Efectos de derivados de naftoquinonas en la viabilidad de células de adenocarcinoma mamario y de embriones de xenopus laevis
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2020
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es
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Universidad Andrés Bello
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Licencia CC
Resumen
El cáncer es una de las principales causas de muerte a nivel mundial, siendo en mujeres el cáncer de mama la principal causa de muerte en Chile. Estudios en varios tipos de cáncer indican que la proteína de choque térmico 90 (HSP90) es un marcador molecular de cáncer. HSP90 es una proteína chaperona con actividad ATPasa que participa en el plegamiento de proteínas. Proteínas dependientes de HSP90 participan en diversas vías de señalización oncogénicas. HSP90 se encuentra sobreexpresado en cáncer, convirtiéndose en uno de los principales objetivos para las quimioterapias.
Derivados de naftoquinonas se postulan como posibles inhibidores de HSP90 y se ha demostrado que poseen actividad anticancerígena. Como parte de una colaboración con el Departamento de Ciencias Químicas, nuevos derivados de naftoquinonas fueron desarrollados con posible actividad antitumoral. En esta memoria, se estudió el efecto de 3 nuevos derivados de naftoquinona en la viabilidad de células in vitro e in vivo. Líneas celulares de cáncer de mama MCF-7 y MDA-MB-231 fueron utilizadas para analizar el efecto de los derivados naftoquinónicos mediante ensayo de viabilidad MTS. Como control se utilizó la línea MCF-10F, una línea no cancerígena de epitelio mamario. Además, se analizó el efecto en líneas de origen embrionario HEK293A como otro modelo de comparación. Se analizó si ocurría muerte celular por apoptosis con análisis de expresión por inmunoblot de caspasa-3. Finalmente, se realizaron ensayos in vivo incubando embriones tempranos de Xenopus laevis en presencia de los derivados. Dos de los tres nuevos derivados fueron citotóxicos en ensayos in vitro e in vivo y fueron menos efectivos en la línea control no cancerígena MCF-10F. El derivado más citotóxico causó muerte celular pero no se detectó activación de la caspasa-3.
Con este trabajo se busca contribuir al desarrollo racional de drogas con potencial actividad antitumoral, aportando información que permita comprender sus mecanismos de acción y optimizar su diseño y especificidad ante determinados marcadores moleculares.
is one of the leading causes of death worldwide, with breast cancer in women being the leading cause of death in Chile. Studies in several types of cancer indicate that Heat-shock protein 90 (HSP90) is a molecular marker for cancer. HSP90 is a chaperone protein with ATPase activity that participates in correct protein folding. HSP90 dependent proteins are involved in various oncogenic signaling pathways. HSP90 is overexpressed in cancer, becoming one of the main targets for chemotherapies. Naphthoquinone derivatives are proposed as possible HSP90 inhibitors and their anticancer activity has been determined. As part of a collaboration with the Chemistry Sciences Department, new naphthoquinone derivatives were developed to test their putative antitumor activity. Here, the effect of three novel naphthoquinone derivatives on cell viability was studied in vitro and in vivo. Breast cancer cell lines MCF-7 and MDA-MB-231 were used to analyze the effect of naphthoquinone derivatives using MTS viability cell assay. MCF-10F, a non- tumorigenic cell line from mammary epithelium was used as control. In addition, the effect on the embryonic cell line HEK293A was analyzed as a supplementary comparison model. Furthermore, it was analyzed whether apoptosis occurred through the analysis of caspase-3 by immunoblot. Finally, in vivo assays were performed by incubating early embryos of Xenopus laevis in the presence of naphthoquinone derivatives. Two out of the three naphthoquinone derivatives were cytotoxic in in vitro and in vivo assays and were less effective on the non-carcinogenic control cell line MCF-10F. The most cytotoxic derivative caused cell death but caspase-3 activation was not detected. This work intends to contribute to the development of rational drug design with potential antitumor activity, providing information that allows us to comprehend their mechanisms of actions and optimize their design and specificity for molecular markers.
is one of the leading causes of death worldwide, with breast cancer in women being the leading cause of death in Chile. Studies in several types of cancer indicate that Heat-shock protein 90 (HSP90) is a molecular marker for cancer. HSP90 is a chaperone protein with ATPase activity that participates in correct protein folding. HSP90 dependent proteins are involved in various oncogenic signaling pathways. HSP90 is overexpressed in cancer, becoming one of the main targets for chemotherapies. Naphthoquinone derivatives are proposed as possible HSP90 inhibitors and their anticancer activity has been determined. As part of a collaboration with the Chemistry Sciences Department, new naphthoquinone derivatives were developed to test their putative antitumor activity. Here, the effect of three novel naphthoquinone derivatives on cell viability was studied in vitro and in vivo. Breast cancer cell lines MCF-7 and MDA-MB-231 were used to analyze the effect of naphthoquinone derivatives using MTS viability cell assay. MCF-10F, a non- tumorigenic cell line from mammary epithelium was used as control. In addition, the effect on the embryonic cell line HEK293A was analyzed as a supplementary comparison model. Furthermore, it was analyzed whether apoptosis occurred through the analysis of caspase-3 by immunoblot. Finally, in vivo assays were performed by incubating early embryos of Xenopus laevis in the presence of naphthoquinone derivatives. Two out of the three naphthoquinone derivatives were cytotoxic in in vitro and in vivo assays and were less effective on the non-carcinogenic control cell line MCF-10F. The most cytotoxic derivative caused cell death but caspase-3 activation was not detected. This work intends to contribute to the development of rational drug design with potential antitumor activity, providing information that allows us to comprehend their mechanisms of actions and optimize their design and specificity for molecular markers.
Notas
Tesis (Ingeniero en Biotecnología)
Palabras clave
Índices de mortalidad en mujeres, Quimioterapia, Desarrollo de drogas con potencial actividad antitumoral, Mecanismos de acción y optimización de diseño, Chile