PUBLICATION
Autophagic flux inhibition enhances cytotoxicity of the receptor tyrosine kinase inhibitor ponatinib
- Authors
- Corallo, D., Pastorino, F., Pantile, M., Mariotto, E., Caicci, F., Viola, G., Ponzoni, M., Tonini, G.P., Aveic, S.
- ID
- ZDB-PUB-201002-131
- Date
- 2020
- Source
- Journal of experimental & clinical cancer research : CR 39: 195 (Journal)
- Registered Authors
- Aveic, Sanja, Corallo, Diana, Pantile, Marcella
- Keywords
- Autophagy, Chloroquine, Drug resistance, Neuroblastoma, Tyrosine kinase inhibitors
- MeSH Terms
-
- Animals
- Apoptosis/drug effects
- Autophagy/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects*
- Cell Survival/drug effects
- Chloroquine/pharmacology
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Imidazoles/pharmacology*
- Lysosomes/drug effects
- Mice
- Neuroblastoma/drug therapy*
- Neuroblastoma/genetics
- Neuroblastoma/pathology
- Protein Kinase Inhibitors/pharmacology
- Pyridazines/pharmacology*
- Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
- Receptor Protein-Tyrosine Kinases/genetics*
- Xenograft Model Antitumor Assays
- PubMed
- 32962733 Full text @ J. Exp. Clin. Cancer Res.
Citation
Corallo, D., Pastorino, F., Pantile, M., Mariotto, E., Caicci, F., Viola, G., Ponzoni, M., Tonini, G.P., Aveic, S. (2020) Autophagic flux inhibition enhances cytotoxicity of the receptor tyrosine kinase inhibitor ponatinib. Journal of experimental & clinical cancer research : CR. 39:195.
Abstract
Background Despite reported advances, acquired resistance to tyrosine kinase inhibitors still represents a serious problem in successful cancer treatment. Among this class of drugs, ponatinib (PON) has been shown to have notable long-term efficacy, although its cytotoxicity might be hampered by autophagy. In this study, we examined the likelihood of PON resistance evolution in neuroblastoma and assessed the extent to which autophagy might provide survival advantages to tumor cells.
Methods The effects of PON in inducing autophagy were determined both in vitro, using SK-N-BE(2), SH-SY5Y, and IMR-32 human neuroblastoma cell lines, and in vivo, using zebrafish and mouse models. Single and combined treatments with chloroquine (CQ)-a blocking agent of lysosomal metabolism and autophagic flux-and PON were conducted, and the effects on cell viability were determined using metabolic and immunohistochemical assays. The activation of the autophagic flux was analyzed through immunoblot and protein arrays, immunofluorescence, and transmission electron microscopy. Combination therapy with PON and CQ was tested in a clinically relevant neuroblastoma mouse model.
Results Our results confirm that, in neuroblastoma cells and wild-type zebrafish embryos, PON induces the accumulation of autophagy vesicles-a sign of autophagy activation. Inhibition of autophagic flux by CQ restores the cytotoxic potential of PON, thus attributing to autophagy a cytoprotective nature. In mice, the use of CQ as adjuvant therapy significantly improves the anti-tumor effects obtained by PON, leading to ulterior reduction of tumor masses.
Conclusions Together, these findings support the importance of autophagy monitoring in the treatment protocols that foresee PON administration, as this may predict drug resistance acquisition. The findings also establish the potential for combined use of CQ and PON, paving the way for their consideration in upcoming treatment protocols against neuroblastoma.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping