Bespoken nanoceria: a new effective treatment in experimental hepatocellular carcinoma

Guillermo Fernández-Varo, Meritxell Perramón, Silvia Carvajal, Denise Oró, Eudald Casals, Loreto Boix, Laura Oller, Laura Macías-Muñoz, Santi Marfà, Gregori Casals, Manuel Morales-Ruiz, Pedro Casado, Pedro R. Cutillas, Jordi Bruix, Miquel Navasa, Josep Fuster, Juan Carlos Garcia-Valdecasas, Mihai C. Pavel, Víctor Puntes*, Wladimiro Jiménez*

*Corresponding author for this work

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Abstract

BACKGROUND & AIMS: Despite the availability of new generation drugs, hepatocellular carcinoma (HCC) is still the third most frequent cause of cancer-related deaths worldwide. Cerium oxide nanoparticles (CeO2 NPs) have emerged as a novel antioxidant agent in experimental liver disease because of their antioxidant, anti-inflammatory and antisteatotic properties. In the present study, we aimed to elucidate the potential of CeO2 NPs as therapeutic agent in HCC.

APPROACH & RESULTS: HCC was induced in 110 Wistar rats by intraperitoneal administration of diethylnitrosamine for 16 weeks. Animals were treated with vehicle or CeO2 NPs at the week 16 and 17. At the 18th week, nanoceria biodistribution was assessed by mass spectrometry (MS). The effect of CeO2 NPs on tumor progression and animal survival was investigated. Hepatic tissue MS-based phosphoproteomics as well as analysis of principal lipid components were performed. The intracellular uptake of CeO2 NPs by human ex vivo perfused livers and human hepatocytes was analyzed. Nanoceria was mainly accumulated in the liver, where it reduced macrophage infiltration and inflammatory gene expression. Nanoceria treatment increased liver apoptotic activity while proliferation was attenuated. Phosphoproteomic analysis revealed that CeO2 NPs affected the phosphorylation of proteins mainly related to cell adhesion and RNA splicing. CeO2 NPs decreased phosphatidylcholine-derived arachidonic acid and reverted the HCC-induced increase of linoleic acid in several lipid components. Furthermore, CeO2 NPs reduced serum alpha-protein levels and improved the survival of HCC-rats. Nanoceria uptake by ex vivo perfused human livers and in vitro human hepatocytes was also demonstrated.

CONCLUSIONS: These data indicate that CeO2 NPs partially revert the cellular mechanisms involved in tumor progression and significantly increase survival in HCC-rats, suggesting that they could be effective in patients with HCC.

Original languageEnglish
Pages (from-to)1267-1282
Number of pages16
JournalHepatology
Volume72
Issue number4
Early online date21 Jan 2020
DOIs
Publication statusPublished - 14 Oct 2020
Externally publishedYes

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    Fernández-Varo, G., Perramón, M., Carvajal, S., Oró, D., Casals, E., Boix, L., Oller, L., Macías-Muñoz, L., Marfà, S., Casals, G., Morales-Ruiz, M., Casado, P., Cutillas, P. R., Bruix, J., Navasa, M., Fuster, J., Garcia-Valdecasas, J. C., Pavel, M. C., Puntes, V., & Jiménez, W. (2020). Bespoken nanoceria: a new effective treatment in experimental hepatocellular carcinoma. Hepatology, 72(4), 1267-1282. https://doi.org/10.1002/hep.31139