In Vitro and In Vivo Antileishmanial Activity of Thioridazine.
Leishmania amazonensis
Leishmania major
Leishmania mexicana
Leishmaniasis
Thioridazine
Journal
Acta parasitologica
ISSN: 1896-1851
Titre abrégé: Acta Parasitol
Pays: Switzerland
ID NLM: 9301947
Informations de publication
Date de publication:
09 Dec 2023
09 Dec 2023
Historique:
received:
20
03
2023
accepted:
06
11
2023
medline:
10
12
2023
pubmed:
10
12
2023
entrez:
9
12
2023
Statut:
aheadofprint
Résumé
Leishmaniasis is a neglected disease with high prevalence and incidence in tropical and subtropical areas. Existing drugs are limited due to cost, toxicity, declining efficacy and unavailability in endemic places. Drug repurposing has established as an efficient way for the discovery of drugs for a variety of diseases. The objective of the present work was testing the antileishmanial activity of thioridazine, an antipsychotic agent with demonstrated effect against other intracellular pathogens. The cytotoxicity for mouse peritoneal macrophages as well as the activity against Leishmania amazonensis, Leishmania mexicana and Leishmania major promastigotes and intracellular amastigotes, as well as in a mouse model of cutaneous leishmaniasis, were assessed. Thioridazine inhibited the in vitro proliferation of promastigotes (50% inhibitory concentration-IC Thioridazine was effective against the promastigote and intracellular amastigote stages of three Leishmania species and in a mouse model of cutaneous leishmaniasis, supporting the potential repurposing of this drug as an antileishmanial agent.
Identifiants
pubmed: 38070122
doi: 10.1007/s11686-023-00746-2
pii: 10.1007/s11686-023-00746-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México
ID : IN212422
Organisme : CONACyT (MX)
ID : 284018
Informations de copyright
© 2023. The Author(s).
Références
Mathison BA, Bradley BT (2023) Review of the clinical presentation, pathology, diagnosis, and treatment of leishmaniasis. Lab Med 54(4):363–371. https://doi.org/10.1093/labmed/lmac134
doi: 10.1093/labmed/lmac134
pubmed: 36468667
Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, Jannin J, den Boer M, The WHO Leishmaniasis Control Team (2012) Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 7(5):e35671. https://doi.org/10.1371/journal.pone.0035671
doi: 10.1371/journal.pone.0035671
pubmed: 22693548
pmcid: 3365071
- WHO. Leishmaniasis. Last updated: 12 January 2023, Accessed: 10 Mar 2023. https://www.who.int/news-room/fact-sheets/detail/leishmaniasis
Brindha J, Balamurali MM, Chanda K (2021) An overview on the therapeutics of neglected infectious diseases—leishmaniasis and chagas diseases. Front Chem 9:622286. https://doi.org/10.3389/fchem.2021.622286
doi: 10.3389/fchem.2021.622286
Chakravarty J, Sundar S (2019) Current and emerging medications for the treatment of leishmaniasis. Expert Opin Pharmacother 20:1251–1265. https://doi.org/10.1080/14656566.2019.1609940
doi: 10.1080/14656566.2019.1609940
pubmed: 31063412
Knight CA, Harris DR, Alshammari SO, Gugssa A, Young T, Lee CM (2023) Leishmaniasis: recent epidemiological studies in the Middle East. Front Microbiol 13:1052478. https://doi.org/10.3389/fmicb.2022.1052478
doi: 10.3389/fmicb.2022.1052478
pubmed: 36817103
pmcid: 9932337
Adams CP, Brantner VV (2006) Estimating the cost of new drug development: Is it really $802 million? Health Aff 25(2):420–428. https://doi.org/10.1377/hlthaff.25.2.420
doi: 10.1377/hlthaff.25.2.420
Wouters OJ, McKee M, Luyten J (2020) Estimated research and development investment needed to bring a new medicine to market, 2009–2018. JAMA 323(9):844–853. https://doi.org/10.1001/jama.2020.1166
doi: 10.1001/jama.2020.1166
pubmed: 32125404
pmcid: 7054832
Andrews KT, Fisher G, Skinner-Adams TS (2014) Drug repurposing and human parasitic protozoan diseases. Int J Parasitol Drugs Drug Resist 4(2):95–111. https://doi.org/10.1016/j.ijpddr.2014.02.002
doi: 10.1016/j.ijpddr.2014.02.002
pubmed: 25057459
pmcid: 4095053
Charlton RL, Rossi-Bergmann B, Denny PW, Steel PG (2018) Repurposing as a strategy for the discovery of new anti-leishmanials: the-state-of-the-art. Parasitology 145(2):219–236. https://doi.org/10.1017/S0031182017000993
doi: 10.1017/S0031182017000993
pubmed: 28805165
Sateriale A, Bessoff K, Sarkar IN, Huston CD (2014) Drug repurposing: mining protozoan proteomes for targets of known bioactive compounds. J Am Med Inform Assoc 21(2):238–244. https://doi.org/10.1136/amiajnl-2013-001700
doi: 10.1136/amiajnl-2013-001700
pubmed: 23757409
Melcon-Fernandez E, Galli G, García-Estrada C, Balaña-Fouce R, Reguera RM, Pérez-Pertejo Y (2023) Miltefosine and nifuratel combination: a promising therapy for the treatment of Leishmania donovani visceral leishmaniasis. Int J Mol Sci 24:1635. https://doi.org/10.3390/ijms24021635
doi: 10.3390/ijms24021635
pubmed: 36675150
pmcid: 9865052
El-Dirany R, Fernández-Rubio C, Peña-Guerrero J (2022) Repurposing the antibacterial agents peptide 19–4LF and peptide 19–2.5 for treatment of cutaneous Leishmaniasis. Pharmaceutics 14(11):2528. https://doi.org/10.3390/pharmaceutics14112528
doi: 10.3390/pharmaceutics14112528
pubmed: 36432719
pmcid: 9697117
Borges BS, Bueno GP, Tomiotto-Pellissier F, Figueiredo FB, Soares Medeiros LC (2023) In vitro anti-Leishmania activity of triclabendazole and its synergic effect with amphotericin B. Front Cell Infect Microbiol 12:1044665. https://doi.org/10.3389/fcimb.2022.1044665
doi: 10.3389/fcimb.2022.1044665
pubmed: 36699729
pmcid: 9868945
Tran TH, Kao M, Liu HS, Hong YR, Su Y, Huang CYF (2023) Repurposing thioridazine for inducing immunogenic cell death in colorectal cancer via eIF2α/ATF4/CHOP and secretory autophagy pathways. J Cell Commun Signal 21(1):184. https://doi.org/10.1186/s12964-023-01190-5
doi: 10.1186/s12964-023-01190-5
Rácz B, Spengler G (2023) Repurposing antidepressants and phenothiazine antipsychotics as efflux pump inhibitors in cancer and infectious diseases. Antibiotics 12(1):137. https://doi.org/10.3390/antibiotics12010137
doi: 10.3390/antibiotics12010137
pubmed: 36671340
pmcid: 9855052
Mirzaii M, Alebouyeh M, Sohrabi MB, Eslami P, Fazli M, Ebrahimi M, Rashidan M (2023) Antibiotic resistance assessment and multi-drug efflux pumps of Enterococcus faecium isolated from clinical specimens. J Infect Dev Ctries 17(05):649–655. https://doi.org/10.3855/jidc.17304
doi: 10.3855/jidc.17304
pubmed: 37279423
Vo N, Sidner BS, Yu Y, Piepenbrink KH (2023) Type IV pilus-mediated inhibition of Acinetobacter baumannii biofilm formation by phenothiazine compounds. Microbiol Spectr. https://doi.org/10.1128/spectrum.01023-23
doi: 10.1128/spectrum.01023-23
pubmed: 37811937
pmcid: 10433872
Rodrigues T (2023) Repositioning of antipsychotic phenothiazines for cancer therapy: nanotechnological opportunities to overcome obstacles. Curr Pharm Des 29(25):1959–1960. https://doi.org/10.2174/1381612829666230821092254
doi: 10.2174/1381612829666230821092254
pubmed: 37605391
Patino I, Preuss C (2023) New drugs in synthesis research for tuberculosis. In: Shegokar R, Pathak Y (eds) Infectious diseases drug delivery systems. Springer International Publishing, Cham, pp 29–50. https://doi.org/10.1007/978-3-031-20521-7_2
doi: 10.1007/978-3-031-20521-7_2
Grimsey EM, Piddock LJV (2019) Do phenothiazines possess antimicrobial and efflux inhibitory properties? FEMS Microbiol Rev 43:577–590. https://doi.org/10.1093/femsre/fuz017
doi: 10.1093/femsre/fuz017
pubmed: 31216574
Poulsen MO, Jacobsen K, Thorsing M, Kristensen NR, Clasen J, Lillebaek EM, Skov MN, Kallipolitis BH, Kolmos HJ, Klitgaard JK (2013) Thioridazine potentiates the effect of a beta-lactam antibiotic against Staphylococcus aureus independently of mecA expression. Res Microbiol 164:181–188. https://doi.org/10.1016/j.resmic.2012.10.007
doi: 10.1016/j.resmic.2012.10.007
pubmed: 23089256
Rasmussen KS, Poulsen MO, Jacobsen K, Skov MN, Kolmos H, Kallipolitis BH, Klitgaard JK (2017) Combination of thioridazine and dicloxacillin as a possible treatment strategy of staphylococci. New Microbiol 40(2):146–147
pubmed: 28255602
Zhou H, Luan W, Wang Y, Song Y, Xu H, Tang X, Yu L (2022) The combination of cloxacillin, thioridazine and tetracycline protects mice against Staphylococcus aureus peritonitis by inhibiting α-Hemolysin-induced MAPK/NF-κB/NLRP3 activation. Int J Biol Macromol 198:1–10. https://doi.org/10.1016/j.ijbiomac.2021.12.112
doi: 10.1016/j.ijbiomac.2021.12.112
pubmed: 34963621
Rodrigues L, Wagner D, Viveiros M, Sampaio D, Couto I, Vavra M, Kern WV, Amaral L (2008) Thioridazine and chlorpromazine inhibition of ethidium bromide efflux in Mycobacterium avium and Mycobacterium smegmatis. J Antimicrob Chemother 61:1076–1082. https://doi.org/10.1093/jac/dkn070
doi: 10.1093/jac/dkn070
pubmed: 18310137
Boshoff HIM, Myers TG, Copp BR, McNeil MR, Wilson MA, Barry CE (2004) The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism. J Biol Chem 279:40174–40184. https://doi.org/10.1074/jbc.M406796200
doi: 10.1074/jbc.M406796200
pubmed: 15247240
Valıyeva G, Durupınar B, Coban AY (2023) Efflux pump effects on Mycobacterium tuberculosis drug resistance. J Chemother. https://doi.org/10.1080/1120009X.2023.2173857
doi: 10.1080/1120009X.2023.2173857
pubmed: 36718107
Lo Presti MS, Bazán PC, Strauss M, Báez AL, Rivarola HW, Paglini-Oliva PA (2015) Trypanothione reductase inhibitors: overview of the action of thioridazine in different stages of Chagas disease. Acta Trop 145:79–87. https://doi.org/10.1016/j.actatropica.2015.02.012
doi: 10.1016/j.actatropica.2015.02.012
pubmed: 25733492
Essodaïgui M, Frézard F, Moreira ES, Dagger F, Garnier-Suillerot A (1999) Energy-dependent efflux from Leishmania promastigotes of substrates of the mammalian multidrug resistance pumps. Mol Biochem Parasitol 100(1):73–84. https://doi.org/10.1016/s0166-6851(99)00036-5
doi: 10.1016/s0166-6851(99)00036-5
pubmed: 10376995
Bodley AL, McGarry MW, Shapiro TA (1995) Drug cytotoxicity assay for African trypanosomes and Leishmania species. J Infect Dis 172(4):1157–1159. https://doi.org/10.1093/infdis/172.4.1157
doi: 10.1093/infdis/172.4.1157
pubmed: 7561203
He P, Li X, Guo X, Bian X, Wang R, Wang Y, Huang S, Qi M, Liu Y, Feng M (2023) Pharmacokinetics and pharmacodynamics of a novel vancomycin derivative LYSC98 in a murine thigh infection model against Staphylococcus aureus. Infect Drug Resist 18(16):1019–1028. https://doi.org/10.2147/IDR.S399150
doi: 10.2147/IDR.S399150
Stat_Soft_Inc (2007) STATISTICA (data analysis software system), version 8.0. https://www.statsoft.com
Titus RG, Marchand M, Boon T, Louis JA (1987) A limiting dilution assay for quantifying Leishmania major in tissues of infected mice. Paras Immunol 7(5):545–555. https://doi.org/10.1111/j.1365-3024.1985.tb00098.x
doi: 10.1111/j.1365-3024.1985.tb00098.x
U.S. National Library of Medicine (2023) LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [internet]. Drug Record: Thioridazine. Last updated July 1, 2020; retrieved 16 Mar 2023. https://www.ncbi.nlm.nih.gov/books/NBK548347/
Luo Y, Yu T, Li X, Qian G (2022) Thioridazine enhances cisplatin-induced DNA damage in cisplatin-resistant human lung cancer cells. Evid Based Complement Alternat Med 30:3702665. https://doi.org/10.1155/2022/3702665
doi: 10.1155/2022/3702665
Wang Y, Xia L, Lin J, Gong XY, Xu Y, Liu L, Bao J, Zhang C, Chai Y, Li H (2022) Thioridazine combined with carboplatin results in synergistic inhibition of triple negative breast cancer by targeting cancer stem cells. Transl Oncol 26:101549. https://doi.org/10.1016/j.tranon.2022.101549
doi: 10.1016/j.tranon.2022.101549
pubmed: 36191461
pmcid: 9530598
Ahmadi F, Khalvati B, Eslami S, Mirzaii M, Roustaei N, Mazloomirad F, Khoramrooz SS (2022) The inhibitory effect of thioridazine on adeB efflux pump gene expression in multidrug-resistant Acinetobacter baumannii isolates using real time PCR. Avicenna J Med Biotechnol 14(2):132–136. https://doi.org/10.18502/ajmb.v14i2.8884
doi: 10.18502/ajmb.v14i2.8884
pubmed: 35633983
pmcid: 9077659
Adkin P, Hitchcock A, Smith LJ, Walsh SE (2022) Priming with biocides: a pathway to antibiotic resistance? J Appl Microbiol 133(2):830–841. https://doi.org/10.1111/jam.15564
doi: 10.1111/jam.15564
pubmed: 35384175
pmcid: 9543593
Yuan W, Dong X, Chen L, Lei X, Zhou Z, Guo L, Wang J (2022) Screening for inhibitors against SARS-CoV-2 and its variants. Biosaf Health 4(3):186–192. https://doi.org/10.1016/j.bsheal.2022.05.002
doi: 10.1016/j.bsheal.2022.05.002
pubmed: 35574239
pmcid: 9077799
- Feinberg SM, Fariba KA, Saadabadi A (2022) Thioridazine. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. [Updated 2022 May 2]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459140/
Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22(3):659–661. https://doi.org/10.1096/fj.07-9574lsf
doi: 10.1096/fj.07-9574lsf
pubmed: 17942826
Potts RO, Guy RH (1992) Predicting skin permeability. Pharm Res 9:663–669. https://doi.org/10.1023/a:1015810312465
doi: 10.1023/a:1015810312465
pubmed: 1608900
Wilschut A, ten Berge WF, Robinson PJ, McKone TE (1995) Estimating skin permeation. The validation of five mathematical skin permeation models. Chemosphere 30(7):1275–1296. https://doi.org/10.1016/0045-6535(95)00023-2
doi: 10.1016/0045-6535(95)00023-2
pubmed: 7749723
Frasch HF (2002) A random walk model of skin permeation. Risk Anal 22:265–276. https://doi.org/10.1111/0272-4332.00024
doi: 10.1111/0272-4332.00024
pubmed: 12022675
Ordway D, Viveiros M, Leandro C, Bettencourt R, Almeida J, Martins M, Kristiansen JE, Molnar J, Amaral L (2003) Clinical concentrations of thioridazine kill intracellular multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 47(3):917–922. https://doi.org/10.1128/aac.47.3.917-922.2003
doi: 10.1128/aac.47.3.917-922.2003
pubmed: 12604522
pmcid: 149316
Thanacoody HKR (2007) Thioridazine: resurrection as an antimicrobial agent? Br J Clin Pharmacol 64(5):566–574. https://doi.org/10.1111/j.1365-2125.2007.03021.x
doi: 10.1111/j.1365-2125.2007.03021.x
pubmed: 17764469
pmcid: 2203271
van Soolingen D, Hernandez-Pando R, Orozco H, Aguilar D, Magis-Escurra C, Amaral L, van Ingen J, Boeree MJ (2010) The antipsychotic thioridazine shows promising therapeutic activity in a mouse model of multidrug-resistant tuberculosis. PLoS ONE 5(9):e12640. https://doi.org/10.1371/journal.pone.0012640
doi: 10.1371/journal.pone.0012640
pubmed: 20844587
pmcid: 2936563
Abbate E, Vescovo M, Natiello M, Cufré M, García A, Gonzalez PM, Ambroggi M, Ritacco V, van Soolingen D (2012) Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine. J Antimicrob Chemother 67(2):473–477. https://doi.org/10.1093/jac/dkr500
doi: 10.1093/jac/dkr500
pubmed: 22134348
Dutta NK, Pinn ML, Karakousis PC (2014) Reduced emergence of isoniazid resistance with concurrent use of thioridazine against acute murine tuberculosis. Antimicrob Agents Chemother 58(7):4048–4053. https://doi.org/10.1128/aac.02981-14
doi: 10.1128/aac.02981-14
pubmed: 24798290
pmcid: 4068531
Gutiérrez-Correa J (2006) Trypanosoma cruzi dihydrolipoamide dehydrogenase as target for phenothiazine cationic radicals. Effect of antioxidants Curr Drug Targets 7(9):1155–1179. https://doi.org/10.2174/138945006778226615
doi: 10.2174/138945006778226615
pubmed: 17017892
Gutierrez-Correa J, Fairlamb AH, Stoppani AO (2011) Trypanosoma cruzi trypanothione reductase is inactivated by peroxidase-generated phenothiazine cationic radicals. Free Radic Res 34(4):363–378. https://doi.org/10.1080/10715760100300311
doi: 10.1080/10715760100300311
Hajiagha MN, Kafil HS (2023) Efflux pumps and microbial biofilm formation. Infect Genet Evol. https://doi.org/10.1016/j.meegid.2023.105459
doi: 10.1016/j.meegid.2023.105459
pubmed: 37271271
Ruth MM, Pennings LJ, Koeken VACM, Schildkraut JA, Hashemi A, Wertheim HFL, Hoefsloot W, van Ingen J (2020) Thioridazine is an efflux pump inhibitor in Mycobacterium avium complex but of limited clinical relevance. Antimicrob Agents Chemother 64(7):e00181–e0018120. https://doi.org/10.1128/AAC.00181-20
doi: 10.1128/AAC.00181-20
pubmed: 32312774
pmcid: 7318027