The antitumour drug ABTL0812 impairs neuroblastoma growth through endoplasmic reticulum stress-mediated autophagy and apoptosis
París-Coderch, Laia (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Soriano, Aroa (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Jiménez Jiménez, Carlos (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Erazo, Tatiana (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Muñoz-Guardiola, Pau (Ability Pharmaceuticals)
Masanas, Marc (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Antonelli, Roberta (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Boloix, Ariadna (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Alfón, José (Ability Pharmaceuticals)
Pérez-Montoyo, Héctor (Ability Pharmaceuticals)
Yeste-Velasco, Marc (Ability Pharmaceuticals)
Domènech, Carles (Ability Pharmaceuticals)
Roma, Josep (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Sánchez de Toledo Codin, Josep (Vall d'Hebron Institut d'Oncologia)
Moreno, Lucas (Vall d'Hebron Institut d'Oncologia)
Lizcano de Vega, José Miguel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Gallego, Soledad (Vall d'Hebron Institut d'Oncologia)
Segura, Miguel F. (Hospital Universitari Vall d'Hebron. Institut de Recerca)

Data:	2020
Resum:	Neuroblastoma is the leading cause of cancer death in children aged 1 to 4 years. Particularly, five-year overall survival for high-risk neuroblastoma is below 50% with no curative options when refractory or relapsed. Most of current therapies target cell division and proliferation, thereby inducing DNA damage and programmed cell death. However, aggressive tumours often present alterations of these processes and are resistant to therapy. Therefore, exploring alternative pathways to induce tumour cell death will provide new therapeutic opportunities for these patients. In this study we aimed at testing the therapeutic potential of ABTL0812, a novel anticancer drug that induces cytotoxic autophagy to eliminate cancer cells, which is currently in phase II clinical trials of adult tumours. Here, we show that ABTL0812 impaired the viability of clinical representative neuroblastoma cell lines regardless of genetic alterations associated to bad prognosis and resistance to therapy. Oral administration of ABTL0812 to mice bearing neuroblastoma xenografts impaired tumour growth. Furthermore, our findings revealed that, in neuroblastoma, ABTL0812 induced cancer cell death via induction of endoplasmic reticulum stress, activation of the unfolded protein response, autophagy and apoptosis. Remarkably, ABTL0812 potentiated the antitumour activity of chemotherapies and differentiating agents such as irinotecan and 13 -cis -retinoic acid. In conclusion, ABTL0812 distinctive mechanism of action makes it standout to be used alone or in combination in high-risk neuroblastoma patients.
Ajuts:	Ministerio de Educación, Cultura y Deporte PU16/01099 Ministerio de Economía y Competitividad CI_2015_24212 Ministerio de Economía y Competitividad JCI_2015_24212 Ministerio de Economía y Competitividad IPT-2012-0614-010000 Ministerio de Economía y Competitividad SAF2015-64237-R Agència de Gestió d'Ajuts Universitaris i de Recerca 2017FI_B_00095
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Drug development ; Paediatric cancer
Publicat a:	Cell death and disease, Vol. 11 (september 2020) , ISSN 2041-4889

DOI: 10.1038/s41419-020-02986-w
PMID: 32943619

10 p, 1.7 MB

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