Pravastatin and Simvastatin Pretreatment in Combination with Pyrimethamine and Sulfadiazine Reduces Infection Process of Toxoplasma gondii Tachyzoites (RH Strain) in HeLa Cells
Tóm tắt
Toxoplasma gondii is a protozoan from phylum Apicomplexa, which causes the toxoplasmosis infection; this one exhibits an apicoplast organelle which assists in the metabolism of isoprenoids and other pivotal mediators for the parasite survival. Statins are drugs that inhibit cholesterol synthesis, blocking the conversion of the substrate HMG-CoA to mevalonate, thus preventing the initial processes of the biosynthesis of these precursors, both in humans and parasite. Our goal was to verify whether the Toxoplasma gondii (RH strain) tachyzoites form pretreated with pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations could affect the infection processes, suggesting direct action on protozoa intracellular proliferation through the inhibition of isoprenoids in the parasite’s apicoplast. To have the adhesion, infection, and parasite proliferation during experimental infection investigated, HeLa cells (105) were subjected to a 24-hour infection by T. gondii tachyzoites forms of RH strain (5 × 105) pretreated for 30 min with pravastatin and/or simvastatin combined or not with pyrimethamine and sulfadiazine. Combined with conventional drugs at low concentrations pravastatin and simvastatin inhibit the adhesion, invasion, and intracellular proliferation of T. gondii in HeLa cells which are similar to the positive control. Pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations can be regarded as a promising, effective alternative to toxoplasmosis treatment with reduced side effects.
Tài liệu tham khảo
Barbosa BF, Gomes AO, Ferro EAV, Napolitano DR, Mineo JR, Silva NM (2012) Enrofloxacin is able to control Toxoplasma gondii infection in both in vitro and in vivo experimental models. Vet Parasitol 187:44–52. https://doi.org/10.1016/j.vetpar.2011.12.039
Bonfim MR, Oliveira ASB, Amaral SLD, Monteiro HL (2015) Treatment of dyslipidemia with statins and physical exercises: recent findings of skeletal muscle responses. Arq Bras Cardiol 104:324–331. https://doi.org/10.5935/abc.20150005
Christians U, Jacobsen W, Floren LC (1998) Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar? Pharmacol Ther 80:1–34. https://doi.org/10.1016/S0163-7258(98)00016-3
Coppens I (2013) Targeting lipid biosynthesis and salvage in apicomplexan parasites for improved chemotherapies. Nat Rev Microbiol 11:823–835. https://doi.org/10.1038/nrmicro3139
Cortez E, Stumbo AC, Oliveira M, Barbosa HS, Carvalho L (2009) Statins inhibit Toxoplasma gondii multiplication in macrophages in vitro. Int J Antimicrob Agents 32:185–186. https://doi.org/10.1016/j.ijantimicag.2008.07.026
Derouin F, Santillana-Hayat M (2000) Anti-toxoplasma activities of antiretroviral drugs and interactions with pyrimethamine and sulfadiazine in vitro. Antimicrob Agents Chemother 44:2575–2577. https://doi.org/10.1128/AAC.44.9.2575-2577.2000
Golomb BA, Evans MA (2008) Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs 8:373–418. https://doi.org/10.2165/0129784-200808060-00004
Li ZH, Ramakrishnan S, Striepen B, Moreno SN (2013) Toxoplasma gondii relies on both host and parasite isoprenoids and can be rendered sensitive to atorvastatin. PLoS Pathog 9:e1003665. https://doi.org/10.1371/journal.ppat.1003665
Liao JK (2002) Isoprenoids as mediators of the biological effects of statins. J Clin Investig 100:285–288. https://doi.org/10.1172/JCI16421
Mason RP (2006) Molecular basis of differences among statins and a comparison with antioxidant vitamins. Am J Cardiol 98:S34–S41. https://doi.org/10.1016/J.AMJCARD.2006.09.018
Nair SC, Brooks CF, Goodman CD, Strurm A, McFadden GI, Sundriyal S et al (2011) Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii. J Exp Med 208:1547–1559. https://doi.org/10.1084/jem.20110039
Nishikawa Y, Ibrahim HM, Kameyama K, Shiga I, Hiasa J, Xuan X (2011) Host Cholesterol Synthesis Contributes to Growth of Intracellular Toxoplasma gondii in Macrophages. J Vet Med Sci 73:633–639. https://doi.org/10.1292/jvms.10-0496
Nyilasi I, Kocsubé S, Krizsán K, Galgóczy L, Pesti M, Papp T et al (2010) In vitro synergistic interactions of the effects of various statins and azoles against some clinically important fungi. FEMS Microbiol Lett 307:175–184. https://doi.org/10.1111/j.1574-6968.2010.01972.x
Saadatnia G, Golkar M (2012) A review on human toxoplasmosis. Scand J Infect Dis 44:805–814. https://doi.org/10.3109/00365548.2012.693197
Sanfelice AR, Machado LF, Bosqui LR, Miranda-Sapla MM, Tomiotto-Pellissier F, de Alcântara Dalevedo G et al (2017) Activity of rosuvastatin in tachyzoites of Toxoplasma gondii (RH strain) in HeLa cells. Exp Parasitol 181:75–81. https://doi.org/10.1016/j.exppara.2017.07.009
Sanfelice RA, da Silva SS, Bosqui LR, Miranda-Sapla MM, Barbosa BF, Silva RJ et al (2017) Pravastatin and simvastatin inhibit the adhesion, replication and proliferation of Toxoplasma gondii (RH strain) in HeLa cells. Acta Trop 167:208–215. https://doi.org/10.1016/j.actatropica.2016.12.006
Sanfelice RA, Bosqui LR, da Silva SS, Miranda-Sapla MM, Panagio LA, Navarro IT et al (2018) Proliferation of Toxoplasma gondii (RH strain) is inhibited by the combination of pravastatin and simvastatin with low concentrations of conventional drugs used in toxoplasmosis. J Appl Biomed 16:29–33. https://doi.org/10.1016/J.JAB.2017.10.009
Schaefer EJ, McNamara JR, Tayler T, Daly JA, Gleason JL, Seman LJ et al (2004) Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease versus control subjects. Am J Cardiol 93:31–39. https://doi.org/10.1016/j.amjcard.2003.09.008
Sonda S, Hehl AB (2006) Lipid biology of Apicomplexa: perspectives for new drug targets, particularly for Toxoplasma gondii. Trends Parasitol 22:41–47. https://doi.org/10.1016/j.pt.2005.11.001
Wooten JM (2018) A brief drug class review: considerations for statin use, toxicity, and drug interactions. South Med J 111:39–44. https://doi.org/10.14423/SMJ.0000000000000752