Proteasome versus Thioredoxin Reductase Competition as Possible Biological Targets in Antitumor Mixed Thiolate-Dithiocarbamate Gold(III) Complexes

Quero, J. ; Cabello, S. ; Fuertes, T. ; Mármol, I. ; Laplaza, R. ; Polo, V. ; Concepción Gimeno, M. (Universidad de Zaragoza) ; Rodriguez-Yoldi, M.J. (Universidad de Zaragoza) ; Cerrada, E. (Universidad de Zaragoza)

Resumen: New mixed gold(III) derivatives with dithiocarbamate and thiolate ligands have been synthesized and characterized. They display high anticancer activity against colon cancer cell lines without affecting to differentiated enterocytes, high stability in phosphate-buffered saline solution, and resistance to gold reduction in the presence of reducing agents in the majority of the derivatives. Some of them show interaction with thioredoxin reductase as derived from in vitro analysis and computational studies. However, a competition between this enzyme and proteasome is detected in cells, which is corroborated by the determination of proteasomal chymotrypsin-like activity inhibition. In addition, some of these dithiocarbamate gold(III) derivatives reduce cell viability and proliferation by intrinsic apoptotic pathway, with changes in mitochondrial membrane potential, cytochrome c release and caspase-3 activation. Consequently, our results show new complexes with proteasome as possible target in colorectal cancer.

Idioma: Inglés

DOI: 10.1021/acs.inorgchem.8b01464

Año: 2018

Publicado en: Inorganic Chemistry 57, 17 (2018), 10832-10845
ISSN: 0020-1669

Factor impacto JCR: 4.85 (2018)

Categ. JCR: CHEMISTRY, INORGANIC & NUCLEAR rank: 4 / 45 = 0.089 (2018) - Q1 - T1

Factor impacto SCIMAGO: 1.501 - Chemistry (miscellaneous) (Q1) - Physical and Theoretical Chemistry (Q1) - Inorganic Chemistry (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/A32
Financiación: info:eu-repo/grantAgreement/ES/DGA/E104
Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2016-75816-C2-1-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/SAF2016-75441-R

Tipo y forma: Artículo (PostPrint)

Área (Departamento): Área Química Inorgánica (Dpto. Química Inorgánica)
Área (Departamento): Área Fisiología (Dpto. Farmacología y Fisiolog.)