Long-term effects after treatment with platinum compounds, cisplatin and [Pt(O,O'-acac)(γ-acac)(DMS)]: Autophagy activation in rat B50 neuroblastoma cells.

Abstract

Cisplatin (cisPt), among the best known components of multi-drug front-line therapies used for the treatments of solid tumors, such as the childhood neuroblastoma, acts through DNA linking. Nevertheless, the cisPt effectiveness is compromised by the onset of severe side effects, including neurotoxicity that results in neurodegeneration, cell death, and drug-resistance. In the field of experimental oncology, aimed at overcoming cytotoxicity and chemoresistance, great efforts are devoted to the synthesis of new platinum-based drugs, such as [Pt(O,O'-acac)(γ-acac)(DMS)] (PtAcacDMS), which shows a specific reactivity with sulfur residues of enzymes involved in apoptosis. Autophagy, an evolutionary conserved degradation pathway for recycling of cytoplasmic components, represents one of the mechanisms adopted by cancer cells which contribute to drug-resistance. In the present study, standard acute (48 h-exposure) and long-term effects (7 day-recovery after treatment or 7 day-recovery followed by reseeding and 96 h-growth), of cisPt and PtAcacDMS (40 and 10 μM, respectively) were investigated in vitro employing rat B50 neuroblastoma as a cancer model. Using fluorescence and electron microscopy, as well as biochemical techniques, our data highlight a key role of the autophagic process in B50 cells. Specifically, long-term effects caused by cisPt lead to inhibition of the apoptotic process and paralleled by the activation of autophagy, thus evidencing that autophagy has a protective role after cisPt exposure, allowing cells to survive. Whereas, long-term effects produced by PtAcacDMS lead toward both apoptosis and autophagy activation. In conclusion, autophagy may represents an alternative cell death pathway, circumventing drug-resistance strategies employed by cancer cells to survive chemoterapy.

• Authors: Maddalena Grimaldi, Veronica Dal Bo, Beatrice Ferrari, Elisa Roda, Fabrizio De Luca, Paola Veneroni, Sergio Barni, Manuela Verri, Sandra A De Pascali, Francesco P Fanizzi, Graziella Bernocchi, Maria G Bottone
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 364 Pg. 1-11 (02 01 2019) ISSN: 1096-0333 [Electronic] United States
• PMID: 30529627 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Atg5 protein, rat
• Autophagy-Related Protein 5
• Beclin-1
• Becn1 protein, rat
• LC3 protein, rat
• Microtubule-Associated Proteins
• Organoplatinum Compounds
• Pt(O,O'-acac)(gamma-acac)(DMS)
• Sequestosome-1 Protein
• Sqstm1 protein, rat
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Autophagy-Related Protein 5 (metabolism)
• Beclin-1 (metabolism)
• Cell Line, Tumor
• Cisplatin (pharmacology, toxicity)
• Drug Resistance, Neoplasm
• Lysosomes (drug effects, metabolism, ultrastructure)
• Microtubule-Associated Proteins (metabolism)
• Mitochondria (drug effects, metabolism, ultrastructure)
• Neuroblastoma (drug therapy, metabolism, ultrastructure)
• Organoplatinum Compounds (pharmacology)
• Rats
• Sequestosome-1 Protein (metabolism)
• Signal Transduction (drug effects)
• Time Factors