Tetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approach

Bayona, Clara ; Alza, Lía ; Randelovic, Teodora ; Sallán, Marta C. ; Visa, Anna ; Cantí, Carles ; Ochoa, Ignacio (Universidad de Zaragoza) ; Oliván, Sara (Universidad de Zaragoza) ; Herreros, Judit

Resumen: Glioblastoma (GBM) is a highly malignant brain tumour characterised by limited treatment options and poor prognosis. The tumour microenvironment, particularly the central hypoxic region of the tumour, is known to play a pivotal role in GBM progression. Cells within this region adapt to hypoxia by stabilising transcription factor HIF1-α, which promotes cell proliferation, dedifferentiation and chemoresistance. In this study we sought to examine the effects of NNC-55-0396, a tetralol compound which overactivates the unfolded protein response inducing apoptosis, using the organ-on-chip technology. We identified an increased sensitivity of the hypoxic core of the chip to NNC, which correlates with decreasing levels of HIF1-α in vitro. Moreover, NNC blocks the macroautophagic process that is unleashed by hypoxia as revealed by increased levels of autophagosomal constituent LC3-II and autophagy chaperone p62/SQSTM1. The specific effects of NNC in the hypoxic microenvironment unveil additional anti-cancer abilities of this compound and further support investigations on its use in combined therapies against GBM.

Idioma: Inglés

DOI: 10.1038/s41419-024-06492-1

Año: 2024

Publicado en: CELL DEATH & DISEASE 15, 2 (2024), 127 [8 pp.]
ISSN: 2041-4889

Financiación: info:eu-repo/grantAgreement/EC/H2020/829010/EU/Advanced and versatile PRInting platform for the next generation of active Microfluidic dEvices/PRIME
Financiación: info:eu-repo/grantAgreement/ES/MINECO/DIN2020-011544
Financiación: info:eu-repo/grantAgreement/ES/MINECO/RTI2018-094739-B-I00

Tipo y forma: Article (Published version)

Área (Departamento): Area Histología (Dpto. Anatom.Histolog.Humanas)