Water-Soluble Pristine C60 Fullerene Inhibits Liver Alterations Associated with Hepatocellular Carcinoma in Rat

Halyna Kuznietsova,Natalia Dziubenko,Peter Scharff,Eric Tauscher,Yuriy Prylutskyy,Tetiana Herheliuk,Uwe Ritter

doi:10.3390/pharmaceutics12090794

Halyna Kuznietsova, Natalia Dziubenko + Show 5 more

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https://doi.org/10.3390/pharmaceutics12090794

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Abstract

Excessive production of reactive oxygen species is the main cause of hepatocellular carcinoma (HCC) initiation and progression. Water-soluble pristine C60 fullerene is a powerful and non-toxic antioxidant, therefore, its effect under rat HCC model and its possible mechanisms were aimed to be discovered. Studies on HepG2 cells (human HCC) demonstrated C60 fullerene ability to inhibit cell growth (IC50 = 108.2 μmol), to induce apoptosis, to downregulate glucose-6-phosphate dehydrogenase, to upregulate vimentin and p53 expression and to alter HepG2 redox state. If applied to animals experienced HCC in dose of 0.25 mg/kg per day starting at liver cirrhosis stage, C60 fullerene improved post-treatment survival similar to reference 5-fluorouracil (31 and 30 compared to 17 weeks) and inhibited metastasis unlike the latter. Furthermore, C60 fullerene substantially attenuated liver injury and fibrosis, decreased liver enzymes, and normalized bilirubin and redox markers (elevated by 1.7–7.7 times under HCC). Thus, C60 fullerene ability to inhibit HepG2 cell growth and HCC development and metastasis and to improve animal survival was concluded. C60 fullerene cytostatic action might be realized through apoptosis induction and glucose-6-phosphate dehydrogenase downregulation in addition to its antioxidant activity.

Highlights

Liver cancer is one of the most common malignancies and occupies the second place among the causes of cancer deaths in the world
The dynamic light scattering (DLS) method has shown that C60FAS contains single C60 molecules (0.72 nm) as well as their aggregates up to 100 nm that is in a good agreement with the calculations [38]
We have shown that C60 fullerene exerts a probable cytostatic effect on HepG2 cells, exacerbates the pool of apoptotic cells in a dose-dependent manner and upregulates the expression of pro-apoptotic protein p53

Summary

Introduction

Liver cancer is one of the most common malignancies and occupies the second place among the causes of cancer deaths in the world. Liver cancer has the fourth-highest incidence for cancer in men following lung, prostate, and stomach cancers, and the seventh-highest incidence in women following breast, lung, cervical, thyroid, colorectal, and stomach cancers. The overall liver cancer mortality reaches 93% for individuals between the ages of 0 and 74 years and has the second-highest death rate for cancers [1]. It accounts for up to 90% of all primary liver malignant tumors. In 70–80% of cases, malignant transformation is observed in the cirrhotically altered liver [2], and the presence of cirrhosis significantly increases the risk of tumor development [3]

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