The antitumour drug ABTL0812 impairs neuroblastoma growth through endoplasmic reticulum stress-mediated autophagy and apoptosis
Por:
París-Coderch, L, Soriano, A, Jiménez, C, Erazo, T, Muñoz-Guardiola, P, Masanas, M, Antonelli, R, Boloix, A, Alfón, J, Pérez-Montoyo, H, Yeste-Velasco, M, Domènech, C, Roma, J, Sanchez deToledo J, Moreno, L, Lizcano, JM, Gallego, S and Segura, MF
Publicada:
17 sep 2020
Resumen:
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.
Filiaciones:
París-Coderch, L:
Vall dHebron Inst Recerca VHIR, Translat Res Child & Adolescent Canc, Barcelona, Spain
Soriano, A:
Vall dHebron Inst Recerca VHIR, Translat Res Child & Adolescent Canc, Barcelona, Spain
Jiménez, C:
Vall dHebron Inst Recerca VHIR, Translat Res Child & Adolescent Canc, Barcelona, Spain
Erazo, T:
Univ Autonoma Barcelona, Prot Kinases & Signal Transduct Lab, Inst Neurociencies, Bellaterra, Spain
Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Bellaterra, Spain
Muñoz-Guardiola, P:
Univ Autonoma Barcelona, Prot Kinases & Signal Transduct Lab, Inst Neurociencies, Bellaterra, Spain
Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Bellaterra, Spain
Abil Pharmaceut SL, Avinguda Parc Tecnol 3,Parc Tecnol Valles, Cerdanyola Del Valles, Spain
Masanas, M:
Vall dHebron Inst Recerca VHIR, Translat Res Child & Adolescent Canc, Barcelona, Spain
Antonelli, R:
Vall dHebron Inst Recerca VHIR, Translat Res Child & Adolescent Canc, Barcelona, Spain
Boloix, A:
Vall dHebron Inst Recerca VHIR, Translat Res Child & Adolescent Canc, Barcelona, Spain
Alfón, J:
Abil Pharmaceut SL, Avinguda Parc Tecnol 3,Parc Tecnol Valles, Cerdanyola Del Valles, Spain
Pérez-Montoyo, H:
Abil Pharmaceut SL, Avinguda Parc Tecnol 3,Parc Tecnol Valles, Cerdanyola Del Valles, Spain
Yeste-Velasco, M:
Abil Pharmaceut SL, Avinguda Parc Tecnol 3,Parc Tecnol Valles, Cerdanyola Del Valles, Spain
Domènech, C:
Abil Pharmaceut SL, Avinguda Parc Tecnol 3,Parc Tecnol Valles, Cerdanyola Del Valles, Spain
Roma, J:
Vall dHebron Inst Recerca VHIR, Translat Res Child & Adolescent Canc, Barcelona, Spain
Sanchez deToledo J:
Univ Autonoma Barcelona, Hosp Univ Vall DHebron, Pediat Oncol & Hematol Unit, Barcelona, Spain
Vall dHebron Inst Recerca VHIR, Translat Res Child & Adolescent Canc, Barcelona, Spain
Moreno, L:
Vall dHebron Inst Recerca VHIR, Translat Res Child & Adolescent Canc, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Univ Vall DHebron, Pediat Oncol & Hematol Unit, Barcelona, Spain
Lizcano, JM:
Univ Autonoma Barcelona, Prot Kinases & Signal Transduct Lab, Inst Neurociencies, Bellaterra, Spain
Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Bellaterra, Spain
Gallego, S:
Vall dHebron Inst Recerca VHIR, Translat Res Child & Adolescent Canc, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Univ Vall DHebron, Pediat Oncol & Hematol Unit, Barcelona, Spain
Segura, MF:
Vall dHebron Inst Recerca VHIR, Translat Res Child & Adolescent Canc, Barcelona, Spain
gold, Green Published
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