Efeito Protetor de Nanopartículas Poliméricas com Indometacina contra Citotoxicidade Induzida por Estresse Oxidativo em Modelo Celular de Adenocarcinoma de Mama Humano

Autores

DOI:

https://doi.org/10.32635/2176-9745.RBC.2022v68n4.2545

Palavras-chave:

indometacina/farmacologia, antioxidantes, nanocápsulas, neoplasias

Resumo

Introdução: Anti-inflamatórios estão sendo empregados para tratamento de câncer por causa do seu ambiente inflamado. Objetivo: Investigar o potencial antioxidante da indometacina e sua genotoxicidade, livre ou carreada em nanocápsulas poliméricas, usando como modelo in vitro células MCF-7 (câncer de mama humano). Método: Desenvolvimento de nanocápsulas de poliepsilon-caprolactona (PCL) por método de deposição interfacial, caracterizada por determinação de pH por potenciômetro; diâmetro médio e índice de polidispersão por espalhamento dinâmico de luz; potencial zeta por mobilidade eletroforética; eficiência de encapsulação por cromatografia líquida de alta eficiência; formação de efeito corona; método de 2’,7’-diclorofluoresceína diacetato (DCFH-DA) por ensaio espectrofluorimétrico; determinação de óxido nítrico (NO) por espectrometria e ensaio de genotoxicidade por método de clivagem do DNA plasmidial. Resultados: Os resultados mostraram leve pH ácido (4,78 ± 0,10), tamanhos em torno de 200 nm e PDI<0,2 com potencial zeta em torno de -20 mV e eficiência de encapsulação de 99% (1 mg mL-1), apresentando perfil de formação de corona dose-dependente em 24 horas de incubação. Conclusão: O ensaio DCFH-DA mostrou que não há produção de espécies reativas de oxigênio (ROS), enquanto a determinação de NO mostrou que Ind-OH-NC de 26,7 a 100 μM aumentou as espécies reativas de nitrogênio (RNS), demonstrando potencial antioxidante contra MCF-7. Nenhuma amostra nas concentrações avaliadas induziu clivagem do DNA, sendo considerado um tratamento seguro.

Downloads

Não há dados estatísticos.

Referências

Rahme E, Ghosn J, Dasgupta K, et al. Association between frequent use of nonsteroidal anti-inflammatory drugs and breast cancer. BMC Cancer. 2005;5:159. doi: https://doi.org/10.1186/1471-2407-5-159

Ackerstaff E, Gimi B, Artemov D, et al. Anti-inflammatory agent indomethacin reduces invasion and alters metabolism in a human breast cancer cell line. Neoplasia. 2007;9(3):222-35. doi: https://doi.org/10.1593/neo.06673

Zappavigna S, Cossu AM, Grimaldi A, et al. Anti-inflammatory drugs as anticancer agents. In J Mol Sci. 2020;21(7):2605. doi: https://doi.org/10.3390/ijms21072605

Halliwell B, Whiteman M. Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean? Br J Pharmacol. 2004;142(2):231-55. doi: https://doi.org/10.1038/sj.bjp.0705776

Sosa V, Moliné T, Somoza R, et al. Oxidative stress and cancer: an overview. Ageing Res Rev. 2013;12(1):376-90. doi: https://doi.org/10.1016/j.arr.2012.10.004

Crawford S. Anti-inflammatory/antioxidant use in long-term maintenance cancer therapy: a new therapeutic approach to disease progression and recurrence. Ther Adv Med Oncol. 2014;6(2):52-68. doi: https://doi.org/10.1177/1758834014521111

Oberley TD. Oxidative damage and cancer. Am J Pathol. 2002;160(2):403-8. doi: https://doi.org/10.1016/S0002-9440(10)64857-2

Kennedy RK, Veena V, Naik PR, et al. Phenazine-1-carboxamide (PCN) from pseudomonas sp. strain PUP6 selectively induced apoptosis in lung (A549) and breast (MDA MB-231) cancer cells by inhibition of antiapoptotic Bcl-2 family proteins. Apoptosis. 2015;20(6):858-68. doi: https://doi.org/10.1007/s10495-015-1118-0

Huerta S, Chilka S, Bonavida B. Nitric oxide donors: novel cancer therapeutics (review). Int J Oncol. 2008;33(5):909-27. doi: https://doi.org/10.3892/ijo_00000079

Galadari S, Rahman A, Pallichankandy S, et al. Reactive oxygen species and cancer paradox: to promote or to suppress? Free Radic Biol Med. 2017;04:144-64. doi: https://doi.org/10.1016/j.freeradbiomed.2017.01.004

Chinery R, Beauchamp RD, Shyr Y, et al. Antioxidants reduce cyclooxygenase-2 expression, prostaglandin production, and proliferation in colorectal cancer cells. Cancer Res [Internet]. 1998 [cited 2021 Dec 14];58(11):2323-7. Available from: https://aacrjournals.org/cancerres/article-pdf/58/11/2323/2466382/cr0580112323.pdf

Kummer CL, Coelho TCRB. Antiinflamatórios não esteróides inibidores da ciclooxigenase-2 (COX-2): aspectos atuais. Rev Bras Anestesiol. 2002;52(4):498-512. doi: https://doi.org/10.1590/S0034-70942002000400014

Farrugia G, Balzan R. The proapoptotic effect of traditional and novel nonsteroidal anti-inflammatory drugs in mammalian and yeast cells. Oxid Med Cell Longev. 2013;2013:504230. doi: https://doi.org/10.1155/2013/504230

Pantziarka P, Sukhatme V, Bouche G, et al. Repurposing drugs in oncology (ReDO) – diclofenac as an anti-cancer agent. Ecancermedicalscience. 2016;10:610. doi: https://doi.org/10.3332/ecancer.2016.610

Bernardi A, Jacques-Silva MC, Delgado-Cañedo A, et al. Nonsteroidal anti-inflammatory drugs inhibit the growth of C6 and U138-MG glioma cell lines. Eur J Pharmacol. 2006;532(3):214-22. doi: https://doi.org/10.1016/j.ejphar.2006.01.008

Franco C, Silva ML, Viana AR, et al. Cytotoxicity evaluation of indomethacin-loaded polymeric nanoparticles in a human breast adenocarcinoma cell model. Braz J Dev. 2021;7(7):67004-14. doi: https://doi.org/10.34117/bjdv7n7-124

Yoshitomi T, Sha S, Vong LB, et al. Indomethacin-loaded redox nanoparticles improve oral bioavailability of indomethacin and suppress its small intestinal inflammation. Ther Deliv. 2014;5(1):29-38. doi: https://doi.org/10.4155/tde.13.133

Riasat R, Guangjun N, Riasat Z, et al. Effects of nanoparticles on gastrointestinal disorders and therapy. J Clin Toxicol. 2016;6(4):1000313. doi: https://doi.org/10.4172/2161-0495.1000313

Sukul A, Das SC, Saha JK, et al. Screening of analgesic, antimicrobial, cytotoxic and antioxidant activities of metal complexes of indomethacin. J Pharm Sci. 2014;13(2):175-80. doi: https://doi.org/10.3329/dujps.v13i2.21895

Pohlmann AR, Weiss V, Mertins O, et al. Spray-dried indomethacin-loaded polyester nanocapsules and nanospheres: development, stability evaluation and nanostructure models. Eur J Pharm Sci. 2002;16(4-5):305-12. doi: https://doi.org/10.1016/s0928-0987(02)00127-6

Bernardi A, Braganhol E, Jäger E, et al. Indomethacin-loaded nanocapsules treatment reduces in vivo glioblastoma growth in a rat glioma model. Cancer Lett. 2009;281(1):53-63. doi: https://doi.org/10.1016/j.canlet.2009.02.018

Esposti MD. Measuring mitochondrial reactive oxygen species. Methods. 2002;26(4):335-40. doi: https://doi.org/10.1016/S1046-2023(02)00039-7

Vizzotto BS, Dias RS, Iglesias BA, et al. DNA photocleavage and melanoma cells cytotoxicity induced by a meso-tetra-ruthenated porphyrin under visible light irradiation. J Photobiol B. 2020;209:111922. doi: https://doi.org/10.1016/j.jphotobiol.2020.111922

Choi WS, Shin PG, Lee JH, et al. The regulatory effect of veratric acid on NO production in LPS-stimulated RAW264.7 macrophage cells. Cell Immunol. 2012;280(2):164-70. doi: https://doi.org/10.1016/j.cellimm.2012.12.007

International Conference on Harmonization. Validation of analytical procedures: text and methodology Q2(R1) [Internet]. Current Step 4 version. Genebra: ICH; 2005 [cited 2021 Dec 14]. Available from: https://www.gmp-compliance.org/files/guidemgr/Q2(R1).pdf

Iavicoli I, Fontana L, Leso V, et al. Hormetic dose-responses in nanotechnology studies. Sci Total Environ. 2014;487:361-74. doi: https://doi.org/10.1016/j.scitotenv.2014.04.023

Remant-Bahadur KC, Thapa B, Xu P. pH and redox dual responsive nanoparticle for nuclear targeted drug delivery. Mol Pharm. 2012;9(9):2719-29. doi: https://doi.org/10.1021/mp300274g

Rota C, Chignell CF, Mason RP. Evidence for free radical formation during the oxidation of 2’-7’-dichlorofluorescin to the fluorescent dye 2’-7’-dichlorofluorescein by horseradish peroxidase: possible implications for oxidative stress measurements. Free Radic Biol Med. 1999;27(7-8):873-81. doi: https://doi.org/10.1016/s0891-5849(99)00137-9

Zhang X, Lin Y, Gillies RJ. Tumor pH and its measurement. J Nucl Med. 2010;51(8):1167-70. doi: https://doi.org/10.2967/jnumed.109.068981

Mahalingaiah PKS, Singh KP. Chronic oxidative stress increases growth and tumorigenic potential of MCF-7 breast cancer cells. PLoS ONE. 2014;9(1):e87371. doi: https://doi.org/10.1371/journal.pone.0087371

Bryan NS, Grisham MB. Methods to detect nitric oxide and its metabolites in biological samples. Free Radic Biol Med. 2007;43(5):645-57. doi: https://doi.org/10.1016/j.freeradbiomed.2007.04.026

Sreenivasulua R, Reddya KT, Sujithab P, et al. Synthesis, antiproliferative and apoptosis induction potential activities of novel bis(indolyl)hydrazide-hydrazone derivatives. Bioorg Med Chem. 2019;27(6):1043-55. doi: https://doi.org/10.1016/j.bmc.2019.02.002

Tor YS, Yazan LS, Foo JB, et al. Induction of apoptosis in MCF-7 cells via oxidative stress generation, mitochondria-dependent and caspase-independent pathway by ethyl acetate extract of Dillenia suffruticosa and Its chemical profile. PLoS ONE. 2015;10(6):e0127441. doi: https://doi.org/10.1371/journal.pone.0127441

Szwed M, Torgersen ML, Kumari RV, et al. Biological response and cytotoxicity induced by lipid nanocapsules. J Nanobiotechnology. 2020;18(1):5. doi: https://doi.org/10.1186/s12951-019-0567-y

Park HB, Kim YJ, Lee SM, et al. Dual drug-loaded liposomes for synergistic efficacy in MCF-7 breast cancer cells and cancer stem cells. Biomed Sci Letters. 2019;25(2):159-69. doi: https://doi.org/10.15616/BSL.2019.25.2.159

Dror Y, Sorkin R, Brand G, et al. The effect of the serum corona on interactions between a single nano-object and a living cell. Sci Rep. 2017;7:45758. doi: https://doi.org/10.1038/srep45758

Westmeier D, Chen C, Stauber RH, et al. The bio-corona and its impact on nanomaterial toxicity. Eur J Nanomed. 2015;7(3):153-68. doi: https://doi.org/10.1515/ejnm-2015-0018

Barbosa KBF, Costa NMB, Alfenas RCG, et al. Estresse oxidativo: conceito, implicações e fatores modulatórios. Rev Nutr. 2010;23(4):629-43. doi: https://doi.org/10.1590/S1415-52732010000400013

Santos MC. Estudo do efeito do potencial de superfície na internalização de nanopartículas de magnetita em células cultivadas [trabalho de conclusão de curso na Internet]. Goiás: Universidade Federal de Goiás; 2007 [acesso 2021 dez 14]. Disponível em: https://www.prpg.ufg.br/up/85/o/modelo1.pdf

Froder JG, Dupeyrón D, Carvalho JCT, et al. In vitro study of the cytotoxic and genotoxic effects of indomethacin-loaded Eudragit(®) L 100 nanocapsules. Genet Mol Res. 2016;15(3). doi: https://doi.org/10.4238/gmr.15038727

Husain MA, Ishqi HM, Sarwar T, et al. Interaction of indomethacin with calf thymus DNA: a multi-spectroscopic, thermodynamic and molecular modelling approach. Medchemcomm. 2017;8(6):1283-96. doi: https://doi.org/10.1039/c7md00094d

Nagai N, Yoshioka C, Yoshimasa I. Topical therapies for rheumatoid arthritis by gel ointments containing indomethacin nanoparticles in adjuvant-induced arthritis rat. J Oleo Sci. 2015;64(3):337-46. doi: https://doi.org/10.5650/jos.ess14170

Publicado

2022-09-13

Como Citar

1.
Franco C, Viana AR, Ourique AF, Vizzotto BS, Krause LMF. Efeito Protetor de Nanopartículas Poliméricas com Indometacina contra Citotoxicidade Induzida por Estresse Oxidativo em Modelo Celular de Adenocarcinoma de Mama Humano. Rev. Bras. Cancerol. [Internet]. 13º de setembro de 2022 [citado 2º de dezembro de 2024];68(4):e-012545. Disponível em: https://rbc.inca.gov.br/index.php/revista/article/view/2545

Edição

Seção

ARTIGO ORIGINAL