Evaluación in Vitro de Nuevas Parasporinas Obtenidas por Evolución Dirigida en Células Cancerígenas de Colon SW480 y SW620
Digital
- Autores:
-
Ardila-Carreño, Natalia Andrea
Alarcón-Aldaba, Juan Sebastián
Rueda-Forero, Nohara Juliana
Suárez -Barrera, Miguel Orlando
- Tipo de recurso:
- Trabajo de grado de pregrado
- Fecha de publicación:
- 2023
- Institución:
- Universidad de Santander
- Repositorio:
- Repositorio Universidad de Santander
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.udes.edu.co:001/10077
- Palabra clave:
- Cáncer
Bacillus thuringiensis
Parasporinas
Apoptosis
- Rights
- closedAccess
- License
- http://purl.org/coar/access_right/c_14cb
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Evaluación in Vitro de Nuevas Parasporinas Obtenidas por Evolución Dirigida en Células Cancerígenas de Colon SW480 y SW620 |
| dc.title.eng.fl_str_mv |
In Vitro Evaluation of Novel Parasporins Obtained by Directed Evolution in SW480 and SW620 Colon Cancer Cells |
| dc.title.por.fl_str_mv |
Avaliação in Vitro de Novas Parasporinas Obtidas por Evolução Dirigida em Células de Câncer de Cólon SW480 e SW620 |
| title |
Evaluación in Vitro de Nuevas Parasporinas Obtenidas por Evolución Dirigida en Células Cancerígenas de Colon SW480 y SW620 |
| spellingShingle |
Evaluación in Vitro de Nuevas Parasporinas Obtenidas por Evolución Dirigida en Células Cancerígenas de Colon SW480 y SW620 Cáncer Bacillus thuringiensis Parasporinas Apoptosis |
| title_short |
Evaluación in Vitro de Nuevas Parasporinas Obtenidas por Evolución Dirigida en Células Cancerígenas de Colon SW480 y SW620 |
| title_full |
Evaluación in Vitro de Nuevas Parasporinas Obtenidas por Evolución Dirigida en Células Cancerígenas de Colon SW480 y SW620 |
| title_fullStr |
Evaluación in Vitro de Nuevas Parasporinas Obtenidas por Evolución Dirigida en Células Cancerígenas de Colon SW480 y SW620 |
| title_full_unstemmed |
Evaluación in Vitro de Nuevas Parasporinas Obtenidas por Evolución Dirigida en Células Cancerígenas de Colon SW480 y SW620 |
| title_sort |
Evaluación in Vitro de Nuevas Parasporinas Obtenidas por Evolución Dirigida en Células Cancerígenas de Colon SW480 y SW620 |
| dc.creator.fl_str_mv |
Ardila-Carreño, Natalia Andrea Alarcón-Aldaba, Juan Sebastián Rueda-Forero, Nohara Juliana Suárez -Barrera, Miguel Orlando |
| dc.contributor.advisor.none.fl_str_mv |
Suárez -Barrera, Miguel Orlando |
| dc.contributor.author.none.fl_str_mv |
Ardila-Carreño, Natalia Andrea Alarcón-Aldaba, Juan Sebastián Rueda-Forero, Nohara Juliana Suárez -Barrera, Miguel Orlando |
| dc.contributor.jury.none.fl_str_mv |
Farfan-Garcia, Ana Elvira Valdivieso-Quintero, Wilfredo |
| dc.contributor.researchgroup.none.fl_str_mv |
Biología Molecular y Biotecnología |
| dc.subject.proposal.none.fl_str_mv |
Cáncer Bacillus thuringiensis Parasporinas Apoptosis |
| topic |
Cáncer Bacillus thuringiensis Parasporinas Apoptosis |
| description |
Digital |
| publishDate |
2023 |
| dc.date.issued.none.fl_str_mv |
2023-11-15 |
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2024-03-07T14:51:16Z |
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2024-03-07T14:51:16Z |
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Trabajo de grado - Pregrado |
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Universidad de Santander |
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T 17.23 A724e |
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Repositorio Digital Institucional Universidad de Santander |
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https://repositorio.udes.edu.co/handle/001/10077 |
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Universidad de Santander T 17.23 A724e Repositorio Digital Institucional Universidad de Santander |
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spa |
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Cappell MS. Pathophysiology, clinical presentation, and management of colon cancer. Gastroenterol ClinNorth Am. 2008;37(1):1–24. http://dx.doi.org/10.1016/j.gtc.2007.12.002 Labianca R, Beretta GD, Kildani B, Milesi L, Merlin F, Mosconi S, et al.Colon cancer. Crit Rev Oncol Hematol. 2010;74(2):106–33. http://dx.doi.org/10.1016/j.critrevonc.2010.01.010 Cáncer [Internet]. Who.int. [citado el 10 de junio de 2023]. Disponible en: https://www.who.int/es/news-room/fact-sheets/detail/cancer Aberkane L, Nacer-Khodja A, Djenane Z, Djouadi LN, Ouafek A, Bouslama L, et al. In vitro cytotoxicity of parasporins from native Algerian Bacillus thuringiensis strains against laryngeal and alveolar cancers. Curr Microbiol. 2020;77(3):405– 14.http://dx.doi.org/10.1007/s00284-019-01841-2 Gatenby R, Brown J. The evolution and ecology of resistance in cancer therapy. Cold SpringHarbPerspectMed.2018;8(3):a033415. https://perspectivesinmedicine.cshlp.org/content/8/3/a033415 Akiba T, Okumura S. Parasporins 1 and 2: Their structure and activity. J Invertebr Pathol. 2017; 142:44–9. http://dx.doi.org/10.1016/j.jip.2016.10.005 Crickmore N, Berry C, Panneerselvam S, Mishra R, Connor TR, Bonning BC. A structure-based nomenclature for Bacillus thuringiensis and other bacteria-derived pesticidal proteins. J Invertebr Pathol. 2021;186(107438):107438.http://dx.doi.org/10.1016/j.jip.2020.107438 Mizuki E, Park YS, Saitoh H, Yamashita S, Akao T, Higuchi K, et al. Parasporin, a human leukemic cell-recognizing parasporal protein of Bacillus thuringiensis. Clin Diagn Lab Immunol. 2000; 7(4):625–34. http://dx.doi.org/10.1128/CDLI.7.4.625-634.2000 Chubicka T, Girija D, Deepa K, Salini S, Meera N, Raghavamenon AC, et al. A parasporin from Bacillus thuringiensis native to Peninsular India induces apoptosis in cancer cells through intrinsic pathway. J Biosci. 2018; 43(2):407–16. https://doi.org/10.1007/s12038-018-9759-0 Mendoza G, Esparza, E, Ayala, J, Mercado, M, Godina, S, Hernández, M, et al.The cytocidal spectrum of Bacillus thuringiensis toxins: From insects to human cancer cells. Toxins (Basel). 2020;12(5):301. http://dx.doi.org/10.3390/toxins12050301 Borin DB, Castrejón-Arroyo K, Cruz-Nolasco A, Peña-Rico M, Sagrillo MR, Santos RCV, et al.Parasporin A13-2 of Bacillus thuringiensis isolates from the Papaloapan region (Mexico) induce a cytotoxic effect by late apoptosis against breast cancer cells. Toxins (Basel). 2021; 13(7):476. http://dx.doi.org/10.3390/toxins13070476 Brasseur K, Auger P, Asselin E, Parent S, Côté J-C, Sirois M. Parasporin-2 from a new Bacillus thuringiensis 4R2 strain induces caspases activation and apoptosis in human cancer cells. PLoS One. 2015; 10(8):e0135106. Disponible en: http://dx.doi.org/10.1371/journal.pone.0135106 Okassov A, Nersesyan A, Kitada S, Ilin A. Parasporins as new natural anticancer agents: a review. J BUON. 2015; 20(1):5–16. https://pubmed.ncbi.nlm.nih.gov/25778289/ Suárez M, Visser L, Pinzón-Reyes EH, Rondón Villarreal P, Alarcón-Aldana J, Rueda, N.Site-directed mutants of parasporin PS2Aa1 with enhanced cytotoxic activity in colorectal cancer cell lines. Molecules. 2022; 27(21):7262. Disponible en: http://dx.doi.org/10.3390/molecules27217262. Cruz J, Suárez-Barrera MO, Rondón-Villarreal P, Olarte A, Guzmán F, Visser L, et al. Computational study, synthesis and evaluation of active peptides derived from Parasporin-2 and spike protein from Alphacoronavirus against colorectal cancer cells. Biosci Rep. 2021;41(12). http://dx.doi.org/10.1042/bsr20211964 Indrayanto G, Putra GS, Suhud F. Validation of in-vitro bioassay methods: Application in herbal drug research. Profiles Drug Subst Excip Relat Methodol. 2021; 46:273–307. http://dx.doi.org/10.1016/bs.podrm.2020.07.005 Peña A, Villarreal L, Álvarez L, Meneses A, Rodríguez V. Cytotoxicity, Post-Treatment Recovery, and Selectivity Analysis of Naturally Occurring Podophyllotoxins from Bursera fagaroides var. fagaroides on Breast Cancer Cell Lines. Molecules. 2016; 21(8):1013. http://dx.doi.org/10.3390/molecules21081013 Vílchez S. Making 3D-Cry toxin mutants: Much more than a tool of understanding toxins mechanism of action. Toxins (Basel). 2020; 12(9):600. http://dx.doi.org/10.3390/toxins12090600 Liu S, Dean D. Redesigning Bacillus thuringiensis Cry1Aa toxin into a mosquito toxin. Protein Eng Des Sel. 2006; 19(3):107–11. http://dx.doi.org/10.1093/protein/gzj009 Padilla C, Pardo L, de la Riva G, Gómez I, Sánchez J, Hernandez G, et al.Role of tryptophan residues in toxicity of Cry1Ab toxin from Bacillus thuringiensis. Appl Environ Microbiol. 2006; 72(1):901–7. http://dx.doi.org/10.1128/AEM.72.1.901-907.2006 Krishnan V, Domanska B, Elhigazi A, Afolabi F, West MJ, Crickmore N. The human cancer cell active toxin Cry41Aa from Bacillus thuringiensis acts like its insecticidal counterparts. Biochem J. 2017; 474(10):1591–602. http://dx.doi.org/10.1042/BCJ20170122 Rajamohan F, Alzate O, Cotrill JA, Curtiss A, Dean H. Protein engineering of Bacillus thuringiensis δ-endotoxin: Mutations at domain II of CryIAb enhance receptor affinity and toxicity toward gypsy moth larvae. Proc Natl Acad Sci U S A. 1996; 93(25):14338–43. http://dx.doi.org/10.1073/pnas.93.25.14338 Pardo-López L, Muñoz-Garay C, Porta H, Rodríguez-Almazán C, Soberón M, Bravo A. Strategies to improve the insecticidal activity of Cry toxins from Bacillus thuringiensis. Peptides 2009; 30(3):589–95. http://dx.doi.org/10.1016/j.peptides.2008.07.027 Kitada S, Abe Y, Maeda T, Shimada H. Parasporin-2 requires GPI-anchored proteins for the efficient cytocidal action to human hepatoma cells. Toxicology. 2009; 264(1–2):80–8. http://dx.doi.org/10.1016/j.tox.2009.07.016 Amano H, Yamagiwa M, Akao T, Mizuki E, Ohba M, Sakai H. A Novel 29-kDa Crystal Protein from Bacillus thuringiensis Induces Caspase Activation and Cell Death of Jurkat T Cells. Biosci Biotechnol Biochem. 2005; 69(11):2063-72. https://doi.org/10.1271/bbb.69.2063 J. D. Ly, D. R. Grubb, and A. Lawen. The mitochondrial membrane potential (Δψm) in apoptosis; Apoptosis: an international journal on programmed cell death. 2003; 8(2):115- 128. https://doi.org/10.1023/A:1022945197762 |
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Facultad de Ciencias Médicas y de la Salud |
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Bucaramanga, Colombia |
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Bacteriología y Laboratorio Clínico |
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Suárez -Barrera, Miguel Orlando335becb1-2371-418a-acf8-21265141ac00-1Ardila-Carreño, Natalia Andreaf904f339-da6d-41ff-b2b9-5d8836bacfc3-1Alarcón-Aldaba, Juan Sebastián785bdc11-7f49-4a66-8872-91aa888a5b76-1Rueda-Forero, Nohara Juliana89d455c6-22e0-4d0a-8846-1887145c6e61-1Suárez -Barrera, Miguel Orlando99b4d9f0-b967-4877-9973-dbb3381a16ff-1Farfan-Garcia, Ana Elvira645eae2a-b313-4cb0-8e5d-13fd5175dc3d600Valdivieso-Quintero, Wilfredo869192ef-b635-464e-91ff-f62395e0944c600Biología Molecular y Biotecnología2024-03-07T14:51:16Z2024-03-07T14:51:16Z2023-11-15DigitalIntroducción: Los tratamientos actuales contra el cáncer colorrectal son la radioterapia y la quimioterapia, sin embargo, presentan efectos secundarios debido a su poca especificidad. Por eso, se buscan nuevas alternativas terapéuticas para reemplazarlos, entre estas, surgen moléculas obtenidas de bacterias, como las parasporinas, más específicamente la parasporina PS2Aa1 (Mpp46Aa1). Este estudio tiene como finalidad determinar la actividad citotóxica de proteínas mutantes de PS2Aa1 obtenidas por aproximación dirigida al sitio en líneas celulares de cáncer colorrectal SW480 y SW620. Materiales y métodos: Las proteínas se obtuvieron por medio del Laboratorio de Biología Molecular de la Universidad de Santander. Las parasporinas tipo PS2Aa1 fueron utilizadas contra las líneas celulares en los ensayos de citotoxicidad, índices de selectividad, y activación de caspasas 3/7. Resultados: La mutante N65 con las sustituciones K92R (dominio I), L175D (dominio II) y S218G (dominio III) y la mutante 3-35 con una sustitución en G257V (dominio I) presentaron un IC50 de 1.0-1.4 y 1.2-1.7 μg/mL comparadas con la PS2Aa1 con un IC50 1.75-2.12 y 1.75-2.12 μg/mL, mientras que la sustitución de G256A de la 0-15 obtuvo un desempeño similar a la PS2Aa1, frente a las líneas celulares cancerígenas SW480 y SW620. Discusión: Las sustituciones en PS2Aa1, produjeron cambios conformacionales que potenciaron o no la actividad citotóxica e inducción de caspasas 3/7 como se ha propuesto en la literatura. Conclusiones: Las modificaciones de la PS2Aa1 revelan la utilidad de la mutación por evolución dirigida en la creación de variantes que potencian la actividad citotóxica frente a líneas celulares de cáncer de colon, manteniendo o aumentando su selectividad frente a líneas celulares de cáncer de colon.Introduction: Current treatments against colorectal cancer are radiotherapy and chemotherapy, however, they present side effects due to their low specificity. Therefore, new therapeutic alternatives are being sought to replace them. Among these, molecules obtained from bacteria, such as parasporins, more specifically parasporin PS2Aa1 (Mpp46Aa1), are emerging. This study aims to determine the cytotoxic activity of PS2Aa1 mutant proteins obtained by site-directed approach in colorectal cancer cell lines SW480 and SW620. Materials and methods: The proteins were obtained from the Molecular Biology Laboratory of the University of Santander. PS2Aa1-type parasporins were used against the cell lines in cytotoxicity and caspase 3/7 activation assays. Results: The N65 mutant with the substitutions K92R (domain I), L175D (domain II) and S218G (domain III) and the 3-35 mutant with a substitution in G257V (domain I) presented an IC50 of 1.0-1.4 and 1.2-1. 7 μg/mL compared to PS2Aa1 with an IC50 1.75-2.12 and 1.75-2.12 μg/mL, while the G256A substitution of 0-15 obtained similar performance to PS2Aa1 against the cancer cell lines SW480 and SW620. Discussion: The substitutions in PS2Aa1, produced conformational changes that enhanced or not the cytotoxic activity and its induction of caspases 3/7 as proposed in the literature. Conclusions: Modifications of PS2Aa1 reveal the utility of mutation by directed evolution in creating variants that enhance cytotoxic activity against colorectal cancer cell lines, maintaining or increasing its selectivity against colon cancer cell lines.Introdução: Os tratamentos atuais contra o câncer colorretal são a radioterapia e a quimioterapia, porém, apresentam efeitos colaterais devido à sua baixa especificidade. Por isso, novas alternativas terapêuticas estão sendo buscadas para substituí-las, incluindo moléculas obtidas de bactérias, como as parasporinas, mais especificamente a parasporina PS2Aa1 (Mpp46Aa1). Este estudo tem como objetivo determinar a atividade citotóxica de proteínas PS2Aa1 mutantes obtidas por abordagem dirigida ao local em linhas celulares de câncer colorretal SW480 e SW620. Materiais e métodos: As proteínas foram obtidas do Laboratório de Biologia Molecular da Universidade de Santander. As parasporinas do tipo PS2Aa1 foram usadas contra as linhagens celulares em ensaios de citotoxicidade e ativação da caspase 3/7. Resultados: O mutante N65 com as substituições K92R (domínio I), L175D (domínio II) e S218G (domínio III) e o mutante 3-35 com uma substituição em G257V (domínio I) apresentaram um IC50 de 1,0-1,4 e 1,2-1. 7 μg/mL em comparação com o PS2Aa1 com um IC50 de 1,75-2,12 e 1,75-2,12 μg/mL, enquanto a substituição G256A de 0-15 teve desempenho semelhante ao PS2Aa1 contra as linhas celulares de câncer SW480 e SW620. Discussão: as substituições no PS2Aa1 produziram alterações conformacionais que aumentaram a atividade citotóxica e sua indução de caspase, conforme proposto na literatura. Conclusões: As modificações do PS2Aa1 revelam a utilidade da mutação por evolução dirigida na criação de variantes que aumentam a atividade citotóxica, mantendo ou aumentando sua seletividade contra linhas celulares de câncer de cólon.PregradoBacteriólogo(a) y Laboratorista ClínicoNanoBiocancerResumen - 2 Introducción - 4 Materiales y métodos - 6 Resultados - 8 Discusión - 13 Conclusiones - 15 Referencias - 1518 papplication/pdfUniversidad de SantanderT 17.23 A724eRepositorio Digital Institucional Universidad de Santanderhttps://repositorio.udes.edu.cohttps://repositorio.udes.edu.co/handle/001/10077spaUniversidad de SantanderBucaramangaFacultad de Ciencias Médicas y de la SaludBucaramanga, ColombiaBacteriología y Laboratorio ClínicoCappell MS. Pathophysiology, clinical presentation, and management of colon cancer. Gastroenterol ClinNorth Am. 2008;37(1):1–24. http://dx.doi.org/10.1016/j.gtc.2007.12.002Labianca R, Beretta GD, Kildani B, Milesi L, Merlin F, Mosconi S, et al.Colon cancer. Crit Rev Oncol Hematol. 2010;74(2):106–33. http://dx.doi.org/10.1016/j.critrevonc.2010.01.010Cáncer [Internet]. Who.int. [citado el 10 de junio de 2023]. Disponible en: https://www.who.int/es/news-room/fact-sheets/detail/cancerAberkane L, Nacer-Khodja A, Djenane Z, Djouadi LN, Ouafek A, Bouslama L, et al. In vitro cytotoxicity of parasporins from native Algerian Bacillus thuringiensis strains against laryngeal and alveolar cancers. Curr Microbiol. 2020;77(3):405– 14.http://dx.doi.org/10.1007/s00284-019-01841-2Gatenby R, Brown J. The evolution and ecology of resistance in cancer therapy. Cold SpringHarbPerspectMed.2018;8(3):a033415. https://perspectivesinmedicine.cshlp.org/content/8/3/a033415Akiba T, Okumura S. Parasporins 1 and 2: Their structure and activity. J Invertebr Pathol. 2017; 142:44–9. http://dx.doi.org/10.1016/j.jip.2016.10.005Crickmore N, Berry C, Panneerselvam S, Mishra R, Connor TR, Bonning BC. 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