Novel benzoate-lipophilic cations selectively induce cell death in human colorectal cancer cell lines
Author
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Jara Sandoval, José Antonio
Author
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Rojas Rivera, Diego
Author
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Castro Castillo, Vicente
Author
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Fuentes Retamal, Sebastián
Author
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Sandoval Acuña, Cristian
Author
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Parra, Eduardo
Author
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Pavani, Mario
Author
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Maya Arango, Juan Diego
Author
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Ferreira Parker, Jorge
Author
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Catalán Díaz, Mabel
Admission date
dc.date.accessioned
2020-05-26T23:33:57Z
Available date
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2020-05-26T23:33:57Z
Publication date
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2020
Cita de ítem
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Toxicology in Vitro 65: (2020): 104814
es_ES
Identifier
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10.1016/j.tiv.2020.104814
Identifier
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https://repositorio.uchile.cl/handle/2250/174977
Abstract
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Introduction: Colorectal cancer (CRC) is a critical health issue worldwide. The high rate of liver and lung metastasis associated with CRC creates a significant barrier to effective and efficient therapy. Tumour cells, including CRC cells, have metabolic alterations, such as high levels of glycolytic activity, increased cell proliferation and invasiveness, and chemo- and radio-resistance. However, the abnormally elevated mitochondrial transmembrane potential of these cells also provides an opportunity to develop drugs that selectively target the mitochondrial functions of tumour cells.
Methods: In this work, we used a new batch of benzoic acid esters with cytotoxic activities attached to the triphenylphosphonium group as a vehicle to target tumour mitochondria and improve their activity. We evaluated the cytotoxicity, selectivity, and mechanism of action of these derivatives, including the effects on energy stress-induced apoptosis and metabolic behaviour in the human CRC cell lines HCT-15 and COLO-205.
Results: The benzoic acid derivatives selectively targeted the tumour cells with high potency and efficacy. The derivatives induced the uncoupling of the oxidative phosphorylation system, decreased the transmembrane potential, and reduced ATP levels while increasing AMPK activation, thereby triggering tumour cell apoptosis in both tumour cell lines tested.
Conclusion: The benzoic acid derivatives studied here are promising candidates for assessing in vivo models of CRC, despite the diverse metabolic characteristics of these tumour cells.
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Patrocinador
dc.description.sponsorship
Consejo Nacional de Ciencia y Tecnologia (CONACyT)
Comisión Nacional de Investigación Cientifica y Tecnológica (CONICYT) FONDECYT 11160281
FONDECYT 1180296 FONDECYT 1130189
Academy Insertion Grant 791220004
Vicerrectoría de Investigación y Desarrollo, Universidad de Chile (Enlace) ENL022/16
Comisión Nacional de Investigación Cientifica y Tecnológica (CONICYT) FONDECYT 11160281
Comisión Nacional de Investigación Cientifica y Tecnológica (CONICYT) CONICYT FONDECYT
1180296 1130189
Universidad de Chile (Enlace) ENL022/16