dx.doi.org/10.1002/jat.3357] [PMID: 27443595] 
[12] 
Torres, M.; de Cock, H.; Celis Ramírez, A.M. In vitro or in vivo models, the next frontier for unraveling interactions between malassezia spp. and hosts. How much do we know? J. Fungi (Basel),  2020, 6(3), 1-16.
[http://dx.doi.org/10.3390/jof6030155] [PMID: 32872112] 
[13] 
Gois, A.M.; Mendonça, D.M.F.; Freire, M.A.M.; Santos, J.R. In vitro and in vivo models of amyotrophic lateral sclerosis: An updated overview. Brain Res. Bull.,  2020, 159, 32-43.
[http://dx.doi.org/10.1016/j.brainresbull.2020.03.012] [PMID: 32247802] 
[14] 
Giunti, S.; Andersen, N.; Rayes, D.; De Rosa, M.J. Drug discovery: Insights from the invertebrate Caenorhabditis elegans. Pharmacol. Res. Perspect.,  2021, 9(2), e00721.
[http://dx.doi.org/10.1002/prp2.721] [PMID: 33641258] 
[15] 
Artal-Sanz, M.; de Jong, L.; Tavernarakis, N. Caenorhabditis elegans: A versatile platform for drug discovery. Biotechnol. J.,  2006, 1(12), 1405-1418.
[http://dx.doi.org/10.1002/biot.200600176] [PMID: 17109493] 
[16] 
Bulterijs, S.; Braeckman, B.P. Phenotypic screening in C. elegans as a tool for the discovery of new geroprotective drugs. Pharmaceuticals (Basel),  2020, 13(8), 1-35.
[http://dx.doi.org/10.3390/ph13080164] [PMID: 32722365] 
[17] 
Schaduangrat, N.; Lampa, S.; Simeon, S.; Gleeson, M.P.; Spjuth, O.; Nantasenamat, C. Towards reproducible computational drug discovery. J. Cheminform.,  2020, 12(1), 9.
[http://dx.doi.org/10.1186/s13321-020-0408-x] [PMID: 33430992] 
[18] 
Leelananda, S.P.; Lindert, S. Computational methods in drug discovery. Beilstein J. Org. Chem.,  2016, 12(1), 2694-2718.
[http://dx.doi.org/10.3762/bjoc.12.267] [PMID: 28144341] 
[19] 
Macalino, S.J.Y.; Gosu, V.; Hong, S.; Choi, S. Role of computer-aided drug design in modern drug discovery. Arch. Pharm. Res.,  2015, 38(9), 1686-1701.
[http://dx.doi.org/10.1007/s12272-015-0640-5] [PMID: 26208641] 
[20] 
Sliwoski, G.; Kothiwale, S.; Meiler, J.; Lowe, E.W., Jr. Computational methods in drug discovery. Pharmacol. Rev.,  2013, 66(1), 334-395.
[http://dx.doi.org/10.1124/pr.112.007336] [PMID: 24381236] 
[21] 
Ou-Yang, S.S.; Lu, J.Y.; Kong, X.Q.; Liang, Z.J.; Luo, C.; Jiang, H. Computational drug discovery. Acta Pharmacol. Sin.,  2012, 33(9), 1131-1140.
[http://dx.doi.org/10.1038/aps.2012.109] [PMID: 22922346] 
[22] 
Karolak, A.; Markov, D.A.; McCawley, L.J.; Rejniak, K.A. Towards personalized computational oncology: From spatial models of tumour spheroids, to organoids, to tissues. J. R. Soc. Interface,  2018, 15(138), 20170703.
[http://dx.doi.org/10.1098/rsif.2017.0703] [PMID: 29367239] 
[23] 
Kather, J.N.; Charoentong, P.; Suarez-Carmona, M.; Herpel, E.; Klupp, F.; Ulrich, A.; Schneider, M.; Zoernig, I.; Luedde, T.; Jaeger, D.; Poleszczuk, J.; Halama, N. High-throughput screening of combinatorial immunotherapies with patient-specific in silico models of metastatic colorectal cancer. Cancer Res.,  2018, 78(17), 5155-5163.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-1126] [PMID: 29967263] 
[24] 
Raies, A.B.; Bajic, V.B. In silico toxicology: Computational methods for the prediction of chemical toxicity. Wiley Interdiscip. Rev. Comput. Mol. Sci.,  2016, 6(2), 147-172.
[http://dx.doi.org/10.1002/wcms.1240] [PMID: 27066112] 
[25] 
Ung, M.H.; Varn, F.S.; Cheng, C. In silico frameworks for systematic pre-clinical screening of potential anti-leukemia therapeutics. Expert Opin. Drug Discov.,  2016, 11(12), 1213-1222.
[http://dx.doi.org/10.1080/17460441.2016.1243524] [PMID: 27689915] 
[26] 
Soo, J.Y.C.; Jansen, J.; Masereeuw, R.; Little, M.H. Advances in predictive in vitro models of drug-induced nephrotoxicity. Nat. Rev. Nephrol.,  2018, 14(6), 378-393.
[http://dx.doi.org/10.1038/s41581-018-0003-9] [PMID: 29626199] 
[27] 
Mittal, R.; Woo, F.W.; Castro, C.S.; Cohen, M.A.; Karanxha, J.; Mittal, J.; Chhibber, T.; Jhaveri, V.M. Organ-on-chip models: Implications in drug discovery and clinical applications. J. Cell. Physiol.,  2019, 234(6), 8352-8380.
[http://dx.doi.org/10.1002/jcp.27729] [PMID: 30443904] 
[28] 
Ma, C.; Peng, Y.; Li, H.; Chen, W. Organ-on-a-chip: A new paradigm for drug development. Trends Pharmacol. Sci.,  2021, 42(2), 119-133.
[http://dx.doi.org/10.1016/j.tips.2020.11.009] [PMID: 33341248] 
[29] 
 Abe F.R.; Accoroni K.A.G.; Gravato C.; de Oliveira D.P. Early Life Stage Assays in Zebrafish. Methods Mol. Biol., 2021, 2240, 77-92
[30] 
Lee, K.Y.; Jang, G.H.; Byun, C.H.; Jeun, M.; Searson, P.C.; Lee, K.H. Zebrafish models for functional and toxicological screening of nanoscale drug delivery systems: Promoting preclinical applications. Biosci. Rep.,  2017, 37(3), BSR20170199.
[http://dx.doi.org/10.1042/BSR20170199] [PMID: 28515222] 
[31] 
Zanandrea, R.; Bonan, C.D.; Campos, M.M. Zebrafish as a model for inflammation and drug discovery. Drug Discov. Today,  2020, 25(12), 2201-2211.
[http://dx.doi.org/10.1016/j.drudis.2020.09.036] [PMID: 33035664] 
[32] 
Konantz, M.; Schürch, C.; Hanns, P.; Müller, J.S.; Sauteur, L.; Lengerke, C. Modeling hematopoietic disorders in zebrafish. Dis. Model. Mech.,  2019, 12(9), 12.
[http://dx.doi.org/10.1242/dmm.040360] [PMID: 31519693] 
[33] 
Han, Y.; Chen, A.; Umansky, K.B.; Oonk, K.A.; Choi, W.Y.; Dickson, A.L.; Ou, J.; Cigliola, V.; Yifa, O.; Cao, J.; Tornini, V.A.; Cox, B.D.; Tzahor, E.; Poss, K.D.; Vitamin, D. Vitamin D stimulates cardiomyocyte proliferation and controls organ size and regeneration in zebrafish. Dev. Cell,  2019, 48(6), 853-863.e5.
[http://dx.doi.org/10.1016/j.devcel.2019.01.001] [PMID: 30713073] 
[34] 
Xu, Y.; Jing, X.; Zhai, W.; Li, X. The enantioselective enrichment, metabolism, and toxicity of fenoxaprop-ethyl and its metabolites in zebrafish. Chirality,  2020, 32(7), 990-997.
[http://dx.doi.org/10.1002/chir.23222] [PMID: 32196770] 
[35] 
Kasture, A.S.; Hummel, T.; Sucic, S.; Freissmuth, M. Big lessons from tiny flies: Drosophila melanogaster as a model to explore dysfunction of dopaminergic and serotonergic neurotransmitter systems. Int. J. Mol. Sci.,  2018, 19(6), 1788.
[http://dx.doi.org/10.3390/ijms19061788] [PMID: 29914172] 
[36] 
Pollitt, S.K.; Pallos, J.; Shao, J.; Desai, U.A.; Ma, A.A.K.; Thompson, L.M.; Marsh, J.L.; Diamond, M.I. A rapid cellular FRET assay of polyglutamine aggregation identifies a novel inhibitor. Neuron,  2003, 40(4), 685-694.
[http://dx.doi.org/10.1016/S0896-6273(03)00697-4] [PMID: 14622574] 
[37] 
Desai, U.A.; Pallos, J.; Ma, A.A.K.; Stockwell, B.R.; Thompson, L.M.; Marsh, J.L.; Diamond, M.I. Biologically active molecules that reduce polyglutamine aggregation and toxicity. Hum. Mol. Genet.,  2006, 15(13), 2114-2124.
[http://dx.doi.org/10.1093/hmg/ddl135] [PMID: 16720620] 
[38] 
Zhang, X.; Smith, D.L.; Meriin, A.B.; Engemann, S.; Russel, D.E.; Roark, M.; Washington, S.L.; Maxwell, M.M.; Marsh, J.L.; Thompson, L.M.; Wanker, E.E.; Young, A.B.; Housman, D.E.; Bates, G.P.; Sherman, M.Y.; Kazantsev, A.G. A potent small molecule inhibits polyglutamine aggregation in Huntington’s disease neurons and suppresses neurodegeneration in vivo. Proc. Natl. Acad. Sci. USA,  2005, 102(3), 892-897.
[http://dx.doi.org/10.1073/pnas.0408936102] [PMID: 15642944] 
[39] 
Chang, S.; Bray, S.M.; Li, Z.; Zarnescu, D.C.; He, C.; Jin, P.; Warren, S.T. Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila. Nat. Chem. Biol.,  2008, 4(4), 256-263.
[http://dx.doi.org/10.1038/nchembio.78] [PMID: 18327252] 
[40] 
Ntungwe N, E.; Domínguez-Martín, E.M.; Roberto, A.; Tavares, J.; Isca, V.M.S.; Pereira, P.; Cebola, M-J.; Rijo, P. Artemia species: An important tool to screen general toxicity samples. Curr. Pharm. Des.,  2020, 26(24), 2892-2908.
[http://dx.doi.org/10.2174/1381612826666200406083035] [PMID: 32250221] 
[41] 
Prado, V.C.; Marcondes Sari, M.H.; Borin, B.C.; do Carmo Pinheiro, R.; Cruz, L.; Schuch, A.; Nogueira, C.W.; Zeni, G. Development of a nanotechnological-based hydrogel containing a novel benzofuroazepine compound in association with vitamin E: An in vitro biological safety and photoprotective hydrogel. Colloids Surf. B Biointerfaces,  2021, 199, 111555.
[http://dx.doi.org/10.1016/j.colsurfb.2020.111555] [PMID: 33434881] 
[42] 
Suay-García, B.; Alemán-López, P.A.; Bueso-Bordils, J.I.; Falcó, A.; Antón-Fos, G.; Pérez-Gracia, M.T. New solvent options for in vivo assays in the Galleria mellonella larvae model. Virulence,  2019, 10(1), 776-782.
[http://dx.doi.org/10.1080/21505594.2019.1659663] [PMID: 31451073] 
[43] 
Erasto, P.; Omolo, J.; Sunguruma, R.; Munissi, J.J.; Wiketye, V.; de Konig, C.; Ahmed, A.F. Evaluation of antimycobacterial activity of higenamine using Galleria mellonella as an in vivo infection model. Nat. Prod. Bioprospect.,  2018, 8(1), 63-69.
[http://dx.doi.org/10.1007/s13659-018-0152-3] [PMID: 29357092] 
[44] 
Asai, M.; Li, Y.; Khara, J.S.; Robertson, B.D.; Langford, P.R.; Newton, S.M. Galleria mellonella: An infection model for screening compounds against the Mycobacterium tuberculosis complex. Front. Microbiol.,  2019, 10, 2630.
[http://dx.doi.org/10.3389/fmicb.2019.02630] [PMID: 31824448] 
[45] 
Meyer, K.A.; Deraedt, M.F.; Harrington, A.T.; Danziger, L.H.; Wenzler, E. Efficacy of oritavancin alone and in combination against vancomycin-susceptible and -resistant enterococci in an in-vivo Galleria mellonella survival model. Int. J. Antimicrob. Agents,  2019, 54(2), 197-201.
[http://dx.doi.org/10.1016/j.ijantimicag.2019.04.010] [PMID: 31034937] 
[46] 
Pagán, O.R. Planaria: An animal model that integrates development, regeneration and pharmacology. Int. J. Dev. Biol.,  2017, 61(8-9), 519-529.
[http://dx.doi.org/10.1387/ijdb.160328op] [PMID: 29139537] 
[47] 
Ireland, D.; Bochenek, V.; Chaiken, D.; Rabeler, C.; Onoe, S.; Soni, A.; Collins, E.S. Dugesia japonica is the best suited of three planarian species for high-throughput toxicology screening. Chemosphere,  2020, 253, 126718.
[http://dx.doi.org/10.1016/j.chemosphere.2020.126718] [PMID: 32298908] 
[48] 
 Orso, R.; Gonçalves, I.L.; Navarini Bampi, E.; Saorin Puton, B.M.; Hepp, L.U.; Dartora, N.; Souza Roman, S.; Valduga, A.T. Analysis of Polysaccharide Fraction from Yerba Mate (Ilex paraguariensis St. Hil.) on Regeneration of Planarian (Girardia tigrina). Starch 2020, 73 (3-4), 2000091. 
[http://dx.doi.org/10.1002/star.202000091] 
[49] 
Córdova López, A.M.; Sarmento, R.A.; de Souza Saraiva, A.; Pereira, R.R.; Soares, A.M.V.M.; Pestana, J.L.T. Exposure to Roundup® affects behaviour, head regeneration and reproduction of the freshwater planarian Girardia tigrina. Sci. Total Environ.,  2019, 675(20), 453-461.
[http://dx.doi.org/10.1016/j.scitotenv.2019.04.234] [PMID: 31030151] 
[50] 
Simão, F.C.P.; Gravato, C.; Machado, A.L.; Soares, A.M.V.M.; Pestana, J.L.T. Toxicity of different polycyclic aromatic hydrocarbons (PAHs) to the freshwater planarian Girardia tigrina. Environ. Pollut.,  2020, 266(Pt 2), 115185.
[http://dx.doi.org/10.1016/j.envpol.2020.115185] [PMID: 32777698] 
[51] 
Raffa, R.B.; Finno, K.E.; Tallarida, C.S.; Rawls, S.M. Topiramate-antagonism of L-glutamate-induced paroxysms in planarians. Eur. J. Pharmacol.,  2010, 649(1-3), 150-153.
[http://dx.doi.org/10.1016/j.ejphar.2010.09.021] [PMID: 20863783] 
[52] 
Pagán, O.R.; Rowlands, A.L.; Azam, M.; Urban, K.R.; Bidja, A.H.; Roy, D.M.; Feeney, R.B.; Afshari, L.K. Reversal of cocaine-induced planarian behavior by parthenolide and related sesquiterpene lactones. Pharmacol. Biochem. Behav.,  2008, 89(2), 160-170.
[http://dx.doi.org/10.1016/j.pbb.2007.12.008] [PMID: 18222535] 
[53] 
Raffa, R.B.; Desai, P. Description and quantification of cocaine withdrawal signs in Planaria. Brain Res.,  2005, 1032(1-2), 200-202.
[http://dx.doi.org/10.1016/j.brainres.2004.10.052] [PMID: 15680960] 
[54] 
Ramoz, L.; Lodi, S.; Bhatt, P.; Reitz, A.B.; Tallarida, C.; Tallarida, R.J.; Raffa, R.B.; Rawls, S.M. Mephedrone (“bath salt”) pharmacology: Insights from invertebrates. Neuroscience,  2012, 208, 79-84.
[http://dx.doi.org/10.1016/j.neuroscience.2012.01.019] [PMID: 22300981] 
[55] 
Zhang, C.; Tallarida, C.S.; Raffa, R.B.; Rawls, S.M. Sucrose produces withdrawal and dopamine-sensitive reinforcing effects in planarians. Physiol. Behav.,  2013, 112-113, 8-13.
[http://dx.doi.org/10.1016/j.physbeh.2013.02.002] [PMID: 23415661] 
[56] 
Nishimura, K.; Inoue, T.; Yoshimoto, K.; Taniguchi, T.; Kitamura, Y.; Agata, K. Regeneration of dopaminergic neurons after 6-hydroxydopamine-induced lesion in planarian brain. J. Neurochem.,  2011, 119(6), 1217-1231.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07518.x] [PMID: 21985107] 
[57] 
Umeda, S.; Stagliano, G.W.; Borenstein, M.R.; Raffa, R.B. A reverse-phase HPLC and fluorescence detection method for measurement of 5-hydroxytryptamine (serotonin) in Planaria. J. Pharmacol. Toxicol. Methods,  2005, 51(1), 73-76.
[http://dx.doi.org/10.1016/j.vascn.2004.07.002] [PMID: 15596117] 
[58] 
Rawls, S.M.; Gomez, T.; Stagliano, G.W.; Raffa, R.B. Measurement of glutamate and aspartate in Planaria. J. Pharmacol. Toxicol. Methods,  2006, 53(3), 291-295.
[http://dx.doi.org/10.1016/j.vascn.2005.10.004] [PMID: 16332445] 
[59] 
 Raffa, R.B. Planaria: A model for drug action and abuse. CRC Press, Boca Raton, 2008.
[http://dx.doi.org/10.1201/9781498713597] 
[60] 
Zhang, J.; Shao, X.; Zhao, B.; Zhai, L.; Liu, N.; Gong, F.; Ma, X.; Pan, X.; Zhao, B.; Yuan, Z.; Zhang, X. Neurotoxicity of perfluorooctanoic acid and post-exposure recovery due to blue berry anthocyanins in the planarians Dugesia japonica. Environ. Pollut.,  2020, 263(Pt B), 114471.
[http://dx.doi.org/10.1016/j.envpol.2020.114471] [PMID: 32268227] 
[61] 
Porfiriev, A.; Yuganova, K.; Belyaev, A.; Vyshtakaliuk, A.; Zobov, V.; Semenov, V. The effect of l-Ascorbate 1-(2-Hydroxyethyl)-4,6-Dimethyl-1,2-dihydropyrimidin-2-One on the regeneration of the planarian Girardia tigrina. Bionanoscience,  2017, 7(4), 570-573.
[http://dx.doi.org/10.1007/s12668-017-0451-x] 
[62] 
Gonçalves, I.L.; Rockenbach, L.; Göethel, G.; Saüer, E.; Kagami, L.P.; das Neves, G.M.H.; Munhoz, T.; Figueiró, F.; Garcia, S.C.; Oliveira Battastini, A.M.; Eifler-Lima, V.L. New pharmacological findings linked to biphenyl DHPMs, kinesin Eg5 ligands: Anticancer and antioxidant effects. Future Med. Chem.,  2020, 12(12), 1137-1154.
[http://dx.doi.org/10.4155/fmc-2019-0256] [PMID: 32513026] 
[63] 
Rawls, S.M.; Cavallo, F.; Capasso, A.; Ding, Z.; Raffa, R.B. The β-lactam antibiotic ceftriaxone inhibits physical dependence and abstinence-induced withdrawal from cocaine, amphetamine, methamphetamine, and clorazepate in planarians. Eur. J. Pharmacol.,  2008, 584(2-3), 278-284.
[http://dx.doi.org/10.1016/j.ejphar.2008.02.018] [PMID: 18342307] 
[64] 
Zewde, A.M.; Yu, F.; Nayak, S.; Tallarida, C.; Reitz, A.B.; Kirby, L.G.; Rawls, S.M. PLDT (planarian light/dark test): An invertebrate assay to quantify defensive responding and study anxiety-like effects. J. Neurosci. Methods,  2018, 293(1), 284-288.
[http://dx.doi.org/10.1016/j.jneumeth.2017.10.010] [PMID: 29042260] 
[65] 
Baker, D.; Deats, S.; Boor, P.; Pruitt, J.; Pagán, O.R. Minimal structural requirements of alkyl γ-lactones capable of antagonizing the cocaine-induced motility decrease in planarians. Pharmacol. Biochem. Behav.,  2011, 100(1), 174-179.
[http://dx.doi.org/10.1016/j.pbb.2011.08.013] [PMID: 21878350] 
[66] 
Pagán, O.R.; Baker, D.; Deats, S.; Montgomery, E.; Tenaglia, M.; Randolph, C.; Kotturu, D.; Tallarida, C.; Bach, D.; Wilk, G.; Rawls, S.; Raffa, R.B. Planarians in pharmacology: Parthenolide is a specific behavioral antagonist of cocaine in the planarian Girardia tigrina. Int. J. Dev. Biol.,  2012, 56(1-3), 193-196.
[http://dx.doi.org/10.1387/ijdb.113486op] [PMID: 22451007] 
[67] 
Voura, E.B.; Montalvo, M.J.; Dela Roca, K.T.; Fisher, J.M.; Defamie, V.; Narala, S.R.; Khokha, R.; Mulligan, M.E.; Evans, C.A. Planarians as models of cadmium-induced neoplasia provide measurable benchmarks for mechanistic studies. Ecotoxicol. Environ. Saf.,  2017, 142, 544-554.
[http://dx.doi.org/10.1016/j.ecoenv.2017.04.044] [PMID: 28482323] 
[68] 
Simão, F.C.P.; Gravato, C.; Machado, A.L.; Soares, A.M.V.M.; Pestana, J.L.T. Effects of pyrene and benzo[a]pyrene on the reproduction and newborn morphology and behavior of the freshwater planarian Girardia tigrina. Chemosphere,  2021, 264(Pt 1), 128448.
[http://dx.doi.org/10.1016/j.chemosphere.2020.128448] [PMID: 33032223] 
[69] 
Shah, S.I.; Williams, A.C.; Lau, W.M.; Khutoryanskiy, V.V. Planarian toxicity fluorescent assay: A rapid and cheap pre-screening tool for potential skin irritants. Toxicol Vitr,  2020, 69.
[70] 
Lilienblum, W.; Dekant, W.; Foth, H.; Gebel, T.; Hengstler, J.G.; Kahl, R.; Kramer, P.J.; Schweinfurth, H.; Wollin, K.M. Alternative methods to safety studies in experimental animals: Role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH). Arch. Toxicol.,  2008, 82(4), 211-236.
[http://dx.doi.org/10.1007/s00204-008-0279-9] [PMID: 18322675] 
[71] 
MM motorcycle C. elegans: Biological model of the present and the future. 2005.
[72] 
Hahnel, S.R.; Dilks, C.M.; Heisler, I.; Andersen, E.C.; Kulke, D. Caenorhabditis elegans in anthelmintic research - Old model, new perspectives. Int. J. Parasitol. Drugs Drug Resist.,  2020, 14, 237-248.
[http://dx.doi.org/10.1016/j.ijpddr.2020.09.005] [PMID: 33249235] 
[73] 
Nayak, S.; Goree, J.; Schedl, T. fog-2 and the evolution of self-fertile hermaphroditism in Caenorhabditis. PLoS Biol.,  2005, 3(1), e6.
[http://dx.doi.org/10.1371/journal.pbio.0030006] [PMID: 15630478] 
[74] 
Kaletta, T.; Hengartner, M.O. Finding function in novel targets: C. elegans as a model organism. Nat. Rev. Drug Discov.,  2006, 5(5), 387-398.
[http://dx.doi.org/10.1038/nrd2031] [PMID: 16672925] 
[75] 
Muschiol, D.; Schroeder, F.; Traunspurger, W. Life cycle and population growth rate of Caenorhabditis elegans studied by a new method. BMC Ecol.,  2009, 9(1), 14.
[http://dx.doi.org/10.1186/1472-6785-9-14] [PMID: 19445697] 
[76] 
 University of Minnesota, Caenorhabditis genetics center (CGC). 2022. [Cited 2021 Apr 6]. Available from: https://cgc.umn.edu
[77] 
Sepúlveda-Crespo, D.; Reguera, R.M.; Rojo-Vázquez, F.; Balaña-Fouce, R.; Martínez-Valladares, M. Drug discovery technologies: Caenorhabditis elegans as a model for anthelmintic therapeutics. Med. Res. Rev.,  2020, 40(5), 1715-1753.
[http://dx.doi.org/10.1002/med.21668] [PMID: 32166776] 
[78] 
Carretero, M.; Solis, G.M.; Petrascheck, M. C. elegans as model for drug discovery. Curr. Top. Med. Chem.,  2017, 17(18), 2067-2076.
[http://dx.doi.org/10.2174/1568026617666170131114401] [PMID: 28137208] 
[79] 
Soares, F.G.N.; Göethel, G.; Kagami, L.P.; das Neves, G.M.H.; Sauer, E.; Birriel, E.; Varela, J.; Gonçalves, I.L.; Von Poser, G.; González, M.; Kawano, D.F.; Paula, F.R.; de Melo, E.B.; Garcia, S.C.; Cerecetto, H.; Eifler-Lima, V.L. Novel coumarins active against Trypanosoma cruzi and toxicity assessment using the animal model Caenorhabditis elegans. BMC Pharmacol. Toxicol.,  2019, 20(Suppl. 1), 76.
[http://dx.doi.org/10.1186/s40360-019-0357-z] [PMID: 31852548] 
[80] 
Li, W.H.; Hsu, F.L.; Liu, J.T.; Liao, V.H.C. The ameliorative and toxic effects of selenite on Caenorhabditis elegans. Food Chem. Toxicol.,  2011, 49(4), 812-819.
[http://dx.doi.org/10.1016/j.fct.2010.12.002] [PMID: 21145367] 
[81] 
Matsunami, K. Frailty and Caenorhabditis elegans as a benchtop animal model for screening drugs including natural herbs. Front. Nutr.,  2018, 5, 111.
[http://dx.doi.org/10.3389/fnut.2018.00111] [PMID: 30534551] 
[82] 
Salgueiro, W.G.; Xavier, M.C.D.F.; Duarte, L.F.B.; Câmara, D.F.; Fagundez, D.A.; Soares, A.T.G.; Perin, G.; Alves, D.; Avila, D.S. Direct synthesis of 4-organylsulfenyl-7-chloro quinolines and their toxicological and pharmacological activities in Caenorhabditis elegans. Eur. J. Med. Chem.,  2014, 75, 448-459.
[http://dx.doi.org/10.1016/j.ejmech.2014.01.037] [PMID: 24561673] 
[83] 
Kong, C.; Eng, S.A.; Lim, M.P.; Nathan, S. Beyond traditional antimicrobials: A Caenorhabditis elegans model for discovery of novel anti-infectives. Front. Microbiol.,  2016, 7, 1956.
[http://dx.doi.org/10.3389/fmicb.2016.01956] [PMID: 27994583] 
[84] 
Kim, W.; Hendricks, G.L.; Lee, K.; Mylonakis, E. An update on the use of C. elegans for preclinical drug discovery: Screening and identifying anti-infective drugs. Expert Opin. Drug Discov.,  2017, 12(6), 625-633.
[http://dx.doi.org/10.1080/17460441.2017.1319358] [PMID: 28402221] 
[85] 
Engleman, E.A.; Steagall, K.B., II; Bredhold, K.E.; Breach, M.; Kline, H.L.; Bell, R.L.; Katner, S.N.; Neal-Beliveau, B.S. Caenorhabditis elegans show preference for stimulants and potential as a model organism for medications screening. Front. Physiol.,  2018, 9, 1200.
[http://dx.doi.org/10.3389/fphys.2018.01200] [PMID: 30214414] 
[86] 
Faravelli, G.; Raimondi, S.; Marchese, L.; Partridge, F.A.; Soria, C.; Mangione, P.P.; Canetti, D.; Perni, M.; Aprile, F.A.; Zorzoli, I.; Di Schiavi, E.; Lomas, D.A.; Bellotti, V.; Sattelle, D.B.; Giorgetti, S. C. elegans expressing D76N β2-microglobulin: A model for in vivo screening of drug candidates targeting amyloidosis. Sci. Rep.,  2019, 9(1), 19960.
[http://dx.doi.org/10.1038/s41598-019-56498-5] [PMID: 31882874] 
[87] 
Galford, K.F.; Jose, A.M. The FDA-approved drugs ticlopidine, sertaconazole, and dexlansoprazole can cause morphological changes in C. elegans. Chemosphere,  2020, 261, 127756.
[http://dx.doi.org/10.1016/j.chemosphere.2020.127756] [PMID: 32731027] 
[88] 
ren, Xie R.; ling, Su C.; Li, W.; Zou, X.Y.; Chen, Y si; Tang, H. Synthesis and biological evaluation of novel 8- substituted sampangine derivatives as potent inhibitor of Zn2+-Aβ complex mediated toxicity, oxidative stress and inflammation. Bioorg. Chem.,  2021, 2021, 109.
[89] 
Zou, X.Y.; Xie, R-R.; Li, W.; Su, C.L.; Chen, Y.S.; Tang, H. Novel sampangine derivatives as potent inhibitors of Cu2+-mediated amyloid-β protein aggregation, oxidative stress and inflammation. Int. J. Biol. Macromol.,  2021, 174, 1-10.
[http://dx.doi.org/10.1016/j.ijbiomac.2021.01.091] [PMID: 33476619] 
[90] 
Luo, S.; Jiang, X.; Jia, L.; Tan, C.; Li, M.; Yang, Q.; Du, Y.; Ding, C. In vivo and in vitro antioxidant activities of methanol extracts from olive leaves on Caenorhabditis elegans. Molecules,  2019, 24(4), 704.
[http://dx.doi.org/10.3390/molecules24040704] [PMID: 30781358] 
[91] 
Xu, K.; Wang, J.L.; Chu, M.P.; Jia, C. Activity of coumarin against Candida albicans biofilms. J. Mycol. Med.,  2019, 29(1), 28-34.
[http://dx.doi.org/10.1016/j.mycmed.2018.12.003] [PMID: 30606640] 
[92] 
Morales, S.A.T.; de Aguilar, M.G.; Pereira, R.C.G.; Duarte, L.P.; Sousa, G.F.; de Oliveira, D.M.; Evangelista, F.C.G.; Sabino, A.P.; Viana, R.O.; Alves, V.S.; Vieira-Filho, S.A. Constituents from roots of Maytenus distichophylla, antimicrobial activity and toxicity for cells and Caenorhabditis elegans. Quim. Nova,  2020, 43(8), 1066-1073.
[http://dx.doi.org/10.21577/0100-4042.20170591] 
[93] 
Gonçalves, I.L.; Rockenbach, L.; das Neves, G.M.; Göethel, G.; Nascimento, F.; Porto Kagami, L.; Figueiró, F.; Oliveira de Azambuja, G.; de Fraga Dias, A.; Amaro, A.; de Souza, L.M.; da Rocha Pitta, I.; Avila, D.S.; Kawano, D.F.; Garcia, S.C.; Battastini, A.M.O.; Eifler-Lima, V.L. Effect of N-1 arylation of monastrol on kinesin Eg5 inhibition in glioma cell lines. MedChemComm,  2018, 9(6), 995-1010.
[http://dx.doi.org/10.1039/C8MD00095F] [PMID: 30108989] 
[94] 
MacRae, C.A.; Peterson, R.T. Zebrafish as tools for drug discovery. Nat. Rev. Drug Discov.,  2015, 14(10), 721-731.
[http://dx.doi.org/10.1038/nrd4627] [PMID: 26361349] 
Rights & Permissions Print Cite
Article Metrics
40
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0929867329666220329190825	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

The Role of Alternative Toxicological Trials in Drug Discovery Programs. The Case of Caenorhabditis elegans and Other Methods

Abstract Play Pause

Related Journals

Related Books

Abstract
