Abstract
The acquisition of resistance to anticancer agents used in chemotherapy is the main cause of treatment failure in malignant disorders, provoking tumours to become resistant during treatment, although they initially respond to it. The main multidrug resistance (MDR) mechanism in tumour cells is the expression of P-glycoprotein (P-gly), that acts as an ATP-dependent active efflux pump of chemotherapeutic agents. Furthermore, an increased detoxification of compounds mediated by high levels of glutathione (GSH) and glutathione S-transferase (GST), has been found in resistant cells. We developed a study aiming to evaluate the evolution of the main drug resistance markers in tumour cells: P-gly, GSH and GST, during the acquisition of resistance to colchicine, for the purpose of studying the adaptation process and its contribution to the MDR phenomenon. A human colon adenocarcinoma cell line was exposed to colchicine during 82 days, being P-gly, GSH levels and GST activity evaluated by flow cytometry, spectrofluorimetry and spectrophotometry, during exposure time. P-gly and GSH levels increased gradually during the exposure to colchicine, reaching 2.35 and 3.21 fold each. On day 82, GST activity increased 1.84 fold at the end of the exposure period. Moreover, an increment in drug cross-resistance was obtained that ranges from 2.62 to 5.22 fold for colchicine, vinblastine, vincristine and mitomycin C. The increments obtained in P-gly, GSH and GST could probably contribute to the MDR phenomenon in this human colon adenocarcinoma cell line.
Resumen
La adquisición de resistencia a los agentes anticancerígenos usados en quimioterapia es la principal causa de fallo en el tratamiento del cáncer. El principal mecanismo de resistencia a múltiples drogas (MDR) en células tumorales es la expresión de la glicoproteína-P (P-gly), que actúa como una bomba extrusora de agentes quimioterápicos. Además, se ha observado en células resistentes un incremento en la detoxificación de compuestos mediada por altos niveles de glutation (GSH) y glutation S-transferasa (GST). El objetivo de este trabajo es el estudio de la evolución de los principales marcadores de resistencia a drogas en células tumorales, P-gly, GSH y GST, durante la adquisición de resistencia a colchicina, con el propósito de estudiar el proceso de adaptación y su contribución al fenómeno MDR. Tras exponer una línea celular de adenocarcinoma de colon humano a colchicina durante 82 días, se evalúan durante el tiempo de exposición los niveles de P-gly, GSH y GST por citometría de flujo, espectrofluorimetría y espectrofotometría. Los niveles de P-gly y GSH se incrementan gradualmente durante la exposición hasta 2,35 y 3,21 veces. La actividad GST se incrementa al final del período de exposición (día 82), alcanzando un valor 1,84 veces superior. Además, se obtiene un incremento en la resistencia cruzada a drogas entre 2,62–5,22 veces para colchicina, vinblastina, vincristina y mitomicina C. Los aumentos observados de P-gly, GSH y GST podrían contribuir al fenómeno MDR en esta línea celular de adenocarcinoma.
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Ruiz-Gómez, M.J., Souviron, A., Martínez-Morillo, M. et al. P-glycoprotein, glutathione and glutathione S-transferase increase in a colon carcinoma. J. Physiol. Biochem. 56, 307–312 (2000). https://doi.org/10.1007/BF03179798
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DOI: https://doi.org/10.1007/BF03179798
Keyword
- Flow cytometry
- Glutathione (GSH)
- Glutathione S-transferase (GST)
- Human colon adenocarcinoma
- Multidrug resistance (MDR)
- P-glycoprotein