The antitumour drug ABTL0812 impairs neuroblastoma growth through endoplasmic reticulum stress-mediated autophagy and apoptosis
Drug development
Antineoplastic Agents
Apoptosis
Endoplasmic Reticulum
Article
Paediatric cancer
Inhibitory Concentration 50
Mice
Neuroblastoma
03 medical and health sciences
Drug Development
Cell Line, Tumor
Autophagy
Animals
Humans
Isotretinoin
Cell Proliferation
0303 health sciences
Endoplasmic Reticulum Stress
3. Good health
Pancreatic Neoplasms
Linoleic Acids
Unfolded Protein Response
Female
Neoplasm Transplantation
DNA Damage
DOI:
10.1038/s41419-020-02986-w
Publication Date:
2020-09-17T21:38:34Z
AUTHORS (18)
ABSTRACT
AbstractNeuroblastoma 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.
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