Alkynyl gold(I) complex triggers necroptosis via ROS generation in colorectal carcinoma cells

Mármol, Inés (Universidad de Zaragoza) ; Virumbrales-Muñoz, María (Universidad de Zaragoza) ; Quero, Javier ; Sánchez-de-Diego, Cristina ; Fernández, Luis (Universidad de Zaragoza) ; Ochoa, Ignacio (Universidad de Zaragoza) ; Cerrada, Elena (Universidad de Zaragoza) ; Rodriguez-Yoldi, María Jesús (Universidad de Zaragoza)

Resumen: Given the rise of apoptosis-resistant tumors, there exist a growing interest in developing new drugs capable of inducing different types of cell death to reduce colorectal cancer-related death rates. As apoptosis and necroptosis do not share cellular machinery, necroptosis induction may have a great therapeutic potential on those apoptosis- resistant cancers, despite the inflammatory effects associated with it. We have synthesized an alkynyl gold(I) complex [Au(CC-2-NC5H4)(PTA)] whose anticancer effect was tested on the colorectal adenocarcinoma Caco-2 cell line. With regard to its mechanism of action, this gold complex enters the mitochondria and disrupts its normal function, leading to an increase in ROS production, which triggers necroptosis. Necroptosis induction has been found dependent of TNF-a (Tumor necrosisfactor a) and TNFR1(Tumor necrosisfactor receptor 1) binding, RIP1(Receptor-Interacting Protein 1) activation and NF-¿B (Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells) signaling. Moreover, the antitumor potential of [Au(CC-2-NC5H4)(PTA)] has also been confirmed on the 3D cancer model spheroid. Overall, the obtained data show firstly that gold complexes might have the ability of inducing necroptosis, and secondarily that our compound [Au(CC-2-NC5H4)(PTA)] is an interesting alternative to current chemotherapy drugs in cases of apoptosis resistance.

Idioma: Inglés

DOI: 10.1016/j.jinorgbio.2017.08.020

Año: 2017

Publicado en: JOURNAL OF INORGANIC BIOCHEMISTRY 176 (2017), 123-133
ISSN: 0162-0134

Factor impacto JCR: 3.063 (2017)

Categ. JCR: CHEMISTRY, INORGANIC & NUCLEAR rank: 10 / 45 = 0.222 (2017) - Q1 - T1
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 137 / 292 = 0.469 (2017) - Q2 - T2

Factor impacto SCIMAGO: 0.743 - Inorganic Chemistry (Q2) - Biochemistry (Q3)

Financiación: info:eu-repo/grantAgreement/ES/DGA/A32
Financiación: info:eu-repo/grantAgreement/ES/DGA/E104
Financiación: info:eu-repo/grantAgreement/ES/MEC/FPU12-05640
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: Article (PostPrint)

Área (Departamento): Área Química Inorgánica (Dpto. Química Inorgánica)
Área (Departamento): Área Fisiología (Dpto. Farmacología y Fisiolog.)
Área (Departamento): Area Histología (Dpto. Anatom.Histolog.Humanas)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)
Área (Departamento): Área Mec.Med.Cont. y Teor.Est. (Dpto. Ingeniería Mecánica)